scholarly journals Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials

2017 ◽  
Vol 4 (2) ◽  
Author(s):  
Elizabeth L. Alexander ◽  
Jeffery Loutit ◽  
Mario Tumbarello ◽  
Richard Wunderink ◽  
Tim Felton ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Patient Population ◽  
Bacterial Pneumonia ◽  
Complicated Urinary Tract Infection ◽  
Clinical Trial Design ◽  
New Drugs ◽  
External Control ◽  
Phase 3 ◽  
Carbapenem Resistant ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background The increasing incidence of multidrug-resistant Gram negatives, such as carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a critical need for new antimicrobials. Most studies of new antimicrobials have been performed in patients with nondrug-resistant pathogens. We performed a retrospective analysis of patients with CRE infections to inform the design of phase 3 clinical trials. Methods This was a retrospective study at 22 centers in 4 countries. Baseline data, treatment, and outcomes were collected in patients with complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia due to CRE. Results Two hundred fifty-six cases of CRE infection were identified: 75 cUTI/AP, 21 HABP, 20 VABP, and 140 bacteremia. The patient population had significant comorbidities: 32.8% had chronic renal insufficiency, and 26.2% were immunocompromised. Illness severity at presentation was high: 29.3% presented with septic shock. Treatment regimens varied widely; however, a majority of patients received combination therapy. Outcomes were universally poor (28-day mortality was 28.1%) across all sites of infection, particularly in dialysis patients and those with sepsis. Conclusions The CRE infections occured in patients with substantial comorbidities and were associated with high mortality and low rates of clinical cure with available antibiotics. Patients with these comorbidities are often excluded from enrollment in clinical trials for registration of new drugs. These results led to changes in the inclusion/exclusion criteria of a phase 3 trial to better represent the patient population with CRE infections and enable enrollment. Observational studies may become increasingly important to guide clinical trial design, inform on the existing standard of care, and provide an external control for subsequent trials.

scholarly journals Heterogeneity of Recent Phase 3 Complicated Urinary Tract Infection Clinical Trials

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Simon Portsmouth ◽  
Almasa Bass ◽  
Roger Echols ◽  
Glenn Tillotson
Keyword(s):  
Clinical Trials ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Study Design ◽  
Patient Population ◽  
Complicated Urinary Tract Infection ◽  
Gram Negative ◽  
Regulatory Guidelines ◽  
New Antibiotics

Abstract Background For new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed. Methods This selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included. Results Microbiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP. Conclusions A study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics.

scholarly journals 484. Metallo-β-Lactamase-Positive Carbapenem-Resistant Enterobacteriaceae and Pseudomonas aeruginosa in the Antibiotic Resistance Laboratory Network, 2017–2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S237-S237
Author(s):  
Allison C Brown ◽  
Sarah Malik ◽  
Jennifer Huang ◽  
Amelia Bhatnagar ◽  
Rocio Balbuena ◽  
...  
Keyword(s):  
United States ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
The United States ◽  
New Drugs ◽  
Carbapenem Resistant ◽  
Laboratory Network ◽  
Therapeutic Decisions ◽  
Carbapenemase Gene ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background Infections with metallo-β-lactamase (MBL)-producing organisms are emerging in the United States. Treatment options for these infections are limited. We describe MBL genes among carbapenemase positive carbapenem-resistant Enterobacteriaceae (CP-CRE) and Pseudomonas aeruginosa (CP-CRPA) isolates tested during the first two years of the Antibiotic Resistance Laboratory Network (AR Lab Network). Methods State and local public health laboratories tested CRE and CRPA isolates for organism identification, antimicrobial susceptibility, and PCR-based detection of blaKPC, blaNDM, blaOXA-48-like, blaVIM, and blaIMP carbapenemase genes. All testing results were sent to CDC at least monthly. Results Since January 2017, the AR Lab Network tested 21,733 CRE and 14,141 CRPA. CP-CRE were detected in 37% of CRE; 2% of CRPA were CP-CRPA. Among CP-CRE, 9% (686/8016) were MBL-producers (NDM, VIM, or IMP). Among MBL-producers, a blaNDM gene was detected most often (81%; 551/686). blaNDM were most common among Klebsiella spp. (47%; 261/551), blaIMP were most common among Providencia spp. (53%; 40/75), blaVIM was most common among Enterobacter spp. (19%; 25/62). Twelve percent (96) of MBL CP-CRE contained more than one carbapenemase gene. Among CP-CRPA, 73% (218/300) were MBL producers and blaVIM was the most common gene (62%; 186). Three (1%) MBL CP-CRPA contained more than one carbapenemase. Conclusion Increased testing of CRE and CRPA isolates through the AR Lab Network has facilitated early and rapid detection of hard-to-treat infections caused by MBL-producing organisms across the United States. The widespread distribution of MBL genes highlights the continued need for containment strategies that help prevent transmission between patients and among healthcare facilities. To support therapeutic decisions for severe infections caused by MBL-producing organisms, the AR Lab Network is now offering rapid susceptibility testing against aztreonam/avibactam, using digital dispenser technology. This testing program aims to close the gap between the availability of new drugs or drug combinations and the availability of commercial AST methods, thereby improving patient safety and antimicrobial stewardship. Disclosures All authors: No reported disclosures.

