Northwell Health, an integrated health system in New York, has treated more than 15,000 inpatients with COVID-19 at the US epicenter of the SARS-CoV-2 pandemic.We describe the demographic characteristics of patients who died of COVID-19, observation of frequent rapid response team/cardiac arrest (RRT/CA) calls for non-intensive care unit (ICU) patients, and factors that contributed to RRT/CA calls.A team of registered nurses reviewed the medical records of inpatients who tested positive for SARS-CoV-2 via polymerase chain reaction before or on admission and who died between March 13 (first Northwell Health inpatient expiration) and April 30, 2020, at 15 Northwell Health hospitals. The findings for these patients were abstracted into a database and statistically analyzed.Of 2634 patients who died of COVID-19, 1478 (56.1%) had oxygen saturation levels ≥90% on presentation and required no respiratory support. At least one RRT/CA was called on 1112/2634 patients (42.2%) at a non-ICU level of care. Before the RRT/CA call, the most recent oxygen saturation levels for 852/1112 (76.6%) of these non-ICU patients were at least 90%. At the time the RRT/CA was called, 479/1112 patients (43.1%) had an oxygen saturation of <80%.This study represents one of the largest reviewed cohorts of mortality that also captures data in nonstructured fields. Approximately 50% of deaths occurred at a non-ICU level of care despite admission to the appropriate care setting with normal staffing. The data imply a sudden, unexpected deterioration in respiratory status requiring RRT/CA in a large number of non-ICU patients. Patients admitted at a non-ICU level of care suffered rapid clinical deterioration, often with a sudden decrease in oxygen saturation. These patients could benefit from additional monitoring (eg, continuous central oxygenation saturation), although this approach warrants further study.
SummaryBackgroundThe broad use of bedaquiline and pretomanid as the mainstay of new regimens to combat tuberculosis is a risk due to increasing bedaquiline resistance. We aimed to assess the safety, bactericidal activity, and pharmacokinetics of BTZ-043, a first-in-class DprE1 inhibitor with strong bactericidal activity in murine models.MethodsThis open-label, dose-expansion, randomised, controlled, phase 1b/2a trial was conducted in two specialised tuberculosis sites in Cape Town, South Africa. Adults aged 18–64 years with newly diagnosed pulmonary tuberculosis sensitive to rifampicin and isoniazid, who weighed at least 40 kg, had a positive sputum smear graded at least 1+, were HIV negative, and had no history of hypertension or other substantial comorbidities were admitted to hospital. In stage 1 (multiple-ascending dose phase 1b with an adaptive continual reassessment method), the starting dose of BTZ-043 was 250 mg, with planned dose increments of 250 mg up to 2000 mg, and cohorts of three participants were enrolled sequentially. In stage 2 (phase 2a dose-expansion stage), participants were randomly assigned (3:3:3:2) to receive one of three doses of oral BTZ-043 (decided after stage 1) or standard of care (isoniazid, rifampicin, pyrazinamide, and ethambutol) using sealed opaque envelopes. The BTZ-043 groups also received oral dolutegravir (a third of participants) or a probe drug cocktail (caffeine [probe for CYP1A2], tolbutamide [CYP2C9], dextromethorphan [CYP2D6], midazolam [CYP3A4], and digoxin [P-glycoprotein]; two-thirds of participants). Study staff and participants were not masked, but laboratory staff were masked to treatment assignment. The primary outcome was to assess the safety and tolerability of BTZ-43 over 14 days of dosing by evaluation of adverse events in the safety analysis population. Secondary outcomes were bactericidal activity, measured by time to positivity (TTP) and colony-forming unit (CFU) count; pharmacokinetics (stage 2; including the food effect on BTZ-043); and drug–drug interactions with CYP450 enzymes, P-glycoprotein, and dolutegravir. This study is registered with ClinicalTrials.gov, NCT04044001 (completed).FindingsIn stage 1, 61 patients were assessed for eligibility and 24 were enrolled into seven dose cohorts between Nov 13, 2019, and Aug 13, 2020. Dose escalations were performed safely up to 1750 mg of BTZ-043 with three participants per dose cohort (and two dose cohorts for the highest dose). In stage 2, 151 patients were assessed for eligibility and 54 were enrolled and randomly assigned between Feb 2, 2021, and Feb 9, 2022, to receive 250, 500, and 1000 mg of BTZ-043 or standard of care. 66 (85%) of 78 participants were male and 