Charlotte Lanteri’s research while affiliated with Uniformed Services University of the Health Sciences and other places

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Publications (77)


Figure 1. Caudal fin morphology of 3 dpf zebrafish. (A) Normal of caudal fin of control fish with no LPS exposure. (B) Caudal fin after 24 h of 60 µg/mL of P. aeruginosa LPS resulting in a tail edema and vascular leakage.
Figure 5. Drug efficacy concentration range response curves for the top 16 rescue drugs. * = p ≤ 0.05, ** = p ≤ 0.01, and *** = p ≤ 0.001. n = 16 for each test condition.
Hit rates for compound libraries tested.
Summary results, receptor targets, and drug owners for top five rescue drugs.
Identification of Potential Sepsis Therapeutic Drugs Using a Zebrafish Rapid Screening Approach
  • Article
  • Full-text available

December 2024

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11 Reads

Life

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Chance Carbaugh

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William van der Schalie

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[...]

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Charlotte Lanteri

In the military, combat wound infections can progress rapidly to life-threatening sepsis. The discovery of effective small-molecule drugs to prevent and/or treat sepsis is a priority. To identify potential sepsis drug candidates, we used an optimized larval zebrafish model of endotoxicity/sepsis to screen commercial libraries of drugs approved by the U.S. Food and Drug Administration (FDA) and other active pharmaceutical ingredients (APIs) known to affect pathways implicated in the initiation and progression of sepsis in humans (i.e., inflammation, mitochondrial dysfunction, coagulation, and apoptosis). We induced endotoxicity in 3- and 5-day post fertilization larval zebrafish (characterized by mortality and tail fin edema (vascular leakage)) by immersion exposure to 60 µg/mL Pseudomonas aeruginosa lipopolysaccharide (LPS) for 24 h, then screened for the rescue potential of 644 selected drugs at 10 µM through simultaneous exposure to LPS. After LPS exposure, we used a neurobehavioral assay (light-dark test) to further evaluate rescue from endotoxicity and to determine possible off-target drug side effects. We identified 29 drugs with > 60% rescue of tail edema and mortality. Three drugs (Ketanserin, Tegaserod, and Brexpiprazole) produced 100% rescue and did not differ from the controls in the light-dark test, suggesting a lack of off-target neurobehavioral effects. Further testing of these three drugs at a nearly 100% lethal concentration of Klebsiella pneumoniae LPS (45 µg/mL) showed 100% rescue from mortality and 88–100% mitigation against tail edema. The success of the three identified drugs in a zebrafish endotoxicity/sepsis model warrants further evaluation in mammalian sepsis models.

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Figure 1: Dose response curves for 3 dpf zebrafish (top graph) and 5 dpf zebrafish (bottom graph) to 24 hour expsures to LPS derived from E.coli 0111:B4, P. aeruginosa, and K. pneumoniae.
Table 1
Figure 2: Caudal fin morphology of 3 dpf zebrafish. A. Images depict normal of caudal fin of control fish with no LPS exposure. B. Images depict the caudal fin after 24 hours of 60 µg/mL of P. aeruginosa LPS resulting in a tail emdema and vascular leakage.
Figure 3: LPS dose response curves for replicate tests during the optimization phase of assay development. The left graph depicts the percentage of fish with tail edemas to increasing P. aeruginosa LPS concentrations. The right graph depicts of the number of dead fish to increasing P. aeruginosa LPS concentrations. The goal was to determine a concentration that yielded close to 50% mortality while eliciting 100% combined tail edema and mortality in all fish. A concentration of 60 µg/mL of P. aeruginosa LPS was chosen for follow-on chemical screening.
Figure 5: Drug efficacy dose range response curves for the top 16 rescue drugs. * = p-value ≤ 0.05, ** = p-value ≤ 0.01, and *** = p-value ≤ 0.001. n = 16 for each test condition.
Identification of potential sepsis therapeutic drugs using a zebrafish rapid screening approach

