Testing the feasibility of operationalizing a prospective, randomized trial with remote cardiac safety EKG monitoring during a pandemic.

BACKGROUND: The coronavirus SARS-CoV-2 is highly contagious. Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2. The FDA authorized emergency use of HCQ against COVID-19. HCQ may have dose-related cardiotoxicity. This clinical trial received ethical approval on May 15, 2020, operationalized in June to evaluate a low prophylaxis dose of HCQ (200mg BID) in household contacts of COVID-19-positive patients without physical contact between investigators and participants. It represents the first report of the FDA approved 6-lead EKGs with a smartphone KardiaMobile® 6L application. METHODS: To reach a sample size of 170, household members were contacted by telephone, emailed consent forms with electronic signature capability, and randomized 2:1 to HCQ or observation for 10 days with follow-up of 14 days. Home saliva PCR tests recorded COVID status on days 1 and 14. Symptoms and 6-lead EKGs were obtained daily. RESULTS: Fifty-one participants were randomized with 42 evaluable at day 14. Remote monitoring of 407 EKGs revealed no QTc prolongation or other ECG changes in either group. At time of consent, no participants were symptomatic or COVID+. On days 1 and 14, COVID tests were positive in 4 and 2 in the HCQ group and 4 and 0 in the observation group. No tests converted to positive. There were no deaths or hospitalizations. CONCLUSIONS: A clinical trial without personal contact, rapidly initiated and operationalized to exclude cardiac toxicity using daily remote 6-lead EKG monitoring, is feasible. Of 407 EKGs from 42 participants, there was no evidence of cardiac toxicity. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov : NCT04652648 registration date: December 3, 2020.

The future is now: our experience starting a remote clinical trial during the beginning of the COVID-19 pandemic.

BACKGROUND: The World Health Organization declared the outbreak of SARS-CoV-2 a pandemic on February 11, 2020. This organism causes COVID-19 disease and the rapid rise in cases and geographic spread strained healthcare systems. Clinical research trials were hindered by infection control measures discouraging physical contact and diversion of resources to meet emergent requirements. The need for effective treatment and prevention of COVID-19 prompted an untested investigational response. Trial groups adapted approaches using remote enrolment and consenting, newly developed diagnostic tests, delivery of study medications and devices to participants' homes, and remote monitoring to ensure investigator/enrollee safety while preserving ethical integrity, confidentiality, and data accuracy. METHODS: Clinical researchers at our community health system in the USA undertook an outpatient randomized open-label study of hydroxychloroquine (HCQ) prophylaxis versus observation of SARS-CoV-2 infection in household COVID-19 contacts. Designed in March 2020, challenges included COVID-19 infection in the research group, HCQ shortage, and lack of well-established home SARS-CoV-2 tests and remote ECG monitoring protocols in populations naive to these procedures. The study was written, funded, and received ethical committee approval in 4 months and was completed by September 2020 during a period of fluctuating infection rates and conflicting political opinions on HCQ use; results have been published. Singular methodology included the use of a new RNA PCR saliva SARS-CoV-2 home diagnostic test and a remote smartphone-based 6-lead ECG recording system. RESULTS: Of 483 households contacted regarding trial participation, 209 (43.3%) did not respond to telephone calls/e-mails and 90 (18.6%) declined; others were not eligible by inclusion or exclusion criteria. Ultimately, 54 individuals were enrolled and 42 completed the study. Numbers were too small to determine the efficacy of HCQ prophylaxis. No serious treatment-related adverse events were encountered. CONCLUSIONS: Flexibility in design, a multidisciplinary research team, prompt cooperation among research, funding, ethics review groups, and finding innovative study approaches enabled this work. Concerns were balancing study recruitment against unduly influencing individuals anxious for protection from the pandemic and exclusion of groups based on lack of Internet access and technology. An issue to address going forward is establishing research cooperation across community health systems before emergencies develop. TRIAL REGISTRATION: ClinicalTrials.gov NCT04652648 . Registered on December 3, 2020.

Bacterial and fungal growth in sputum cultures from 165 COVID-19 pneumonia patients requiring intubation: evidence for antimicrobial resistance development and analysis of risk factors.

