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

Abstract 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)

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Oral beta-lactam step down in bacteremic E. coli urinary tract infections

BMC Infectious Diseases ◽

10.1186/s12879-020-05498-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Stephan Saad ◽

Neil Mina ◽

Colin Lee ◽

Kevin Afra

Keyword(s):

Urinary Tract ◽

Propensity Score ◽

Urinary Tract Infections ◽

Clinical Cure ◽

Beta Lactam ◽

Beta Lactams ◽

E Coli ◽

Secondary Outcomes ◽

Step Down ◽

Tract Infections

Abstract Background Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones. Methods This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding. Results A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference − 4.2, 95% confidence interval [CI] -10.3 to 1.9%, p = 0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05–1.90, p = 0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes. Conclusions Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.

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1473. Structured Patient Interview in Complicated Urinary Tract Infections to Assess Clinical Outcomes vs. Investigator’s Evaluation in the APEKS-cUTI Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1337 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S537-S537

Author(s):

Simon Portsmouth ◽

Kiichiro Toyoizumi ◽

Tsutae Den Nagata ◽

Glenn S Tillotson ◽

Roger Echols

Keyword(s):

Urinary Tract ◽

Clinical Outcomes ◽

Clinical Cure ◽

Response To Therapy ◽

Alternative Measure ◽

Double Blind Study ◽

Treatment Difference ◽

Patient Interview ◽

Patient Reported ◽

Tract Infections

Abstract Background Based on the 2009 US FDA guidance, patient-reported outcome (PRO) measures are recommended in clinical study designs for certain indications to evaluate response to therapy from the patient’s perspective, and a PRO was recommended in the final complicated urinary tract infection (cUTI) guidance in 2014. Several PRO tools have been rigorously validated, but currently, no tool exists for evaluating cUTI. We included a “structured patient interview (SPI)“ while conducting a randomized, double-blind, study (NCT02321800) investigating cefiderocol (CFDC) vs. imipenem–cilastatin (IPM/CS) in cUTI patients to support the physician’s assessment of clinical response. Methods Patients, who were fully alert and oriented, were interviewed at randomization, end of treatment, test of cure (TOC), and follow-up (FUP) by the same interviewer. The questionnaire identified the presence or absence of relevant symptoms pertinent to cUTI. Responses were graded as none, or if present, mild, moderate, or severe. Investigator assessment included objective measures of clinical outcome(s) and was performed independently from the patient-reported symptoms collected in the SPI. Changes in the patient’s responses were compared with the investigator’s assessment at randomization and at each study visit. A kappa correlation coefficient comparing the SPI and physician’s clinical assessment was calculated at each evaluation time point. Results Based on investigator assessment, 89.7% (226 out of 252 patients) in the CFDC arm and 87.4% (104 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 2.39%; 95% CI: –4.66; 9.44) at TOC. Based on the SPI responses, 89.7% (226 out of 252 patients) in the CFDC arm and 84.9% (101 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 4.96%; 95% CI: –2.48; 12.39) in favor of CFDC. The correlation between SPI evaluation and physician’s assessment of clinical outcomes was very high at TOC and FUP visits (Kappa coefficients: 0.820 and 0.766, respectively). Conclusion The strong correlation between patients’ reported symptoms collected in the SPI and investigator assessment showed that SPI responses could be a useful alternative measure of clinical outcomes in cUTI studies. Disclosures All authors: No reported disclosures.

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1154. Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Pediatric Participants With Complicated Intra-abdominal Infection: A Phase 2, Randomized Clinical Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1347 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S668-S669

Author(s):

Carl-Christian A Jackson ◽

Jason Newland ◽

Natalia Dementieva ◽

Julia Lonchar ◽

Feng-Hsiu Su ◽

...