October 2024

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23 Reads

In the military, combat wound infections can progress rapidly to life-threatening sepsis. Discovery of effective small molecule drugs to prevent and/or treat sepsis is a priority. To identify potential sepsis drug candidates, we used an optimized larval zebrafish model of endotoxicity/sepsis (Philip et al., 2017) to screen commercial libraries of U.S. Food and Drug Administration (FDA)- approved drugs and other active pharmaceutical ingredients (API) known to affect pathways implicated in the initiation and progression of sepsis in humans (i.e., inflammation, mitochondrial dysfunction, coagulation, and apoptosis). We induced endotoxicity in 3- and 5-day post fertilization larval zebrafish (characterized by mortality and tail fin edema (vascular leakage)) by immersion exposure to Pseudomonas aeruginosa 60 μg/mL lipopolysaccharide (LPS) for 24 hours, then screened for the rescue potential of 644 selected drugs simultaneously with LPS at 10 μM. After LPS exposure, we used a neurobehavioral assay (light-dark test) to further evaluate rescue from endotoxicity and to determine possible off-target drug side effects. We identified 29 drugs with > 60% rescue of tail edema and mortality. Three drugs (Ketanserin, Tegaserod, and Brexpiprazole) produced 100% rescue and did not differ from the controls in the light-dark test, suggesting a lack of off-target neurobehavioral effects. Further testing of these three drugs at a nearly 100% lethal concentration of Klebsiella pneumoniae LPS (45 μg/mL) showed 100% rescue from mortality and 88%-100% mitigation against tail edema. The success of the three identified drugs in a zebrafish endotoxicity/sepsis model warrants further evaluation in mammalian sepsis models.


Figure 3. Total number of (A) lactose-fermenting Gram-negative bacilli and (B) nonlactose-fermenting Gram-negative bacilli bloodstream infection (BSI) episodes and deaths, including occurrence of difficult-to-treat resistance (DTR). Of the 16 DTR BSI episodes with deaths, one patient had two different DTR GNB (Pseudomonas aeruginosa and Klebsiella pneumoniae) on the same day and one patient had a polymicrobial BSI (DTR P. aeruginosa plus three susceptible pathogens: Enterococcus spp., K. pneumoniae, and Staphylococcus aureus)
Demographics, Epidemiology, Mortality, and Difficult-To-Treat Resistance Patterns of Bacterial Bloodstream Infections in the Global United States Military Health System from 2010-2019: A Retrospective Cohort Study

October 2024

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20 Reads

Objective: To describe demographics, causative pathogens, hospitalization, mortality, and antimicrobial resistance of bacterial bloodstream infections (BSIs) among beneficiaries in the global U.S. Military Health System (MHS), a single-provider healthcare system with 10-year longitudinal follow-up. Design: Retrospective cohort study Setting: Clinical and demographic data collected from the MHS Data Repository and collated with microbiological data obtained from the Defense Centers for Public Health-Portsmouth. Participants: 12,748 MHS beneficiaries diagnosed with 15,357 bacterial BSIs (2010-2019). Main Outcome(s) and Measure(s): Demographic data and diagnosis codes preceding BSI episodes and during hospitalizations were collected. Inpatient admission data identified acute clinical diagnoses, intensive care unit (ICU) admission, and mortality. BSI pathogens were evaluated for antimicrobial resistance, including difficult-to-treat resistance (DTR). Crude mortality trends were assessed. Results: The decade analyzed included 15,357 BSI episodes in 12,748 patients; 6,216 patients (48.8%) were ≥65 years and 83.7% of episodes had ≥1 comorbidity (12,856 of 15,357). Approximately 29% of episodes with hospitalization required ICU admission and ~34% had concurrent urinary tract infections. Pathogen distribution was 53% and 47% for Gram-positive bacteria and Gram-negative bacilli (GNB), respectively. Inpatient mortality was 4.4%, and at one year was 23.4%; 0.5% (16 of 2,977) of deaths were associated with DTR GNB. Among an average 8,145,778 individuals receiving care annually in the MHS, annual rates of overall BSI, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and DTR GNB BSI were 18.9, 1.30, 0.25, and 0.05 per 100,000 beneficiaries, respectively. Over the decade, annual mortality did not significantly increase for any pathogen and decreased by ~3% for lactose-fermenting GNB BSI (p=0.048). Conclusions: In the global U.S. MHS, mortality burden associated with BSI was substantial (approximately 1 in 4 dying at 1 year), relatively unchanged over a decade, and associated with older age and comorbidities. First-line treatment options remained available for 99.7% of BSIs. Population-level improvements in BSI survival might be maximally influenced by focusing on prevention, early detection, prompt antibiotics, and other novel therapies not contingent on in vitro activity.