12 (15%) were female. The most frequently observed adverse events were nausea (12 [8%] of 154), headache (11 [7%]), dizziness (11 [7%]), and vomiting (eight [5%]). Most participants had adverse events of mild (46 [60%] of 77 participants) or moderate (22 [29%]) severity. Transient increases in alanine aminotransferase were observed in both stages, which declined again despite continued dosing and were classified as signs of adaptation of hepatic metabolism rather than hepatotoxicity. The worsening of pre-existing anaemia and QTcF interval prolongation in one individual each were rated as possibly related to the study drug. One patient died before the first scheduled dose of BTZ-043 500 mg due to a pulmonary embolism. In stage 1, bactericidal activity measured as CFU counts on solid media was highest at doses 750–1500 mg; in stage 2, all doses of BTZ-043 showed 14-day bactericidal activity, highest at 1000 mg on solid media (log10 CFU/mL per day –0·115 [95% CI –0·162 to –0·069]) and TTP estimates were highest at 500 mg in liquid media (log10 h per day 0·015 [0·010 to 0·019]). BTZ-043 pharmacokinetics showed increased exposure with high-fat food versus fasting (area under the curve [AUC]0–last geometric mean ratio 4·13 [90% CI 1·65 to 10·30] for BTZ-043; 2·99 [1·39 to 6·41] for BTZ-043total [BTZ-043 plus metabolite 2]; and 1·25 [0·66 to 2·39] for metabolite 1). When taken with a standard breakfast, BTZ-043total AUC showed a dose-proportional increase up to 33 200 ng/mL × h (range 12 500 to 48 200) at 1000 mg. The maximum concentration (Cmax) increased to 5060 ng/mL (2450 to 8020); and median half-life was 3·72 h (2·45 to 6·60). Probe drug evaluations showed bioequivalence (ie, 90% CI of the AUC0–infinity geometric mean ratio from administration to day 14 entirely within the range of 80 to 125%) for caffeine (100·0% [90% CI 86·3 to 115·9]), digoxin (113·4% [105·9 to 121·5]), and dolutegravir (106·1% [91·5 to 122·9]). Dextromethorphan (116·2% [104·6 to 129·1]), tolbutamide (252·7% [230·7 to 276·9]), and midazolam (77·0% [69·2 to 85·6]) did not meet the bioequivalence criterion.InterpretationBased on a small sample size, BTZ-043 is a promising antituberculosis drug candidate with favourable safety and good bactericidal activity. Larger follow-up studies are needed to detect any less frequent safety signals, further explore drug–drug interactions, identify the best dose, and evaluate efficacy in combination with other drugs.FundingEDCTP2 programme; German Ministry for Education and Research; German Center for Infection Research; InfectControl; Bavarian Ministry for Science and the Arts; Swiss State Secretariat for Education, Research, and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.
Northwell Health (Northwell), an integrated health system in New York, treated more than 15000 inpatients with coronavirus disease (COVID-19) at the US epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We describe the demographic characteristics of COVID-19 mortalities, observation of frequent rapid response teams (RRT)/cardiac arrest (CA) calls for non-intensive care unit (ICU) patients, and factors that contributed to RRT/CA calls.A team of registered nurses reviewed medical records of inpatients who tested positive for SARS-CoV-2 via polymerase chain reaction (PCR) before or on admission and died between March 13 (first Northwell inpatient expiration) and April 30, 2020 at 15 Northwell hospitals. Findings for these patients were abstracted into a database and statistically analyzed.Of 2634 COVID-19 mortalities, 56.1% had oxygen saturation levels greater than or equal to 90% on presentation and required no respiratory support. At least one RRT/CA was called on 42.2% of patients at a non-ICU level of care. Before the RRT/CA call, the most recent oxygen saturation levels for 76.6% of non-ICU patients were at least 90%. At the time RRT/CA was called, 43.1% had an oxygen saturation less than 80%.This study represents one of the largest cohorts of reviewed mortalities that also captures data in non-structured fields. Approximately 50% of deaths occurred at a non-ICU level of care, despite admission to the appropriate care setting with normal staffing. The data imply a sudden, unexpected deterioration in respiratory status requiring RRT/CA in a large number of non-ICU patients. Patients admitted to a non-ICU level of care suffer rapid clinical deterioration, often with a sudden decrease in oxygen saturation. These patients could benefit from additional monitoring (eg, continuous central oxygenation saturation), although this approach warrants further study.