Metastatic colorectal cancer (mCRC) patterns of care: Implications for clinical trial design

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4079-4079 ◽  
Author(s):  
C. S. Denlinger ◽  
M. A. Collins ◽  
Y. Wong ◽  
S. Litwin ◽  
N. J. Meropol
Keyword(s):  
Clinical Trial ◽  
Decision Making ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
New Drugs ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Treatment Change ◽  
Therapy Regimen

4079 Background: New approaches have expanded options for patients (pts) with mCRC. To characterize current practice paradigms that might bear on clinical trial design, we analyzed decision-making and treatment patterns in pts treated at a Comprehensive Cancer Center since the introduction of cetuximab (CET), and bevacizumab (BV). Methods: A retrospective review of all pts diagnosed with mCRC between 3/1/04 and 8/28/06 treated at Fox Chase Cancer Center. Results: 160 pts were treated, with 157 pts receiving at least one therapy regimen by 10 attending oncologists. There were 350 changes in therapy with 246 (70%) including continuation of at least one prior drug (92 BV, 111 fluoropyrimidines, 43 other). The most common reasons for treatment change were toxicity (33%), progressive disease (PD) (29%), treatment breaks (15%), and metastasectomy (11%) ( Table ). PD was a more common cause for treatment discontinuation in later phases of treatment (18% initial regimen vs. 36% subsequent regimens, p=0.0002). 24% of pts treated with oxaliplatin (OX) discontinued due to neuropathy. Hypersensitivity caused discontinuation in 5% of pts with OX and 7% of pts with CET. Resection of metastases was undertaken in 38% of pts. 43% of these pts received neoadjuvant therapy, and 56% received adjuvant therapy. 30% of pts have died, 29% remain on active treatment, 28% are on a treatment break, 3% are on hospice, and 11% are lost to follow-up. Conclusions: PD is no longer the primary reason for change of therapy in pts with mCRC. Metastasectomy is common and OX neuropathy is often treatment-limiting. These findings have important implications for endpoint selection and design of clinical trials in mCRC. Future clinical trials in mCRC must recognize treatment complexities and capture key components of decision-making that may result in prolonged survival. Furthermore, treatment breaks represent a potential window for the evaluation of new drugs. [Table: see text] No significant financial relationships to disclose.

scholarly journals Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain

2021 ◽  
Author(s):  
Ricard Ferrer ◽  
María Carmen Fariñas ◽  
Emilio Maseda ◽  
Miguel Salavert ◽  
German Bou ◽  
...  
Keyword(s):  
Clinical Management ◽  
Bacterial Pneumonia ◽  
Chart Review ◽  
Complicated Urinary Tract Infection ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Post Discharge ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Healthcare Associated

Introduction. Carbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals. Methods. The study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) attributable to CRGN pathogens. Results. In the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbapenems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%. Conclusion. Our results reflect the high burden and unmet needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections.

