Browsing by Author "Holland, Thomas L"
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Item Open Access A Desirability of Outcome Ranking Analysis of a Randomized Clinical Trial Comparing Seven Versus Fourteen Days of Antibiotics for Uncomplicated Gram-Negative Bloodstream Infection.(Open forum infectious diseases, 2022-06) Howard-Anderson, Jessica; Dai, Weixiao; Yahav, Dafna; Hamasaki, Toshimitsu; Turjeman, Adi; Koppel, Fidi; Franceschini, Erica; Hill, Carol; Sund, Zoë; Chambers, Henry F; Fowler, Vance G; Boucher, Helen W; Evans, Scott R; Paul, Mical; Holland, Thomas L; Doernberg, Sarah BBackground
Although a short course (7 days) of antibiotics has been demonstrated to be noninferior to a conventional course (14 days) in terms of mortality and infectious complications for patients with a Gram-negative bacterial bloodstream infection (GNB), it is unknown whether a shorter treatment duration can provide a better overall clinical outcome.Methods
We applied a bloodstream infection-specific desirability of outcome ranking (DOOR) analysis to the results of a previously completed, randomized controlled trial comparing short versus conventional course antibiotic therapy for hospitalized patients with uncomplicated GNB. We determined the probability that a randomly selected participant in the short course group would have a more desirable overall outcome than a participant in the conventional duration group. We performed (1) partial credit analyses allowing for calculated and variable weighting of DOOR ranks and (2) subgroup analyses to elucidate which patients may benefit the most from short durations of therapy.Results
For the 604 patients included in the original study (306 short course, 298 conventional course), the probability of having a more desirable outcome with a short course of antibiotics compared with a conventional course was 51.1% (95% confidence interval, 46.7% to 55.4%), indicating no significant difference. Partial credit analyses indicated that the DOOR results were similar across different patient preferences. Prespecified subgroup analyses using DOOR did not reveal significant differences between short and conventional courses of therapy.Conclusions
Both short and conventional durations of antibiotic therapy provide comparable clinical outcomes when using DOOR to consider benefits and risks of treatment options for GNB.Item Open Access Antibacterial Resistance Leadership Group 2.0: Back to Business.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-08) Chambers, Henry F; Evans, Scott R; Patel, Robin; Cross, Heather R; Harris, Anthony D; Doi, Yohei; Boucher, Helen W; van Duin, David; Tsalik, Ephraim L; Holland, Thomas L; Pettigrew, Melinda M; Tamma, Pranita D; Hodges, Kathryn R; Souli, Maria; Fowler, Vance GIn December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.Item Open Access Antiplatelet Therapy in Staphylococcus aureus Bacteremia: No Time Like the Past?(Antimicrobial agents and chemotherapy, 2022-06) Mourad, Ahmad; Holland, Thomas L; Turner, Nicholas AIn this invited commentary, we reflect on the accompanying study by A. R. Caffrey, H. J. Appaneal, K. L. LaPlante, V. V. Lopes, et al. (Antimicrob Agents Chemother 66:e02117-21, 2022, https://doi.org/10.1128/aac.02117-21), which analyzed the impact of clopidogrel use on clinical outcomes in Staphylococcus aureus bacteremia.Item Open Access Blood pressure level impacts risk of death among HIV seropositive adults in Kenya: a retrospective analysis of electronic health records.(BMC Infect Dis, 2014-05-22) Bloomfield, Gerald S; Hogan, Joseph W; Keter, Alfred; Holland, Thomas L; Sang, Edwin; Kimaiyo, Sylvester; Velazquez, Eric JBACKGROUND: Mortality among people with human immunodeficiency virus (HIV) infection is increasingly due to non-communicable causes. This has been observed mostly in developed countries and the routine care of HIV infected individuals has now expanded to include attention to cardiovascular risk factors. Cardiovascular risk factors such as high blood pressure are often overlooked among HIV seropositive (+) individuals in sub-Saharan Africa. We aimed to determine the effect of blood pressure on mortality among HIV+ adults in Kenya. METHODS: We performed a retrospective analysis of electronic medical records of a large HIV treatment program in western Kenya between 2005 and 2010. All included individuals were HIV+. We excluded participants with AIDS, who were <16 or >80 years old, or had data out of acceptable ranges. Missing data for key covariates was addressed by inverse probability weighting. Primary outcome measures were crude mortality rate and