Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19).

OBJECTIVE: In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a retrospective study. METHODS: Subjects admitted to 11 designated public hospitals in Taiwan between April 1 and May 31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ (400 mg twice for 1 d or HCQ 200 mg twice daily for 6 days) was administered. Both the study and control group received standard of care (SOC). Pharyngeal swabs and sputum were collected every other day. The proportion and time to negative viral PCR were assessed on day 14. In the retrospective study, medical records were reviewed for patients admitted before March 31, 2020. RESULTS: There were 33 and 37 cases in the RCT and retrospective study, respectively. In the RCT, the median times to negative rRT-PCR from randomization to hospital day 14 were 5 days (95% CI; 1, 9 days) and 10 days (95% CI; 2, 12 days) for the HCQ and SOC groups, respectively (p = 0.40). On day 14, 81.0% (17/21) and 75.0% (9/12) of the subjects in the HCQ and SOC groups, respectively, had undetected virus (p = 0.36). In the retrospective study, 12 (42.9%) in the HCQ group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 (p = 0.70). CONCLUSIONS: Neither study demonstrated that HCQ shortened viral shedding in mild to moderate COVID-19 subjects.

Prevalence of and risk factor for community-onset third-generation cephalosporin-resistant Escherichia coli bacteremia at a medical center in Taiwan.

BACKGROUND: Increased resistance to third-generation cephalosporin (3GC) is a serious concern for community-onset Escherichia coli infection because this resistance easily delays effective treatment. This study surveyed the current antimicrobial resistance pattern among E. coli isolates that cause community-onset bacteremia, with a special focus on the prevalence of and the risk factors for 3GC resistance, and determined factors for poor outcomes among patients with community-onset E. coli bacteremia. METHODS: This retrospective study was conducted at a tertiary-care teaching hospital in Taiwan. All adult patients with community-onset E. coli bacteremia between January 1, 2015, and December 31, 2015 were enrolled and were divided into two groups depending on whether the E. coli isolate was susceptible to 3GCs. Risk factors for 3GC resistance, 14-day all-cause mortality, and length of hospital stay were analyzed. RESULTS: The overall rate of 3GC resistance among E. coli isolates causing community-onset bacteremia was 19.7%, whereas it was 9.6% if only isolates causing community-acquired bacteremia were considered. Independent risk factors for 3GC-resistant community-onset E. coli bacteremia were hospitalization within the past 1 year (odds ratio: 2.4, 95% confidence interval: 1.6-3.7, P < 0.001), exposure to antibiotics within the past 15 days (2.6, 1.4-4.9, P = 0.002), residence in nursing home or long-term care facility (3.6, 1.0-12.3, P = 0.044), presence of underlying genitourinary disease (1.9, 1.2-2.9, P = 0.005), and presence of indwelling implantable intravenous port (2.2, 1.1-4.1, P = 0.021). 3GC resistance was independently associated with increased length of hospital stays (P < 0.001). CONCLUSION: In this study, the prevalence of 3GC resistance was high among both patients with community-onset and those with community-acquired E. coli bacteremia. 3GC resistance is a strong independent risk factor for length of hospital stay. The effectiveness of empirical antibiotic treatment would partially explain the impact of 3GC resistance, but more evidence is needed. The choice of appropriate empirical antibiotics for community-onset E. coli bacteremia might impact outcomes in terms of the length of hospital stay and need to be individualized according to the patient-specific risk for acquiring drug-resistant pathogens.

Multimodal interventions for bundle implementation to decrease central line-associated bloodstream infections in adult intensive care units in a teaching hospital in Taiwan, 2009-2013.

BACKGROUND: Central line (CL)-associated bloodstream infection (CLABSI) poses a major threat to patient safety and is associated with additional cost. This study investigated the sustained effect of multimodal interventions focusing on CL bundle improvement in the adult intensive care units (ICUs) of a teaching hospital in Taiwan. METHODS: A before-after prospective study was conducted in 17 adult ICUs of a medical center in northern Taiwan from January 2009 to December 2013. Many interventions that aimed to facilitate CL bundle implementation were initiated in January 2011. The incidence rates of CLABSI and catheter-related bloodstream infection (CRBSI) were compared between the baseline and intervention periods. Catheter utilization ratios and microbiological characteristics were also analyzed. RESULTS: The incidence rates of both CLABSI and CRBSI decreased significantly from the baseline to the intervention periods (from 9.27 to 7.66 per 1000 CL-days and from 1.51 to 0.89 per 1000 CL-days, respectively). The yearly incidence rate decreased by up to 31% (incidence rate ratio [IRR], 0.69; 95% confidence interval [CI], 0.59-0.81) for CLABSI and 59% (IRR, 0.41; 95% CI, 0.26-0.65) for CRBSI since the initiation of the interventions. The catheter utilization ratio also decreased from 0.71 to 0.63 (p < 0.001). Microbiological analysis showed that among all CLABSI isolates, the proportion of coagulase-negative staphylococci significantly decreased during the intervention period. CONCLUSION: Implementing multimodal interventions focusing on CL bundle improvement was effective in reducing the incidence rates of CLABSI and CRBSI in Taiwan's adult ICUs.

The Antimicrobial Susceptibility of Klebsiella pneumoniae from Community Settings in Taiwan, a Trend Analysis.

Drug-resistant Klebsiella pneumoniae, especially extended-spectrum ß-lactamase (ESBL)- and/or AmpC ß-lactamase-producing strains, is an emerging problem worldwide. However, few data focusing on drug susceptibility of K. pneumoniae from community is available. In this study, we analyzed 1016 K. pneumoniae isolates from outpatients or those visiting emergency rooms collected during 2002-2012 from Taiwan Surveillance of Antimicrobial Resistance program. Significantly decreased susceptibilities to 3rd generation cephalosporins and ciprofloxacin were found during the study period. By 2012, susceptibility to cefotaxime and ciprofloxacin was 83.6% and 81.6%, respectively. The prevalence of ESBL-producers increased from 4.8% in 2002 to 11.9% in 2012 (P = 0.012), while that of AmpC ß-lactamase-producers increased from 0% to 9.5% in the same period (P < 0.001). Phylogenic analysis of the ESBL and AmpC-ß-lactamase-producers by pulsed-field gel electrophoresis and multi-locus sequence typing revealed wide genetic diversity even among the most common sequence type 11 isolates (33.0%). By multivariate analysis, later study year, elderly, and urine isolates were associated with carriage of ESBL genes, while only urine isolates were associated with carriage of AmpC ß-lactamase genes. Further studies are needed to determine which antibiotics are reasonable empirical therapy options for patients presenting with severe sepsis that might be caused by K. pneumoniae.