The risk and risk factors of chikungunya virus infection and rheumatological sequelae in a cohort of U.S. Military Health System beneficiaries: Implications for the vaccine era

August 2024

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20 Reads

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2 Citations

Background Understanding the risk of chikungunya virus (CHIKV) infection and rheumatic sequelae across populations, including travelers and the military, is critical. We leveraged healthcare delivery data of over 9 million U.S. Military Health System (MHS) beneficiaries to identify cases, and sampled controls, to estimate the risk of post-CHIKV rheumatic sequelae. Methodology/principal findings MHS beneficiary CHIKV infections diagnosed 2014–2018 were identified from the Disease Reporting System internet, TRICARE Encounter Data Non-Institutional, and Comprehensive Ambulatory/Professional Encounter Record systems. Non-CHIKV controls were matched (1:4) by age, gender, beneficiary status, and encounter date. The frequency of comorbidities and incident rheumatic diagnoses through December 2018 were derived from International Classification of Diseases codes and compared between cases and controls. Poisson regression models estimated the association of CHIKV infection with rheumatic sequelae. We further performed a nested case-control study to estimate risk factors for post-CHIKV sequelae in those with prior CHIKV. 195 CHIKV cases were diagnosed between July 2014 and December 2018. The median age was 42 years, and 43.6% were active duty. 63/195 (32.3%) of CHIKV cases had an incident rheumatic diagnosis, including arthralgia, polyarthritis, polymyalgia rheumatica, and/or rheumatoid arthritis, compared to 156/780 (20.0%) of controls (p < 0.001). CHIKV infection remained associated with rheumatic sequelae (aRR = 1.579, p = 0.008) after adjusting for prior rheumatic disease and demography. Those with rheumatic CHIKV sequelae had a median 7 healthcare encounters (IQR 3–15). Among CHIKV infections, we found no association between post-CHIKV rheumatic sequelae and demography, service characteristics, or comorbidities. Conclusions/significance CHIKV infection is uncommon but associated with rheumatic sequelae among MHS beneficiaries, with substantial healthcare requirements in a proportion of cases with such sequelae. No demographic, clinical, or occupational variables were associated with post-CHIKV rheumatic sequelae, suggesting that prediction of these complications is challenging in MHS beneficiaries. These findings are important context for future CHIKV vaccine decision making in this and other populations.


PKPD indices to support breakpoint decision making.
Cont.
Comparison of epidemiologic cutoffs and breakpoints.
Animal Models in Regulatory Breakpoint Determination: Review of New Drug Applications of Approved Antibiotics from 2014–2022

January 2024

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20 Reads

Journal of Personalized Medicine

We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014–2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes.


The risk and risk factors of chikungunya virus infection and rheumatological sequelae in a cohort of U.S. Military Health System beneficiaries: implications for the vaccine era

November 2023

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29 Reads

Background Understanding the risk of chikungunya virus (CHIKV) infection and rheumatic sequelae across populations, including travelers and the military, is critical. We leveraged the electronic medical records of about 9.5 million U.S. Military Health System (MHS) beneficiaries to identify the risk of post-CHIKV rheumatic sequelae. Methodology/Principal Findings MHS beneficiary CHIKV infections diagnosed 2014–2018 were identified from the Disease Reporting System internet, TRICARE Encounter Data Non-Institutional, and Comprehensive Ambulatory/Professional Encounter Record systems. Non-CHIKV controls were matched (1:4) by age, gender, beneficiary status, and encounter date. The frequency of comorbidities and incident rheumatic diagnoses through 2020 were derived from International Classification of Diseases codes and compared between cases and controls. Logistic regression models estimated the association of CHIKV infection with rheumatic sequelae and risk factors for post-CHIKV sequelae. 195 CHIKV cases were diagnosed between July 2014 and December 2018. The mean age was 42 years, and 43.6% were active duty. 63/195 (32.3%) of CHIKV cases had an incident rheumatic diagnosis, including arthralgia, polyarthritis, polymyalgia rheumatica, and/or rheumatoid arthritis, compared to 156/780 (20.0%) of controls (p < 0.001). CHIKV infection remained associated with rheumatic sequelae (aOR = 1.911, p = 0.002) after adjusting for prior rheumatic disease and demography. Those with rheumatic CHIKV sequelae had a median 7 healthcare encounters (IQR 3–15). Among CHIKV infections, we found no association between post-CHIKV rheumatic sequelae and demography, service characteristics, or comorbidities. Conclusions/Significance CHIKV infection is uncommon but associated with rheumatic sequelae among MHS beneficiaries, with substantial healthcare requirements in a proportion of cases with such sequelae. No demographic, clinical, or occupational variables were associated with post-CHIKV rheumatic sequelae, suggesting that prediction of these complications is challenging in MHS beneficiaries. These findings are important context for future CHIKV vaccine decision making in this and other populations. Author summary We examined U.S. Military Health System (MHS) electronic medical records during to identify the likelihood of rheumatic complications after chikungunya virus (CHIKV) infection. Overall, CHIKV infections were rare in the MHS, with 195 cases found in the records between 2014 and 2018 (a period which encompassed the peak of the CHIKV epidemic in the Americas). Of these, about 32% received a rheumatic diagnosis after infection, including arthralgia, polyarthritis, polymyalgia rheumatica, and rheumatoid arthritis. Patients who had a rheumatic diagnosis had on average 7 healthcare encounters for their post-CHIKV rheumatic complication, and a quarter had more than 15 healthcare encounters. We did not find any demographic, clinical, or occupational characteristics associated with developing rheumatic complications after CHIKV, suggesting that predicting rheumatic complications from CHIKV may be challenging in MHS beneficiaries. These findings may provide important context for decisions about implementing an approved chikungunya vaccine to military servicemembers and other MHS beneficiaries.