mortality hazard ratio (HR) using Cox proportional hazards models adjusted for potential confounders including HIV stage. RESULTS: There were 49,475 (74% women) HIV+ individuals who met inclusion and exclusion criteria. Mortality rates for men and women were 3.8 and 1.8/100 person-years, respectively, and highest among those with the lowest blood pressures. Low blood pressure was associated with the highest mortality incidence rate (IR) (systolic <100 mmHg IR 5.2 [4.8-5.7]; diastolic <60 mmHg IR 9.2 [8.3-10.2]). Mortality rate among men with high systolic blood pressure without advanced HIV (3.0, 95% CI: 1.6-5.5) was higher than men with normal systolic blood pressure (1.1, 95% CI: 0.7-1.7). In weighted proportional hazards regression models, men without advanced HIV disease and systolic blood pressure ≥140 mmHg carried a higher mortality risk than normotensive men (HR: 2.39, 95% CI: 0.94-6.08). CONCLUSIONS: Although there has been little attention paid to high blood pressure among HIV+ Africans, we show that blood pressure level among HIV+ patients in Kenya is related to mortality. Low blood pressure carries the highest mortality risk. High systolic blood pressure is associated with mortality among patients whose disease is not advanced. Further investigation is needed into the cause of death for such patients.Item Open Access Compiling Observational Research During a Pandemic: A Necessary Bridge.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-12-11) Moehring, Rebekah W; Holland, Thomas LItem Open Access Contribution of urinary tract infection to the burden of febrile illnesses in young children in rural Kenya.(PLoS One, 2017) Masika, Wechuli Geoffrey; O'Meara, Wendy Prudhomme; Holland, Thomas L; Armstrong, JaniceINTRODUCTION: The clinical features of UTI in young children may not localize to the urinary tract and closely resemble other febrile illnesses. In malaria endemic areas, a child presenting with fever is often treated presumptively for malaria without investigation for UTI. Delayed or inadequate treatment of UTI increases the risk of bacteremia and renal scarring in young children and subsequently complications as hypertension and end stage renal disease in adulthood. METHODS: A cross-sectional study was carried out in a hospital in western Kenya. Inpatients and outpatients 2 months to five years with axillary temperature ≥37.5°C and no antibiotic use in the previous week were enrolled between September 2012 and April 2013. Urine dipstick tests, microscopy, and cultures were done and susceptibility patterns to commonly prescribed antibiotics established. UTI was defined as presence of pyuria (a positive urine dipstick or microscopy test) plus a positive urine culture. RESULTS: A total of 260 subjects were recruited; 45.8% were female and the median age was 25months (IQR: 13, 43.5). The overall prevalence of UTI was 11.9%. Inpatients had a higher prevalence compared to outpatients (17.9% v 7.8%, p = 0.027). UTI co-existed with malaria but the association was not significant (OR 0.80, p = 0.570). The most common organisms isolated were Escherichia coli (64.5%) and Staphylococcus aureus (12.9%) and were sensitive to ciproflaxin, cefuroxime, ceftriaxone, gentamycin and nitrofurantoin but largely resistant to more commonly used antibiotics such as ampicillin (0%), amoxicillin (16.7%), cotrimoxazole (16.7%) and amoxicillin-clavulinate (25%). CONCLUSION: Our study demonstrates UTI contributes significantly to the burden of febrile illness in young children and often co-exists with other infections. Multi-drug resistant organisms are common therefore choice of antimicrobial therapy should be based on local sensitivity pattern.Item Open Access Dalbavancin as an option for treatment of S. aureus bacteremia (DOTS): study protocol for a phase 2b, multicenter, randomized, open-label clinical trial.(Trials, 2022-05) Turner, Nicholas A; Zaharoff, Smitha; King, Heather; Evans, Scott; Hamasaki, Toshimitsu; Lodise, Thomas; Ghazaryan, Varduhi; Beresnev, Tatiana; Riccobene, Todd; Patel, Rinal; Doernberg, Sarah B; Rappo, Urania; Fowler, Vance G; Holland, Thomas L; Antibacterial Resistance Leadership Group (ARLG)Background
Staphylococcus aureus bacteremia is a life-threatening infection and leading cause of infective endocarditis, with mortality rates of 15-50%. Treatment typically requires prolonged administration of parenteral therapy, itself associated with high costs and potential catheter-associated complications. Dalbavancin is a lipoglycopeptide with potent activity against Staphylococcus and a long half-life, making it an appealing potential therapy for S. aureus bacteremia without the need for durable central venous access.Methods