Analysis of proportion of geriatric patients in phase III cancer clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e23032-e23032
Author(s):  
Swathi Gopishetty ◽  
Vamsi Kota ◽  
Achuta Kumar Guddati
Keyword(s):  
Clinical Trials ◽  
Patient Population ◽  
Geriatric Patients ◽  
Lymphoblastic Leukemia ◽  
Age Distribution ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
Phase 3 ◽  
Organ Specific

e23032 Background: Geriatric patients are often under-represented in cancer clinical trials. The presence of multiple comorbidities makes geriatric patients ineligible for most clinical trials. However, the increase in cancer incidence in geriatric patients raises the question of applicability of the results is such clinical trials. Methods: Data about Phase 3 trials was extracted from the clinical trials.gov for 3 common solid organs and 3 hematological malignancies [breast, colon, lung, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)]. The time period studied was for the past 10 years and included only adult patients (≥ 18 years). The age distribution of the patient population in these trials were extracted and analyzed. Results: Geriatric patients are heavily under-represented in all phase 3 cancer clinical trials. Table shows the proportion of patients below 65 years, above 65 years and older in clinical trials for each organ specific malignancy. The range of the proportion of geriatric patients varied from 10% to 40%. Conclusions: The results of phase 3 clinical trials that are currently conducted on non-geriatric patient population may not meaningfully be applicable to geriatric patients. This study highlights the disparity of age for patients enrolled in clinical trials as against the patients seen in the real world.[Table: see text]

scholarly journals Estimating the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in the United States Using Antibiotic Prescription Data

2019 ◽  
Vol 6 (8) ◽  
Author(s):  
Cornelius J Clancy ◽  
Brian A Potoski ◽  
Deanna Buehrle ◽  
M Hong Nguyen
Keyword(s):  
United States ◽  
Online Survey ◽  
Antibiotic Use ◽  
The United States ◽  
New Drugs ◽  
Prescription Data ◽  
First Line ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background Polymyxins (colistin, polymyxin B) have been first-line antibiotics against carbapenem-resistant Enterobacteriaceae (CRE) infections. New anti-CRE antibiotics (ceftazidime-avibactam, meropenem-vaborbactam, plazomicin) improve outcomes in CRE-infected patients and reduce toxicity compared with polymyxins. It is unclear how widely polymyxins and newer agents are used to treat CRE infections. Methods We conducted an online survey of US hospital-based pharmacists to determine antibiotic positioning against CRE infections. Numbers of all infections and CRE infections treated with different antibiotics in the United States were determined using IQVIA prescription data and Driving Re-investment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) estimates of CRE infections. Results Ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin were positioned as first-line agents against CRE pneumonia, bacteremia, intra-abdominal infections, and urinary tract infections at 87%, 90%, 83%, and 56% of surveyed US hospitals, respectively. From February 2018 to January 2019, an estimated 9437 and 7941 CRE infections were treated with an intravenous polymyxin or new agent, respectively; these figures represented ~28% (range, 19%–50%) and ~23% (range, 16%–42%) of CRE infections in the United States. Use of ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin exceeded that of intravenous polymyxins against CRE infections as of December 2018. Currently, the new drugs are estimated to treat 35% (23% to 62%) of CRE infections in which they were expected to be first-line agents. Conclusions New anti-CRE agents recently surpassed intravenous polymyxins as treatment for CRE infections, but use is less than expected from their positioning at US hospitals. Research on behavioral and economic factors that impact use of new antibiotics is needed, as are financial “pull” incentives that promote an economically viable marketplace.

scholarly journals Development of new drugs for treatment of heart failure (adventures, disasters and joys)

ANALES RANM ◽  
2021 ◽  
Vol 138 (138(01)) ◽  
pp. 44-51
Author(s):  
Juan Tamargo
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Ejection Fraction ◽  
New Drugs ◽  
Response To Treatment ◽  
Phase 3 ◽  
Reduced Ejection Fraction ◽  
High Prevalence ◽  
Large Phase ◽  
Made In

Heart failure (HF) represents an important healthcare problem due to its high prevalence, high rates of hospitalization and mortality, and significant healthcare costs. HF comprises a heterogeneous group of syndromes with different pathophysiology, clinical presentation, and response to treatment. In recent years, multiple therapeutic targets implicated in the pathogenesis of HF have been identified and numerous drugs have been developed against multiple targets. But despite important advances in the pharmacological treatment of HF with reduced ejection fraction, no treatment has convincingly shown to date to reduce mortality in HF patients with preserved ejection fraction. Furthermore, the vast majority of drugs that appeared very promising in animal models or in phase 2 clinical trials have not been able to be commercialized due to their lack of efficacy and / or safety in large phase 3 clinical trials. In this article we analyze the objectives of the treatment of HF, the progress made in recent years and the possible causes that could explain our repeated failures.

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