Figure 3. Box plots of markers selected in stepwise regression to identify characteristic biomarkers of each cluster: Ferritin (A), IL1RA (B), RAGE (C), and VEGFA (D) by cluster. Kruskal-Wallis test performed comparing analyte levels between clusters. **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.
Comparison of the Ella biomarkers across TDA clusters. For each subject, one sample was selected based on highest coefficient of variation. *Distributions among all clusters compared using a Kruskal-Wallis test. Significant values are in bold.
Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

December 2022

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103 Reads

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6 Citations

The associations between clinical phenotypes of coronavirus disease 2019 (COVID-19) and the host inflammatory response during the transition from peak illness to convalescence are not yet well understood. Blood plasma samples were collected from 129 adult SARS-CoV-2 positive inpatient and outpatient participants between April 2020 and January 2021, in a multi-center prospective cohort study at 8 military hospitals across the United States. Plasma inflammatory protein biomarkers were measured in samples from 15 to 28 days post symptom onset. Topological Data Analysis (TDA) was used to identify patterns of inflammation, and associations with peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated using logistic regression. The study population (n = 129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct inflammatory biomarker clusters were identified and were associated with significant differences in peak disease severity (p < 0.001), age (p < 0.001), BMI (p < 0.001), and CCI (p = 0.001). Host-biomarker profiles stratified a heterogeneous population of COVID-19 patients during the transition from peak illness to convalescence, and these distinct inflammatory patterns were associated with comorbid disease and severe illness due to COVID-19.


1830. Epidemiology of Recurrent Bacterial Bloodstream Infections in the US Military Health System

December 2022

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23 Reads

Open Forum Infectious Diseases

Background The epidemiology of recurrent bacterial bloodstream infections (rBSI) has not been fully characterized. Evaluating rBSI represents opportunities to inform morbidity risk factors and prevention strategies. We describe the clinical and microbiological features of rBSI in the US Military Health System (MHS) in a prospective cohort study, including retired and active-duty US uniformed service members and their beneficiaries. Methods We collected data for rBSI episodes from MHS beneficiaries (Jan 2010 – Dec 2019). A rBSI is defined as growth of the same bacterial pathogen in blood culture >14 days after the index or previous episode. Demographics and comorbidities were collected prior to the index BSI. Microbiological data were obtained from the Navy and Marine Corps Public Health Center. Descriptive statistics are presented. Results A total of 12,749 beneficiaries were diagnosed with a BSI attributed to 1 of the 15 most common bacterial pathogens associated with BSI in the MHS, with 646 (5.1%) experiencing a rBSI. Escherichia coli had the largest proportion among all patients with rBSI (31% of 646); however, Enterococcus spp. accounted for the highest proportion of rBSI within a given pathogen subgroup (7.4% of 1,154 Enterococcus BSI; Table). Pseudomonas aeruginosa BSI had the shortest average time to recurrence (119 days), and Acinetobacter spp. had the highest frequency of BSI recurrences per patient (mean of 3). Male sex (59.9%) and age ≥65 years (52.9%) were most common among the rBSI patients. The updated Charlson Comorbidity index score preceding the index BSI was a median of 5.0, and chronic pulmonary disease (57.3%) and diabetes (56.6%) contributed the largest proportion of common comorbidities. A total of 88 (13%) rBSI patients had their index BSI while hospitalized following trauma where S. aureus was the most common (37.5%) bacterial pathogen. Conclusion Overall, the proportion of rBSI (5.1%) in our cohort of MHS beneficiaries was generally lower than that previously reported in the literature. Individuals with rBSI had a substantial burden of comorbid disease with 13% having trauma precede the index BSI. Identifying risk factors for recurrence may improve management strategies of primary BSI and may reduce morbidity of subsequent BSI. Disclosures John H. Powers, III, MD, Arrevus: Advisor/Consultant|Eicos: Advisor/Consultant|Evofem: Advisor/Consultant|Eyecheck: Advisor/Consultant|Gilead: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|OPKO: Advisor/Consultant|Resolve: Advisor/Consultant|Romark: Advisor/Consultant|SpineBioPharma: Advisor/Consultant|UTIlity: Advisor/Consultant|Vir: Advisor/Consultant.