DOTS is a phase 2b, multicenter, randomized, assessor-blinded, superiority, active-controlled, parallel-group trial. The trial will enroll 200 adults diagnosed with complicated S. aureus bacteremia, including definite or possible right-sided infective endocarditis, who have been treated with effective antibiotic therapy for at least 72 h (maximum 10 days) and with subsequent clearance of bacteremia prior to randomization to study treatment. Subjects will be randomized 1:1 to complete their antibiotic treatment course with either two doses of dalbavancin on days 1 and 8, or with a total of 4-8 weeks of standard intravenous antibiotic therapy. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at day 70 for patients randomized to dalbavancin versus standard of care. Key secondary endpoints include quality of life outcomes and pharmacokinetic analyses of dalbavancin.Discussion
The DOTS trial will establish whether dalbavancin is superior to standard parenteral antibiotic therapy for the completion of treatment of complicated S. aureus bacteremia.Trial registration
US National Institutes of Health ClinicalTrials.gov NCT04775953 . Registered on 1 March 2021.Item Open Access Determination of plasma protein binding of dalbavancin.(The Journal of antimicrobial chemotherapy, 2022-06) Turner, Nicholas A; Xu, Allan; Zaharoff, Smitha; Holland, Thomas L; Lodise, Thomas PObjectives
Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations.Methods
The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding.Results
Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%.Conclusions
Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.Item Open Access Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.(JAMA, 2018-09) Holland, Thomas L; Raad, Issam; Boucher, Helen W; Anderson, Deverick J; Cosgrove, Sara E; Aycock, P Suzanne; Baddley, John W; Chaftari, Anne-Marie; Chow, Shein-Chung; Chu, Vivian H; Carugati, Manuela; Cook, Paul; Corey, G Ralph; Crowley, Anna Lisa; Daly, Jennifer; Gu, Jiezhun; Hachem, Ray; Horton, James; Jenkins, Timothy C; Levine, Donald; Miro, Jose M; Pericas, Juan M; Riska, Paul; Rubin, Zachary; Rupp, Mark E; Schrank, John; Sims, Matthew; Wray, Dannah; Zervos, Marcus; Fowler, Vance G; Staphylococcal Bacteremia InvestigatorsImportance
The appropriate duration of antibiotics for staphylococcal bacteremia is unknown.Objective
To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events.Design, setting, and participants
A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization.Interventions
Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care.Main outcomes and measures
Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia.Results
Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]).Conclusions and relevance
Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm.Trial registration
ClinicalTrials.gov Identifier: NCT01191840.Item Open Access Exploration of a Potential Desirability of Outcome Ranking Endpoint for Complicated Intra-Abdominal Infections Using 9 Registrational Trials for Antibacterial Drugs.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023-08) Kinamon, Tori; Gopinath, Ramya; Waack, Ursula; Needles, Mark; Rubin, Daniel; Collyar, Deborah; Doernberg, Sarah B; Evans, Scott; Hamasaki, Toshimitsu; Holland, Thomas L; Howard-Anderson, Jessica; Chambers, Henry; Fowler, Vance G; Nambiar, Sumati; Kim, Peter; Boucher, Helen WBackground
Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI).Methods
Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator.Results
Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator.Conclusions
We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease-specific DOOR endpoints.Item Open Access Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023-02) Howard-Anderson, Jessica; Hamasaki, Toshimitsu; Dai, Weixiao; Collyar, Deborah; Rubin, Daniel; Nambiar, Sumathi; Kinamon, Tori; Hill, Carol; Gelone, Steven P; Mariano, David; Baba, Takamichi; Holland, Thomas L; Doernberg, Sarah B; Chambers, Henry F; Fowler, Vance G; Evans, Scott R; Boucher, Helen WBackground
Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience.Methods
Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug.Results
In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR.Conclusions
DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials.Item Open Access Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research(Nature Reviews Microbiology) Turner, Nicholas A; Sharma-Kuinkel, Batu K; Maskarinec, Stacey A; Eichenberger, Emily M; Shah, Pratik P; Carugati, Manuela; Holland, Thomas L; Fowler, Vance GItem Open Access Patients' Experiences With Staphylococcus aureus and Gram-Negative Bacterial Bloodstream Infections: Results From Cognitive Interviews to Inform Assessment of Health-Related Quality of Life.(Open forum infectious diseases, 2022-02) King, Heather A; Doernberg, Sarah B; Grover, Kiran; Miller, Julie; Oakes, Megan; Wang, Tsai-Wei; McFatrich, Molly; Ruffin, Felicia; Staman, Karen; Lane, Hannah G; Rader, Abigail; Sund, Zoë; Bosworth, Hayden B; Reeve, Bryce B; Fowler, Vance G; Holland, Thomas LBackground
We previously conducted a concept elicitation study on the impact of Staphylococcus aureus and gram-negative bacterial bloodstream infections (SAB/GNB) on health-related quality of life (HRQoL) from the patient's perspective and found significant impacts on HRQoL, particularly in the physical and functional domains. Using this information and following guidance on the development of patient-reported outcome (PRO) measures, we determined which combination of measures and items (ie, specific questions) would be most appropriate in a survey assessing HRQoL in bloodstream infections.Methods
We selected a variety of measures/items from the Patient-Reported Outcomes Measurement Information System (PROMIS) representing different domains. We purposefully sampled patients ~6-12 weeks post-SAB/GNB and conducted 2 rounds of cognitive interviews to refine the survey by exploring patients' understanding of items and answer selection as well as relevance for capturing HRQoL.Results
We interviewed 17 SAB/GNB patients. Based on the first round of cognitive interviews (n = 10), we revised the survey. After round 2 of cognitive interviewing (n = 7), we finalized the survey to include 10 different PROMIS short forms/measures of the most salient HRQoL domains and 2 adapted questions (41 items total) that were found to adequately capture HRQoL.Conclusions
We developed a survey from well-established PRO measures that captures what matters most to SAB/GNB patients as they recover. This survey, uniquely tailored to bloodstream infections, can be used to assess these meaningful, important HRQoL outcomes in clinical trials and in patient care. Engaging patients is crucial to developing treatments for bloodstream infections.Item Open Access Patients' Experiences With Staphylococcus aureus and Gram-negative Bacterial Bloodstream Infections: A Qualitative Descriptive Study and Concept Elicitation Phase To Inform Measurement of Patient-reported Quality of Life.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-07) King, Heather A; Doernberg, Sarah B; Miller, Julie; Grover, Kiran; Oakes, Megan; Ruffin, Felicia; Gonzales, Sarah; Rader, Abigail; Neuss, Michael J; Bosworth, Hayden B; Sund, Zoë; Drennan, Caitlin; Hill-Rorie, Jonathan M; Shah, Pratik; Winn, Laura; Fowler, Vance G; Holland, Thomas LBackground
Although Staphylococcus aureus and gram-negative bacterial bloodstream infections (SAB/GNB) cause substantial morbidity, little is known regarding patient perceptions' of their impact on quality of life (QOL). Guidance for assessing QOL and disease-specific measures are lacking. We conducted a descriptive qualitative study to gain an in-depth understanding of patients' experiences with SAB/GNB and concept elicitation phase to inform a patient-reported QOL outcome measure.Methods
We conducted prospective one-time, in-depth, semi-structured, individual, qualitative telephone interviews 6- 8 weeks following bloodstream infection with either SAB or GNB. Patients were enrolled in an institutional registry (tertiary academic medical center) for SAB or GNB. Interviews were audio-recorded, transcribed, and coded. Directed content analysis identified a priori and emergent themes. Theme matrix techniques were used to facilitate analysis and presentation.Results
Interviews were completed with 30 patients with SAB and 31 patients with GNB. Most patients were at or near the end of intravenous antibiotic treatment when interviewed. We identified 3 primary high-level concepts: impact on QOL domains, time as a critical index, and sources of variability across patients. Across both types of bloodstream infection, the QOL domains most impacted were physical and functional, which was particularly evident among patients with SAB.Conclusions
