Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome

Sulaiman et al., MedRxiv.

Posted: February 24th 2021



Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

Rate of Antibiotic Use and Associated Risk Factors in COVID-19 Hospitalized Patients

Martin et al., MedRxiv.

Posted: December 22nd 2020.



A total of 208 encounters (198 patients) were included in the final analysis. Eighty-three percent of patients received at least one course of antibiotics, despite low rates of microbiologically confirmed infection (12%). Almost one-third of patients (30%) received more than one course of antibiotics. Risk factors identified for both antibiotic prescribing and receiving more than one course of antibiotics were more serious illness, increased hospital length of stay, intensive care unit admission, mechanical ventilation, and acute respiratory distress syndrome.


There were high rates of antibiotic prescribing with low rates of bacterial co-infection. Many patients received more than one course of antibiotics during hospitalization. This study highlights the need for increased antibiotic stewardship practices in COVID-19 patients.

Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Horby et al., MedRxiv.

Posted: December 14th 2020.



Between 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1·00; 95% confidence interval [CI] 0·90-1·12; p=0·99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1·03; 95% CI 0·97-1·10; p=0·29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0·97; 95% CI 0·89-1·07; p=0·54).


In patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication.

Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring antibiotic-resistant bacterial pneumonia

Massey et al.MedRxiv.

Posted: September 22nd 2020.



The COVID-19 pandemic has brought with it the largest ever cohort of patients requiring mechanical ventilation. Here we describe such a patient who developed a recurring ventilator-associated pneumonia caused by a strain of Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis recovered whole genomes of the bacterium directly from samples, revealing the AMR genotype. While immunological analysis of longitudinally-collected blood samples revealed escalating levels of T-cell activation targeting both bacteria and virus, with evidence of bystander-activation, a feature which may have contributed to the continuing inflammation and prolonged requirement for ventilation.


Study participant was an otherwise healthy male between 45 and 55 years of age. After a week in the ICU he was diagnosed with ventilator-associated pneumonia (VAP). An antibiotic sensitive P. aeruginosa strain was cultured from an aspirate collected from his endotracheal tube (ETT-1). He was prescribed a seven-day course of piperacillin tazobactam (pip/taz), and clinically recovered from this bacterial infection. Eight days after finishing this first course of antibiotics his VAP recurred, and a pip/taz resistant P. aeruginosa was cultured from ETT-2 (MIC >16mg/l). He was prescribed a seven-day course of meropenem and showed signs of clinical improvement. There were no further concerns about a bacterial infection during his ICU stay although a third P. aeruginosa was cultured from a sample (ETT-3) collected two days after he completed his course of meropenem, that was resistant to both pip/taz and meropenem (MICs >16 mg/l and >8mg/l respectively). His health continued to improve, and he was discharged to the respiratory ward a week later. The patient attended a follow-up clinic 2-weeks after hospital discharge where he reported on-going symptoms such as breathlessness and myalgia. The most striking feature of this COVID-19 case was the escalating number of circulating activated T-cells more than two months after testing positive for SARS-CoV-2, and six weeks after clearing the viral infection. Whether the immune perturbations associated here with a case of post-acute COVID-19 are attributable to the secondary bacterial infection is currently under investigation.


Routine measurement of serum procalcitonin allows antibiotics to be safely withheld in patients admitted to hospital with SARS-CoV-2 infection.

Williams et al., 2020. MedRxiv.

Posted: July 2nd 2020.



Background. It can be a diagnostic challenge to identify COVID-19 patients without bacterial co-infection in whom antibiotics can be safely stopped. We sought to evaluate the validity of a guideline that recommends withholding antibiotics in patients with a low serum procalcitonin (PCT). Methods. We retrospectively collected 28-day outcome data on patients admitted to Sheffield Teaching Hospitals NHS Foundation Trust, UK, between 5 March and 15 April 2020, with a positive SARS-CoV-2 polymerase chain reaction (PCR) and PCT within 48 hours of diagnosis. PCT was considered negative if ≤0.25ng/ml and positive if >0.25ng/ml. Primary outcomes included antibiotic consumption, mortality, intensive care admission and length of hospital stay. Results. 368 patients met the inclusion criteria; 218 (59%) had a negative PCT and 150 (41%) positive. At 48 hours post-diagnosis, 73 (33%) of those with a negative PCT were receiving antimicrobials compared to 126 (84%) with a positive PCT (p<0.001), with a corresponding reduction in antimicrobial usage over 28 days (median DDD of 3.0 vs 6.8 (p<0.001); median DOT 2 vs 5 days (p<0.001) between the negative and positive PCT groups.) In the negative PCT group, there were fewer deaths (62 (28%) vs. 54 (36%), (p=0.021)) and critical care admissions (19 (9%) vs. 28 (19%), (p=0.007)) than in the positive PCT group. Median length of hospital stay was 8.7 and 9 days in the negative and positive PCT groups respectively. Conclusions. Procalcitonin is a valuable tool in the assessment of patients with SARS-CoV-2 infection, safely reducing the potential burden of unnecessary antibiotic usage.

Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients

Carlucci et al., MedRxiv.

Published: May 8th 2020.



Background: COVID-19 has rapidly emerged as a pandemic infection that has caused significant mortality and economic losses. Potential therapies and means of prophylaxis against COVID-19 are urgently needed to combat this novel infection. As a result of in vitro evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin. We performed a retrospective observational study to compare hospital outcomes among patients who received hydroxychloroquine and azithromycin plus zinc versus hydroxychloroquine and azithromycin alone. Methods: Data was collected from electronic medical records for all patients being treated with admission dates ranging from March 2, 2020 through April 5, 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. Patients in the study were excluded if they were treated with other investigational medications. Results: The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744). Conclusion: This study provides the first in vivo evidence that zinc sulfate in combination with hydroxychloroquine may play a role in therapeutic management for COVID-19.

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19

Magagnoli et al., MedRxiv.

Published: April 21st 2020.



BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study.

Lane et al. 2020. MedRxiv

Published: April 10th 2020



Background: Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin.

Methods: New user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine-azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%.

Results: Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45])

Conclusions: Short-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.


Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. This study looked at the safety of hydroxychloroquine, alone and in combination with azithromycin. Severe adverse events associated with hydroxychloroquine-azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Overall, 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included.

Teicoplanin potently blocks the cell entry of 2019-nCoV

Zhang et al. 2020. BioRxiv

Published: February 13th 2020



Since December 2019, the outbreak of a new coronavirus, named 2019-nCoV, has greatly threatened the public health in China and raised great concerns worldwide. No specific treatment for this infection is currently available. We previously reported that teicoplanin, a glycopeptide antibiotic which has routinely been used in the clinic to treat bacterial infection with low toxicity, significantly inhibits the invasion of cells by Ebola virus, SARS-CoV and MERS-CoV, via specifically inhibiting the activity of cathepsin L. Here, we tested the efficacy of teicoplanin against 2019-nCoV virus infection and found that teicoplanin potently prevents the entrance of 2019-nCoV-Spike-pseudoviruses into the cytoplasm, with an IC50 of 1.66 μM. Although the inhibitory effect upon the replication of wildtype viruses ex vivo and in vivo remains to be determined, our preliminary result indicates that the potential antiviral activity of teicoplanin could be applied for the treatment of 2019-nCoV virus infection.

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