BACKGROUND: Coronavirus SARS-CoV-2 causes COVID-19 illness which can progress to severe pneumonia. Empiric antibacterials are often employed though frequency of bacterial coinfection superinfection is debated and concerns raised about selection of bacterial antimicrobial resistance. We evaluated sputum bacterial and fungal growth from 165 intubated COVID-19 pneumonia patients. Objectives were to determine frequency of culture positivity, risk factors for and outcomes of positive cultures, and timing of antimicrobial resistance development. METHODS: Retrospective reviews were conducted of COVID-19 pneumonia patients requiring intubation admitted to a 1058-bed four community hospital system on the east coast United States, March 1 to May 1, 2020. Length of stay (LOS) was expressed as mean (standard deviation); 95% confidence interval (95% CI) was computed for overall mortality rate using the exact binomial method, and overall mortality was compared across each level of a potential risk factor using a Chi-Square Test of Independence. All tests were two-sided, and significance level was set to 0.05. RESULTS: Average patient age was 68.7 years and LOS 19.9 days. Eighty-three patients (50.3% of total) originated from home, 10 from group homes (6.1% of total), and 72 from nursing facilities (43.6% of total). Mortality was 62.4%, highest for nursing home residents (80.6%). Findings from 253 sputum cultures overall did not suggest acute bacterial or fungal infection in 73 (45%) of 165 individuals sampled within 24 h of intubation. Cultures ≥ 1 week following intubation did grow potential pathogens in 72 (64.9%) of 111 cases with 70.8% consistent with late pneumonia and 29.2% suggesting colonization. Twelve (10.8% of total) of these late post-intubation cultures revealed worsened antimicrobial resistance predominantly in Pseudomonas, Enterobacter, or Staphylococcus aureus. CONCLUSIONS: In severe COVID-19 pneumonia, a radiographic ground glass interstitial pattern and lack of purulent sputum prior to/around the time of intubation correlated with no culture growth or recovery of normal oral flora ± yeast. Discontinuation of empiric antibacterials should be considered in these patients aided by other clinical findings, history of prior antimicrobials, laboratory testing, and overall clinical course. Continuing longterm hospitalisation and antibiotics are associated with sputum cultures reflective of hospital-acquired microbes and increasing antimicrobial resistance. TRIAL REGISTRATION: Not applicable as this was a retrospective chart review study without interventional arm.

Increasing Babesiosis in Southeastern Pennsylvania, 2008-2017.

Tick-borne illnesses are increasing but are often underreported. Few cases of babesiosis have been reported from Pennsylvania. Our 4-hospital system in southeastern Pennsylvania saw a rise in cases from 7 or fewer yearly in 2008-2014 to 26 cases in 2015. There appear to be multiple potential causes of this increase in frequency.

A multicentre surveillance study on the characteristics, bacterial aetiologies and in vitro antibiotic susceptibilities in patients with acute exacerbations of chronic bronchitis.

BACKGROUND AND OBJECTIVE: Antimicrobial resistance is a global problem and the prevalence is high in many Asian countries. METHODS: A prospective observational study of the prevalence of bacterial pathogens and their antimicrobial susceptibilities in patients with acute exacerbations of chronic bronchitis (AECB) was conducted in Indonesia, Philippines, Korea, Thailand, Malaysia, Taiwan and Hong Kong from August 2006 to April 2008. The diagnosis of AECB was based on increased cough and worsening of two of following: dyspnoea, increased sputum volume or purulence. Patients who had taken antibiotics within 72 h of presentation were excluded. All bacterial strains were submitted to a central laboratory for re-identification and antimicrobial susceptibility testing to 16 antimicrobial agents according to Clinical and Laboratory Standards Institute. RESULTS: Four hundred and seven isolates were identified among 447 patients of AECB. The most frequent organisms isolated were Klebsiella pneumoniae and associated species (n = 91 + 17), Haemophilus influenzae (n = 71), Pseudomonas aeruginosa (n = 63), Streptococcus pneumoniae (n = 32), Acinetobacter baumannii (n = 22) and Moraxella catarrhalis (n = 21). According to Clinical and Laboratory Standards Institute susceptibility breakpoints, 85.7% and >90% of these pathogens were susceptible to levofloxacin and cefepime respectively. Other options with overall lower susceptibilities include imipenem, ceftazidime, ceftriaxone and amoxicillin/clavulanate. CONCLUSIONS: Gram-negative bacteria including Klebsiella spp., P. aeruginosa and Acinetobacter spp. constitute a large proportion of pathogens identified in patients with AECB in some Asian countries. Surveillance on the local prevalence and antibiotic resistance of these organisms is important in guiding appropriate choice of antimicrobials in the management of AECB.

Safety profile of the fluoroquinolones: focus on levofloxacin.