SAB/GNB impact QOL among survivors. In particular, SAB had major impacts on multiple QOL domains. A combination of existing, generic measures that are purposefully selected and disease-specific items, if necessary, could best capture these impacts. Engaging patients as stakeholders and obtaining their feedback is crucial to conducting patient-centered clinical trials and providing patient-centered care.Item Open Access Persistent Methicilin-Resistant Staphylococcus aureus Bacteremia: Resetting the Clock for Optimal Management.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022-10) Holland, Thomas L; Bayer, Arnold S; Fowler, Vance GA positive follow-up blood culture for methicillin-resistant Staphylococcus aureus (MRSA) while on seemingly appropriate therapy is a common and ominous development. However, the definition and management of persistent MRSA bacteremia is unstandardized. In this Opinion Paper, we identify the presence of bacteremia for > 1 calendar day as a "worry point" that should trigger an intensive diagnostic evaluation to identify metastatic infection sites. Next, we define the duration of MRSA bacteremia that likely constitutes antibiotic failure and outline a potential management algorithm for such patients. Finally, we propose pragmatic clinical trial designs to test treatment strategies for persistent MRSA bacteremia.Item Open Access Prophetic EU: Prospective Identification of Pneumonia in Hospitalized Patients in the Intensive Care Unit–A Comparison of European and United States CohortsBergin, Stephen P; Calvert, Sara B; Farley, John; Sun, Jie-Lena; Chiswell, Karen; Dieperink, Willem; Kluytmans, Jan; Lopez-Delgado, Juan Carlos; Leon-Lopez, Rafael; Zervos, Marcus J; Kollef, Marin H; Sims, Matthew; Kabchi, Badih A; Rubin, Daniel; Santiago, Jonas; Natarajan, Mukil; Tenaerts, Pamela; Fowler, Vance G; Holland, Thomas L; Bonten, Marc J; Hullegie, Sebastiaan JItem Open Access PROPHETIC: Prospective Identification of Pneumonia in Hospitalized Patients in the Intensive Care Unit.(Chest, 2020-06-29) Bergin, Stephen P; Coles, Adrian; Calvert, Sara B; Farley, John; Powers, John H; Zervos, Marcus J; Sims, Matthew; Kollef, Marin H; Durkin, Michael J; Kabchi, Badih A; Donnelly, Helen K; Bardossy, Ana Cecilia; Greenshields, Claire; Rubin, Daniel; Sun, Jie-Lena; Chiswell, Karen; Santiago, Jonas; Gu, Peidi; Tenaerts, Pamela; Fowler, Vance G; Holland, Thomas LBACKGROUND:Pneumonia is the leading infection-related cause of death. Using simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials. RESEARCH QUESTION:What are the clinical criteria and contemporary epidemiology trends helpful in identifying patients at high risk of nosocomial pneumonia? STUDY DESIGN AND METHODS:Within the intensive care units of 28 United States hospitals, we conducted a prospective cohort study among adults hospitalized more than 48 hours and considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients developing nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures associated with increased risk of pneumonia development during the intensive care unit admission. RESULTS:Between February 6, 2016 and October 7, 2016, 4613 high-risk patients were enrolled. Among 1464/4613 (32%) high-risk patients treated for possible nosocomial pneumonia, 537/1464 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures associated with increased risk of nosocomial pneumonia development (c-statistic 0.709, 95% confidence interval 0.686 to 0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days. INTERPRETATION:Treatment for nosocomial pneumonia is common among intensive care unit patients receiving high levels of respiratory support, yet more than half of patients treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.Item Open Access Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial.(Critical care (London, England), 2022-11) Chastre, Jean; François, Bruno; Bourgeois, Marc; Komnos, Apostolos; Ferrer, Ricard; Rahav, Galia; De Schryver, Nicolas; Lepape, Alain; Koksal, Iftihar; Luyt, Charles-Edouard; Sánchez-García, Miguel; Torres, Antoni; Eggimann, Philippe; Koulenti, Despoina; Holland, Thomas L; Ali, Omar; Shoemaker, Kathryn; Ren, Pin; Sauser, Julien; Ruzin, Alexey; Tabor, David E; Akhgar, Ahmad; Wu, Yuling; Jiang, Yu; DiGiandomenico, Antonio; Colbert, Susan; Vandamme, Drieke; Coenjaerts, Frank; Malhotra-Kumar, Surbhi; Timbermont, Leen; Oliver, Antonio; Barraud, Olivier; Bellamy, Terramika; Bonten, Marc; Goossens, Herman; Reisner, Colin; Esser, Mark T; Jafri, Hasan S; COMBACTE-MAGNET EVADE Study GroupBackground
Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects.Methods
EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee.Results
Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: - 23.7%; 80% confidence interval [CI] - 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups.Conclusions
The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.