Background: New drugs are needed to combat tuberculosis. BTZ-043 is a promising first-in-class benzothiazinone DprE1 inhibitor with good activity and lesion penetration in mouse models.Methods: We conducted an adaptive two-stage phase 1b/2a dose-finding study using the continual reassessment method with expansion cohort at two sites in Cape Town, South Africa. Participants with pulmonary TB were hospitalized for screening and 14 days of treatment undergoing safety assessments, sputum sampling, and pharmacokinetic studies evaluating food effects and drug-drug-interaction potential.Findings: Among 24 participants in stage 1, dose escalation was conducted safely up to 1750mg daily. In stage 2, 54 participants were randomized to 250mg, 500mg, 1000mg BTZ-043, or control. Mild and moderate nausea were the most frequent AEs. Mild to moderate raises in transaminases were transient and declined despite continued dosing. All doses in stage 2 showed 14-day bactericidal activity, highest with 1000mg at -0.115log10CFU/ml*d (95%CI: -0.162,-0.069). BTZ-043 pharmacokinetics demonstrated a 3-fold exposure increase with high-fat food; probe drug evaluations suggested a moderate inhibition of CYP2C9 activity. BTZ-043 showed an exposure-response with inferior killing on 250mg (fasted).Interpretation: In this innovative phase 1b/2a study, BTZ-043 was active and safe from 250mg to 1750mg over 14 days. BTZ-043 can be safely co-administered with other TB drugs and dolutegravir.Trial Registration: NCT04044001. Funding: EDCTP2 programme (TRIA2015-1102); German Ministry for Education and Research (BMBF, 01KA1701); German Center for Infection Research (DZIF); InfectControl (03ZZ0803A, 03ZZ0835A and 03ZZ0826A); Bavarian Ministry for Science and the Arts; Swiss State Secretariat for Education, Research, and Innovation (SERI); Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).Declaration of Interest: NH, VdJ, JD, PGD, SS, SG, FK, RD, KN, LM, LW, TMcH, CM, LtB, MB, RA, ES, XG, PP, AD, MH declare receiving grant funding for this work from EDCTP, BMBF, DZIF, Bavarian Ministry to their respective institutions. NH, JD, SS, LW, TMcH, CM, LtB, MB, RA, ES, XG, PP, MH declare receiving funding from LegoChem Biosciences for the evaluation of delpazolid to their institutions. ES declares receiving funding to her institution from Janssen Pharmaceuticals for scientific project related to bedaquiline, and from TB Alliance for projects related to paediatric development of pretomanid.Ethical Approval: Participants provided written informed consent and the study was approved by ethics committees of the sites in South Africa and the sponsor in Germany and by the South African Health Products Regulatory Agency (SAHPRA; Ref 20190606).
BACKGROUND Northwell Health, an integrated health system in New York, has treated more than 15,000 inpatients with COVID-19 at the US epicenter of the SARS-CoV-2 pandemic. OBJECTIVE We describe the demographic characteristics of patients who died of COVID-19, observation of frequent rapid response team/cardiac arrest (RRT/CA) calls for non–intensive care unit (ICU) patients, and factors that contributed to RRT/CA calls. METHODS A team of registered nurses reviewed the medical records of inpatients who tested positive for SARS-CoV-2 via polymerase chain reaction before or on admission and who died between March 13 (first Northwell Health inpatient expiration) and April 30, 2020, at 15 Northwell Health hospitals. The findings for these patients were abstracted into a database and statistically analyzed. RESULTS Of 2634 patients who died of COVID-19, 1478 (56.1%) had oxygen saturation levels ≥90% on presentation and required no respiratory support. At least one RRT/CA was called on 1112/2634 patients (42.2%) at a non-ICU level of care. Before the RRT/CA call, the most recent oxygen saturation levels for 852/1112 (76.6%) of these non-ICU patients were at least 90%. At the time the RRT/CA was called, 479/1112 patients (43.1%) had an oxygen saturation of <80%. CONCLUSIONS This study represents one of the largest reviewed cohorts of mortality that also captures data in nonstructured fields. Approximately 50% of deaths occurred at a non-ICU level of care despite admission to the appropriate care setting with normal staffing. The data imply a sudden, unexpected deterioration in respiratory status requiring RRT/CA in a large number of non-ICU patients. Patients admitted at a non-ICU level of care suffered rapid clinical deterioration, often with a sudden decrease in oxygen saturation. These patients could benefit from additional monitoring (eg, continuous central oxygenation saturation), although this approach warrants further study.
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