The IDentif.AI 2.0 Pandemic Readiness Platform: Rapid Prioritization of Optimized COVID-19 Combination Therapy Regimens

ObjectivesWe aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19. MethodsA pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain, B.1.351 and B.1.617.2 variants) and Vero E6 assay with a quadratic optimization workflow. ResultsWithin 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived. ConclusionsIDentif.AI 2.0 rapidly revealed promising drug combinations for clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/21259321v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@f8a159org.highwire.dtl.DTLVardef@12908b7org.highwire.dtl.DTLVardef@fb6485org.highwire.dtl.DTLVardef@8493c3_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- When novel pathogens emerge, the immediate strategy is to repurpose drugs. - Good drugs delivered together in suboptimal combinations and doses can yield low or no efficacy, leading to misperception that the drugs are ineffective. - IDentif.AI 2.0 does not use in silico modeling or pre-existing data. - IDentif.AI 2.0 pairs optimization with prospectively acquired experimental data using a SARS-CoV-2/Vero E6 assay. - IDentif.AI 2.0 pinpoints EIDD-1931 as a foundation for optimized anti-SARS-CoV-2 combination therapies.

Antibiotic therapy and clinical outcomes of Pseudomonas aeruginosa (PA) bacteraemia

<p><b>INTRODUCTION</b>Pseudomonas aeruginosa (PA) bacteraemia is associated with high morbidity and mortality. We assessed clinical outcomes in patients with PA bacteraemia treated with piperacillin-tazobactam (TZP) versus other antibiotics, and monotherapy versus combination, all with proven activity by disc testing without minimum inhibitory concentration (MIC) data.</p><p><b>MATERIALS AND METHODS</b>All patients with PA bacteraemia in 2007 to 2008 were reviewed for demographic, comorbidity, clinical, laboratory, treatment and outcome data. Primary outcome was 30-day mortality. Secondary outcomes included microbiological clearance, clinical response and length of stay (LOS).</p><p><b>RESULTS</b>Median age for 91 patients was 65 years. Median Simplified Acute Physiology Score (SAPS) II score was 30. Monotherapy was used in 77 cases: 42 on ceftazidime, 17 on TZP, 10 on carbapenems, and 8 on other antipseudomonal antibiotics. The 30-day mortality was 20.9%, and similar between ceftazidime and TZP versus other antibiotics respectively. More patients in combination versus monotherapy group had cardiovascular diseases, diabetes mellitus and vascular access as source of bacteraemia. Patients on monotherapy had higher 30-day mortality (24.7% vs 0%, P = 0.037). Multivariate analysis identified SAPS II score (OR = 1.097, 95% CI, 1.032 to 1.166, P = 0.003) and cancer (OR = 4.873, 95% CI, 1.235 to 19.223, P = 0.024) as independent predictors of 30-day mortality.</p><p><b>CONCLUSION</b>TZP appeared to be an effective culture-guided antibiotic for PA bacteraemia. High 30-day mortality in monotherapy might be confounded by comorbidity, illness severity and sample size. Cancer patients and a high SAPS II score were independent predictors of 30-day mortality.</p>

Review of human infections with avian influenza H5N1 and proposed local clinical management guideline

<p><b>INTRODUCTION</b>The current avian and human H5N1 influenza epidemic has been in resurgence since 2004. We decided to evaluate published evidence in relation to epidemiology, clinical features and course, laboratory diagnosis, treatment and outcome of human H5N1 influenza, and develop institutional clinical management guidelines.</p><p><b>METHODS</b>A search of PubMed was conducted for all English language articles with search terms "avian", "influenza" and "H5N1". The bibliography of articles was searched for other references of interest.</p><p><b>RESULTS</b>Published case series from Hong Kong in 1997, and Thailand and Vietnam since 2004 have indicated a rapidly progressive primary viral pneumonia resulting in acute respiratory distress syndrome. The majority of human H5N1 infections can be linked to poultry exposure. Hitherto there has been no evidence of efficient human-to-human transmission. Case fatality rates have varied from 71% in Thailand to 100% in Cambodia. Oseltamivir appears to be the only potentially effective antiviral therapy. H5N1 isolates in Vietnam have become resistant to oseltamivir, resulting in persistent viral replication and death. There is as yet no effective human H5N1 vaccine.</p><p><b>CONCLUSIONS</b>National and international preparedness plans are well advised. Clinical trials to evaluate higher dose oseltamivir therapy and immunomodulatory treatment are urgently needed.</p>

Cluster of Staphylococcus aureus and dengue co-infection in Singapore

<p><b>INTRODUCTION</b>Singapore saw a resurgence of dengue infections in 2005. Concurrent bacterial co-infections in dengue is rare.</p><p><b>CLINICAL PICTURE</b>We report a cluster of serious methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia or severe soft tissue infection in 5 epidemiologically linked construction workers presenting with dengue and non-resolving fever.</p><p><b>TREATMENT</b>Surgical intervention was indicated in 4 of the 5 patients despite appropriate antistaphylococcal therapy.</p><p><b>OUTCOME</b>All but 1 patient were eventually discharged. Clonality and Panton-Valentine leucocidin genes were not demonstrated. Epidemiological investigations suggested that occupational contact dermatitis could have predisposed the patients to this opportunistic co-infection.</p><p><b>CONCLUSION</b>Clinicians need to be vigilant to unusual manifestations of dengue which may signal a concomitant aetiology.</p>