80. SARS-CoV-2 infection is associated with decreased reported physical fitness in a US military longitudinal cohort

December 2022

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30 Reads

Open Forum Infectious Diseases

Background COVID-19 may have deleterious effects on the fitness of active duty US military service members. We seek to understand the long-term functional consequences of SARS-CoV-2 infection in this critical population, and in other military healthcare beneficiaries. Methods The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal cohort study to describe the outcomes of SARS-CoV-2 infection in US Military Health System beneficiaries. Subjects provided information about difficulties experienced with daily activities, exercise, and physical fitness performance via electronic surveys. Subjects completed surveys at enrollment and at 1, 3, 6, 9, and 12 months. Results 5,910 subjects completed survey fitness questions, 3,244 (55%) of whom tested SARS-CoV-2 positive at least once during the period of observation. Over 75% of subjects were young adults and over half were male (Table 1). 1,093 (34.3%) of SARS-CoV-2-positive subjects reported new or increased difficulty exercising compared to 393 (14.8%) SARS-CoV-2 negative subjects (p < 0.01) (Table 2). The most commonly reported symptoms related to problems with exercise and activities were dyspnea and fatigue. Among the active-duty members who answered the question about their service-mandated physical fitness test scores, 43.2% of SARS-CoV-2-positive participants reported that their scores had worsened in the study period, compared with 24.3% of SARS-CoV-2 negative participants. Among SARS-CoV-2-positive subjects, reports of difficulty exercising and performing daily activities were highest within one month of the first positive test, decreasing in prevalence among the cohort only slightly to 24% and 18%, respectively, at 12 months (Figure 1). Conclusion A substantial proportion of military service-members in this cohort have reported impairment of their service-mandated physical fitness scores after COVID-19; this proportion is significantly higher than those who are SARS-CoV-2 negative and persists to 12 months in many; similar complaints were reported among non-active duty. Further objective evaluation of post-COVID fitness impairment in this population is warranted. Disclosures Ryan C. Maves, MD, AiCuris: Grant/Research Support|Sound Pharmaceuticals: Grant/Research Support|Trauma Insights, LLC: Advisor/Consultant Julia S. Rozman, n/a, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Mark P. Simons, PhD, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.


1831. Longitudinal Changes in Antimicrobial-resistant Bacterial Bloodstream Infections in the US Military Health System from 2010-2019