The fluoroquinolone class of antibacterial agents are among the most frequently prescribed drugs, with utility in a broad range of bacterial infections. Although very useful agents, the fluoroquinolones as a class are associated with a number of adverse events, some with considerable clinical significance. In the past 15-20 years, tolerability concerns have led to restrictions on the use of the fluoroquinolones and, in some instances, the withdrawal of agents from the market. This review focuses on the safety and tolerability of levofloxacin, a third-generation fluoroquinolone, relative to other fluoroquinolones. A literature search was performed of the MEDLINE database encompassing the dates 1980-2009, using as keywords the drug names levofloxacin and concurrently marketed fluoroquinolones combined with the words 'safety', 'adverse effect' or 'adverse drug reaction', or the name of the specific adverse effect. Adverse events commonly associated with the fluoroquinolones include gastrointestinal and CNS toxicity (most frequently headache and dizziness), as well as other adverse events including ECG abnormalities (for example QT interval prolongation), disrupted glucose metabolism, phototoxicity, tendon and joint disorders, hypersensitivity and skin disorders, and hepatic toxicity. Package inserts for the fluoroquinolones in Europe and the US contain warnings regarding these risks. US package inserts also carry 'black-box' warnings regarding the risk of tendon rupture and joint disorders with these agents; however, there is a substantial body of evidence to indicate that there are marked differences in the tolerability profiles of the individual agents within the fluoroquinolone class. These differences may be explained, at least in part, by structural differences: all fluoroquinolones share a basic quinolone core, with differences in specific side chains underlying the adverse event relationships. Furthermore, many of the fluoroquinolone-associated adverse effects and toxicities occur more frequently in patients with pre-existing risk factors, or in certain subpopulations. Notably, package inserts for the fluoroquinolones carry warnings regarding use in the elderly, paediatric patients and patients with pre-existing, or factors predisposing to, seizure disorders. Because of this, many adverse reactions with these agents could be prevented by improving patient screening and education. The recent withdrawal of gatifloxacin due to dysglycaemia makes it timely to review the safety and tolerability of the individual agents in this class. Overall, it appears that levofloxacin is relatively well tolerated, with low rates of clinically important adverse events such as CNS toxicity, cardiovascular toxicity and dysglycaemia.

Use of the respiratory fluoroquinolones for the outpatient management of community-acquired pneumonia.

BACKGROUND: Approximately 4 million cases of community-acquired pneumonia (CAP) occur in the United States each year, with the majority treated on an outpatient basis. The first fluoroquinolones (eg, ciprofloxacin) were used with caution for respiratory tract infections due to limited in vitro activity against common gram-positive pathogens. With the availability of levofloxacin, followed by gatifloxacin and moxifloxacin hydrochloride, which exhibited increased activity against gram-positive organisms, the fluoroquinolones have become a practical choice for the treatment of CAP. OBJECTIVE: The aim of this review was to compare the respiratory fluoroquinolones in the outpatient management of CAP. METHODS: We conducted a search for English-language articles (key terms: fluoroquinolone, levofloxacin, gatifloxacin, moxifloxacin, and pneumonia; years: 1996-2004). Data from published literature were reviewed regarding clinical and microbiologic efficacy and tolerability; pharmacokinetic and pharmacodynamic properties; and drug costs of levofloxacin, gatifloxacin, and moxifloxacin. RESULTS: The 3 fluoroquinolones reviewed showed comparable clinical and microbiologic efficacy for the treatment of CAP. In general, the fluoroquinolones were well tolerated, although some differences have been reported, including higher rates of gastrointestinal and other adverse events for gatifloxacin and moxifloxacin. Gatifloxacin and moxifloxacin exhibited greater in vitro potency than levofloxacin against Streptococcus pneumoniae. However, levofloxacin achieved a higher serum drug concentration than the other agents, allowing similar attainment of pharmacokinetic and pharmacodynamic targets required for effective treatment. CONCLUSIONS: The respiratory fluoroquinolones provided appropriate first line treatment in select patients with CAP on the basis of their microbiologic and clinical efficacy and their safety profiles.

A large outbreak of histoplasmosis among American travelers associated with a hotel in Acapulco, Mexico, spring 2001.

During spring 2001, college students from Pennsylvania reported an acute febrile respiratory illness after returning from spring break vacation in Acapulco, Mexico. Acute pulmonary histoplasmosis was presumptively diagnosed and the cluster of illness was reported to the Centers of Disease Control and Prevention. A large investigation then ensued, which included finding student-travelers for interviews and requesting sera for histoplasmosis testing. We defined a clinical case by fever and at least one of the following: cough, shortness of breath, chest pain, or headache, in an Acapulco traveler during March-May 2001. A laboratory-confirmed case had positive serology. An initial study determined that the likely site of histoplasmosis exposure was Hotel H; we therefore performed a large cohort study among travelers who stayed at Hotel H. Of 757 contacted, 262 (36%) met the clinical case definition. Of 273 serum specimens tested, 148 (54%) were positive. Frequent use of Hotel H's stairwells, where construction was ongoing, was associated with increased risk of illness (relative risk = 10.5, 95% confidence interval = 3.7-30.5; P < 0.001). This is the first histoplasmosis outbreak associated with a hotel undergoing construction. Hotels in endemic areas should consider construction precaution measures to prevent histoplasmosis among their guests.