Keyword(s):

Clinical Cure ◽

Clinical Success ◽

Study Drug ◽

Primary Objective ◽

Phase 2 ◽

Safety And Efficacy ◽

Mitt Population ◽

Common Diagnosis ◽

Intra Abdominal Infection ◽

Tract Infections

Abstract Background Ceftolozane/tazobactam (C/T), a cephalosporin–β-lactamase inhibitor combination, is approved for treatment of complicated urinary tract infections, complicated intra-abdominal infections (cIAI), and nosocomial pneumonia in adults. Safety and efficacy of C/T in pediatric participants with cIAI was assessed. Methods This phase 2 study (NCT03217136) compared C/T + metronidazole (MTZ) with meropenem (MEM) for treatment of cIAI. Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to evaluate the safety and tolerability of C/T + MTZ compared with MEM. A key secondary endpoint was clinical cure at end of treatment (EOT) and test of cure (TOC). Table 1. Summary of Dosing and Pharmacokinetic Sampling Schedule by Age Cohort Results A total of 94 participants were randomized 3:1; 91 were treated with C/T + MTZ (n=70) or MEM (n=21) comprising the modified intent-to-treat (MITT) population. The clinically evaluable population included 78 participants at EOT (C/T + MTZ, n=59; MEM, n=19) and 77 participants at TOC (C/T + MTZ, n=58; MEM, n=19). The most common diagnosis and pathogen in the MITT population were complicated appendicitis (C/T + MTZ, 91.4%; MEM, 100%) and Escherichia coli (C/T + MTZ, 67.1%; MEM, 61.9%). The mean (SD) intravenous therapy/overall treatment duration was 6.4 (2.8)/9.3 (3.6) days and 5.8 (1.8)/9.0 (3.2) days for C/T + MTZ and MEM, respectively. In total, ≥1 adverse events (AE) occurred in 80.0% and 61.9% of participants receiving C/T + MTZ and MEM, respectively (Table 2), of which 18.6% and 14.3% were considered drug related. Serious AE occurred in 11.4% (8/70) and 0% (0/21) of participants receiving C/T + MTZ and MEM, respectively; none were considered drug related. No drug-related study drug discontinuations occurred. In the MITT population, rates of clinical cure for C/T + MTZ and MEM at EOT were 80.0% and 95.2%, and at TOC were 80.0% and 100%, respectively (Figure 1); 6 of the 14 failures for C/T + MTZ were indeterminate responses scored as endpoint failures per protocol. In the clinically evaluable (CE) population, rates of clinical cure for C/T + MTZ and MEM were 89.8% and 100% at EOT, and 89.7% and 100% at TOC, respectively (Figure 1). Conclusion C/T + MTZ was well tolerated in pediatric participants with cIAI, and rates of clinical success were high with C/T treatment. C/T is a promising new treatment option for children with cIAI. Disclosures Carl-Christian A. Jackson, MD, Merck & Co. Inc. (Shareholder) 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) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Myra W. Popejoy, PharmD, Merck Sharp & Dohme Corp. (Employee) Matthew G. Johnson, MD, 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)

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1689. Oral Beta-lactam Step Down in Bacteremic E. coli Urinary Tract Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1867 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S828-S829

Author(s):

Stephan Saad ◽

Neil Mina ◽

Colin Lee ◽

Kevin Afra

Keyword(s):

Urinary Tract ◽

Propensity Score ◽

Urinary Tract Infections ◽

Clinical Cure ◽

Beta Lactam ◽

Beta Lactams ◽

E Coli ◽

Secondary Outcomes ◽

Step Down ◽

Tract Infections

Abstract Background Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones. Methods This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding. Results A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference -4.2%, 95% confidence interval [CI] -10.3% to 1.9%, p=0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05 – 1.90, p=0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes. Table 2 Table 3 Table 4 Conclusion Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones. Disclosures All Authors: No reported disclosures

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1292. Safety Profile of the Novel Siderophore Cephalosporin Cefiderocol in Randomized Phase 2 and Phase 3 Clinical Studies of Serious Gram-Negative Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1475 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S661-S662

Author(s):

Yuko Matsunaga ◽

Takuhiro Sonoyama ◽

Luis Casanova ◽

Tsutae Den Nagata ◽

Roger Echols ◽

...