December 2022

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28 Reads

Open Forum Infectious Diseases

Background The epidemiology of antibiotic-resistant pathogens guides antimicrobial therapy for bacterial bloodstream infections (BSI). We describe changes in antimicrobial-resistant BSI pathogens over time within the US Military Health System (MHS), which prospectively captures clinical and microbiological data from both retired and active-duty US Uniformed service members and their beneficiaries. Methods The study population included MHS beneficiaries with blood cultures positive for any bacterial pathogens (Jan 2010 – Dec 2019). Microbiological data were obtained from the Navy and Marine Corps Public Health Center and antibiotic resistance was interpreted using CLSI breakpoints corresponding to collection year. Blood contaminants were excluded. Difficult to treat resistance (DTR) was defined in Gram-negative bacteria (GNB) as isolates with in vitro resistance to three classes of antibiotics: carbapenems, extended-spectrum cephalosporins, and fluoroquinolones. Results The 15 most frequent bacterial pathogens, representing 15,358 BSI episodes from 12,749 individuals, were subcategorized in four groups based on shared BSI clinical features. Lactose-fermenting GNB (LFGNB) were most common, accounting for 42% of BSI pathogens, following by Streptococcus/Enterococcus spp. (33%), Staphylococcus aureus (20%), and non-lactose fermenting GNB (NLGNB, 5.5%). The rate of LFGNB BSI increased from 7.57 per 100,000 beneficiaries in 2010 to 8.42 in 2019 (peak of 8.83 in 2016), resulting in an increase of 11.3% during the study period (Figure). Rates of BSI attributed to Streptococcus/Enterococcus spp., S. aureus, and NLGNB decreased 26%, 29%, and 45%, respectively, over the study period. The average annual rates of methicillin-resistant S. aureus, vancomycin-resistant Enterococcus spp., and DTR GNB BSI were 1.30, 0.25, and 0.05 per 100,000 beneficiaries, respectively. Over the study period, these rates decreased 58.3%, 72.4% and 24.2%, respectively. Conclusion LFGNB BSI numerically increased over time while NLGNB BSI (e.g., Pseudomonas aeruginosa and Acinetobacter spp.) decreased. The burden of DTR GNB BSI also decreased, indicating that first-line antibiotics remain clinically available for most patients with BSI. Disclosures John H. Powers, III, MD, Arrevus: Advisor/Consultant|Eicos: Advisor/Consultant|Evofem: Advisor/Consultant|Eyecheck: Advisor/Consultant|Gilead: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|OPKO: Advisor/Consultant|Resolve: Advisor/Consultant|Romark: Advisor/Consultant|SpineBioPharma: Advisor/Consultant|UTIlity: Advisor/Consultant|Vir: Advisor/Consultant.


Citations (46)


... Some of these patients may suffer from a long-lasting arthritis akin to rheumatoid arthritis [35,36]. Recently, cases of PMR have been reported in a cohort of U.S. Military Health System beneficiaries [37]. However, the median age was 42 years, and no diagnostic or classification criterion for PMR was specified. ...

Reference:

Infective agents and polymyalgia rheumatica: key discussion points emerging from a narrative review of published literature
The risk and risk factors of chikungunya virus infection and rheumatological sequelae in a cohort of U.S. Military Health System beneficiaries: Implications for the vaccine era

... 19 These traits have helped drive this model's utility and acceptance as evidenced by its common use in translational biomedical research, toxicology, molecular genetics, neurophysiology, and drug discovery. 6,11,13,18,19 The discovery and use of anesthetics that provide safe, reliable, and increasingly longer-duration anesthesia is critical to the continued expansion of the use of zebrafish in research and the development of novel procedures. The ideal surgical anesthetic for zebrafish should provide a reliable, rapid, and consistent surgical plane of anesthesia. ...

An Automated Method for the Assessment of Memory and Learning in Larval Zebrafish

Journal of Psychiatry and Psychiatric Disorders

... A cluster of older patients affected by COVID-19 characterized by high levels of CRP and high mortality rate was also reported by the study of Cidade JP et al. [46]. Using several inflammatory biomarkers drawn from 129 patients with COVID-19 and topological data analysis, Blair PW et al. [47]identified 3 clusters: the cluster exhibiting the highest concentration of inflammatory biomarkers, in particular IL-1RA, was also characterized by the highest age (median 51.8) and the highest mortality and hospitalization rate. ...

Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

... 5,6-orthoquinone (5,6-POQ), a downstream product of 5-hydoxyprimaquine, is detected in RBCs (Khan et al., 2021) with substantial amounts excreted in the urine. (Spring et al., 2019;Luzzatto et al., 2020;Pookmanee et al., 2021;Khan et al., 2022;Vanachayangkul et al., 2022;Pookmanee et al., 2024) This has been interpreted as 5,6-POQ being a relatively stable metabolite, which is useful as a "surrogate" measure to infer the presence of the more hemolytic 5-hydroxy PMs. (Camarda et al., 2019;Fasinu et al., 2019) However, this view presupposes that 5,6-POQ is not itself hemolytic, which to the best of our knowledge has not been directly tested with regards to clearance of G6PDd RBCs. ...

Measurements of 5,6 orthoquinone, surrogate for presumed active primaquine metabolite 5-hydroxyprimaquine, in the urine of Cambodian adults

... Validated survey tools used are described and displayed in the Supplementary Methods, Supplementary Table 2) [5,20]. Participants were asked at each study visit if they had any other symptoms not already listed. ...

Performance of the inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus©) instrument in patients with COVID-19

Open Forum Infectious Diseases

... The apparent opposing selection pressures of LUM on pfmdr1 suggest that DHA-PPQ may be a good choice of partner drug in areas where AL was previously largely used [8-10, 19, 23, 24]. Although some authors [23,25,26] consider pfpm2 amplification sufficient to confer PPQ resistance without additional gene mutations (e.g., P. falciparum chloroquine resistance transporter; pfcrt), others argue that plasmepsin amplification alone is not enough. It may facilitate the selection of mutations in other P. falciparum genes, such as pfcrt, pfmdr1 or P. falciparum exonuclease (pfexo), which could, in turn, enhance PPQ resistance levels [27,28]. ...

Plasmodium falciparum phenotypic and genotypic resistance profile during the emergence of Piperaquine resistance in Northeastern Thailand

... For the antibody binding assay used for screening at enrollment, serum samples were diluted 1:400 and 1:8000 and screened for immunoglobulin G (IgG) reactivity with SARS-CoV-2 spike protein and nucleocapsid protein (N), and four human coronavirus (HCoV) spike proteins using a multiplex microsphere-based immunoassay, as previously described. 54 Post-infection sera from the EPICC study The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a cohort study of U.S. Military Health System (MHS) beneficiaries that includes enrollment and longitudinal follow up of those with a history of SARS-CoV-2 infection. 55 Eligibility criteria for enrollment included presenting to clinical care with COVID-19-like illness and being tested for SARS-CoV-2 by polymerase chain reaction (PCR) assay (See Tables S1A and S1B). ...

Antigen-based multiplex strategies to discriminate SARS-CoV-2 natural and vaccine induced immunity from seasonal human coronavirus humoral responses

... Initially described in chloroquine resistance [83,84], recent studies have demonstrated, more specifically via CRISPR-cas9 mutagenesis, the role of several new mutations (T93S, H97Y, C101F, F145I, I218F, M343L, C350R, and G353V) in the Pfcrt gene in piperaquine resistance [37, [85][86][87][88]. The T93S, H97Y/L F145I, and I218F mutations were identified in Asian isolates and showed in vitro reduced susceptibility to piperaquine [89][90][91][92] 94], were associated with in vitro decreased piperaquine susceptibility and with dihydroartemisinin-piperaquine treatment failure. However, none of these mutations were detected in African isolates [95]. ...

Distribution and temporal dynamics of P. falciparum chloroquine resistance transporter mutations associated with piperaquine resistance in Northern Cambodia
  • Citing Article
  • February 2021

The Journal of Infectious Diseases

... These assays use pathogen-specific antigens covalently bonded to fluorophore-loaded carboxyl beads, facilitating simultaneous identification of multiple pathogen-specific antibodies. MMIAs have been used to detect and differentiate antibodies against viral infections such as human herpesviruses and flaviviruses (e.g., Epstein-Barr, West Nile, Zika, and dengue viruses) (25,26), used to identify SARS-CoV-2 IgG seroconversion (27)(28)(29)(30) and proposed for public health use since the early 2000s (31,32). ...

A betacoronavirus multiplex microsphere immunoassay detects early SARS-CoV-2 seroconversion and antibody cross reactions

... It is currently debated whether prior infection with seasonal HCoVs elicits cross-reactive antibodies against SARS-CoV-2, and more importantly, if this translates into protection against SARS-CoV-2. Cross-reactive antibodies [47][48][49][50][51][52][53][54] and T-cell responses [55][56][57][58][59][60][61] were detected in pre-pandemic sera and healthy donors; however, similar experimental approaches have shown the opposite to be true by other investigators [62]. In addition, in many of the aforementioned articles that revealed cross-reactive antibodies in pre-pandemic samples, the number of cross-reactive samples was a small portion of the total sera analysed, suggesting that cross-reactivity, whilst it exists, is low. ...

A betacoronavirus multiplex microsphere immunoassay detects early SARS-CoV-2 seroconversion and controls for pre-existing seasonal human coronavirus antibody cross-reactivity