Keyword(s):

Safety Profile ◽

Clinical Studies ◽

Treatment Duration ◽

Iron Homeostasis ◽

The United States ◽

Phase 2 ◽

Phase 3 ◽

Double Blind ◽

Gram Negative ◽

Tract Infections

Abstract Background Cefiderocol (CFDC), the first siderophore cephalosporin, is approved in the United States (complicated urinary tract infections [cUTI]) and Europe for the treatment of patients with Gram-negative (GN) infections with limited treatment options. Methods This analysis investigated the safety profile of CFDC across three prospective, multicenter, randomized clinical studies: APEKS-cUTI (double-blind, non-inferiority Phase 2 study in patients with cUTI) vs imipenem-cilastatin (1 g/1 g, three-times daily); APEKS-NP (double-blind, non-inferiority Phase 3 study in patients with nosocomial pneumonia [NP]) vs meropenem (2 g, q8h); CREDIBLE-CR (open-label, descriptive Phase 3 study in patients with cUTI, NP, bloodstream infections/sepsis [BSI/sepsis]) caused by carbapenem-resistant GN bacteria; patients in the control arm received best available therapy (BAT; up to 3 agents, dosing based on local label). CFDC was given at 2 g, q8h, infused over 1 (APEKS-cUTI) or 3 (APEKS-NP, CREDIBLE-CR) hours. One adjunctive agent with CFDC was only allowed in CREDIBLE-CR. Results 549 patients were treated with CFDC, 347 control treated (Table 1). More than 50% of patients were aged ≥65 years, except BAT arm in CREDIBLE-CR. The majority of patients were admitted to the ICU in APEKS-NP and CREDIBLE-CR. The median treatment duration with CFDC was similar (9–11 days) across studies. The rates of TEAEs and serious AEs (SAEs) between CDFC and comparators were similar in each study (Table 2). The rates of adverse drug reactions were lower with CFDC than with comparators in each study, with a greater difference in CREDIBLE-CR than in APEKS-cUTI and APEKS-NP. TEAEs leading to death rates are shown in Table 2. Eight CFDC-related Clostridioides difficile infections occurred across studies (APEKS-cUTI: n=1; APEKS-NP: n=4; CREDIBLE-CR: n=3 [ie, C. difficile colitis; pseudomembranous colitis]). In total, eight experienced seizures (APEKS-cUTI: CFDC n=1; APEKS-NP: CFDC n=3, meropenem n=2; CREDIBLE-CR: CFDC n=1, BAT n=1), none of which were related to study drugs. Parameters of iron homeostasis showed no differences between CFDC and comparators. Table 1. Baseline characteristics and treatment duration (safety populations) Table 2. Overall safety parameters (safety populations) Conclusion CFDC demonstrated a comparable safety profile to carbapenems or other cephalosporins and was generally well tolerated in critically ill patients. Disclosures Yuko Matsunaga, MD, Shionogi Inc. (Employee) Takuhiro Sonoyama, MD, Shionogi & Co., Ltd. (Employee) Luis Casanova, PharmD, Shionogi B.V. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Fabio De Gregorio, MD, Shionogi B.V. (Employee) Eriko Ogura, MD, Shionogi & Co., Ltd. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee)

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Oral beta-lactam step down in bacteremic E. coli urinary tract infections

10.21203/rs.3.rs-61675/v2 ◽

2020 ◽

Author(s):

Stephan Saad ◽

Neil Mina ◽

Colin Lee ◽

Kevin Afra

Keyword(s):

Urinary Tract ◽

Propensity Score ◽

Urinary Tract Infections ◽

Clinical Cure ◽

Beta Lactam ◽

Beta Lactams ◽

E Coli ◽

Secondary Outcomes ◽

Step Down ◽

Tract Infections

Abstract Background. Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones.Methods. This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding.Results. A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference -4.2%, 95% confidence interval [CI] -10.3% to 1.9%, p=0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05 – 1.90, p=0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes.Conclusions. Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.

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Oral beta-lactam step down in bacteremic E. coli urinary tract infections

10.21203/rs.3.rs-61675/v1 ◽

2020 ◽

Author(s):

Stephan Saad ◽

Neil Mina ◽

Colin Lee ◽

Kevin Afra

Keyword(s):

Urinary Tract ◽

Propensity Score ◽

Urinary Tract Infections ◽

Clinical Cure ◽

Beta Lactam ◽

Beta Lactams ◽

E Coli ◽

Secondary Outcomes ◽

Step Down ◽

Tract Infections

Abstract Background: Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones.Methods: This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding.Results: A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference − 4.2%, 95% confidence interval [CI] -10.3–1.9%, p = 0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05–1.90, p = 0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes.Conclusions: Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.

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