Complicated Staphylococcus aureus bacteremia (SAB) is a serious, common, and frequently lethal infection. Treatment options are complicated by resistance, drug intolerance, or relapse. Novel therapeutics are urgently needed. We performed a phase 2a randomized, double-blind, controlled trial of the efficacy and safety of an IV bacteriophage cocktail, AP-SA02, q6 hrs x 5 days vs. placebo (2:1 ratio) in combination with BAT in patients with complicated SAB. Clinical response (Table 1) was assessed in the intent-to-treat (ITT) population at Test of Cure (TOC) on Day 12, post-BAT, and End of Study (EOS) four weeks after BAT completion. Safety analysis included data from the Phase 1b trial (n=8). We enrolled 42 patients from 17 sites (95% US), with 29 randomized to AP-SA02 (A) and 13 to placebo (P). MRSA was the pathogen in 39% of the (A) and 44% (P) groups, respectively. Site of infection and antibiotics used were similar for both arms. (Table 2). Treatment-emergent adverse events (TEAEs) occurred in 6% (2/35) and 0% (0/15) in the (A) and (P) groups, respectively. (Table 3). Day 12 clinical response rates were 88% (21/24) in SA-PA02 vs. 58% (7/12) in the placebo (p = 0.047) as assessed by blinded site investigators (PI), and 83% (20/24) vs. 58% (7/12) as assessed by the blinded Adjudication Committee (AC). At post-BAT and EOS, non-response/relapse rate was 0% and 0% in the (A) group by both PI and AC assessment compared to 23% by AC and 25% PI in the (P) group (p < 0.025, Figure 1). Patients on AP-SA02 had trends toward rapid normalization of C-reactive protein, shorter time to negative blood culture, shorter ICU and hospital stay. (Table 2) The intravenous bacteriophage cocktail, AP-SA02, combined with BAT, had a higher and earlier cure rate compared to placebo in patients with complicated SAB at day 12, at post BAT, and EOS as assessed by both blinded site investigators and independent adjudicators. AP-SA02 appears safe with clinical efficacy against both MRSA and MSSA and trends toward earlier resolution, shorter hospitalization, and no evidence of relapse 4 weeks post-therapy. Results strongly support proceeding to a Phase III trial of this novel bacteriophage cocktail for SAB. All Authors: No reported disclosures

This review explores mammalian immune responses to phages with a particular emphasis on human immune responses to therapeutic phages and their potential implications for the outcomes of phage therapy. Despite the ubiquity of phages in the human microbiome, particularly in the gut (the phageome), research on immunological mechanisms governing immune responses to both endogenous and therapeutic phages are still in their infancy. We highlight key components of the immune system that contribute to clearance of phages in vivo and examine how various factors- including patient-specific variables, treatment regimens and phage characteristics can influence immune responses and, consequently, phage pharmacokinetics during therapy. A clearer understanding of human immune responses to phages is urgently needed to inform the development of more targeted and effective personalized phage therapies-an essential step in combating the escalating threat of antimicrobial resistance.

Conjugative plasmids are major drivers of horizontal gene transfer and play a central role in the dissemination of antibiotic resistance (AbR) genes among bacteria. To establish successfully in new hosts, these plasmids must overcome recipient defenses, often through anti-defense proteins expressed from the leading DNA strand immediately upon transfer. IncM and IncL plasmids are globally significant vectors for dissemination of important AbR genes, yet the key leading-strand determinants underlying their success have remained unclear. Here, we systematically analysed the leading regions of these plasmids and identified a network of previously uncharacterised anti-defense genes driven by single-strand-specific promoters. Experimental deletion of this region resulted in a marked reduction in conjugation efficiency across diverse bacteria. This reduction was linked to the presence of recipient restriction enzymes targeting incoming plasmid DNA. Together, our findings reveal the leading region as a critical anti-defense hub that promotes efficient conjugation and establishment of high-risk AbR plasmids.

The Australian Group on Antimicrobial Resistance (AGAR) performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric gram-negative pathogens. From 1 January 2023 to 31 December 2023, a total of 57 hospitals across Australia participated in the Australian Gram-negative Surveillance Outcome Program (GnSOP). The 2023 survey tested 10,453 isolates, comprising Enterobacterales (9,503; 90.9%), P. aeruginosa (806; 7.7%) and Acinetobacter species (144; 1.4%), using commercial automated methods. The results were analysed using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2024). Key resistances reported are to the third-generation cephalosporin ceftriaxone in 12.9% of Escherichia coli and in 6.9% of Klebsiella pneumoniae complex isolates. Resistance rates to ciprofloxacin were 14.5% for E. coli; 7.8% for the K. pneumoniae complex; 3.2% for the Enterobacter cloacae complex; and 7.6% for P. aeruginosa. Resistance rates to piperacillin-tazobactam were 6.0%; 9.4%; 23.3%; and 13.7% for the same four species/complexes, respectively. Thirty Enterobacterales isolates from 30 patients were shown to harbour a carbapenemase gene: ten with a blaNDM gene (blaNDM-1 [4], blaNDM-5 [4], blaNDM-7 [2]); nine with a blaOXA-48-like gene (blaOXA-244 [4], blaOXA-48 [2], blaOXA-181 [1], blaOXA-232 [1], blaOXA-484 [1]); eight with blaIMP-4; two with blaNDM-5 + a blaOXA-181-like gene; and one with blaKPC-2 + blaNDM-5 + blaOXA-181. Transmissible carbapenemase genes were also detected in two Acinetobacter baumannii complex isolates (blaOXA-23; blaOXA-23 + blaOXA-58 + blaIMP-4) and one P. aeruginosa (blaIMP-4).

Pseudomonas aeruginosa, a multidrug-resistant pathogen, significantly impacts patients with chronic respiratory conditions like cystic fibrosis (CF) and non-CF chronic suppurative lung disease (CSLD), contributing to progressive lung damage and poor clinical outcomes. This bacterium thrives in the airway environments of individuals with impaired mucociliary clearance, leading to persistent infections and increased morbidity and mortality. Despite advancements in management of these conditions, treatment failure remains common, emphasising the need for alternative or adjunctive treatment strategies. Bacteriophage therapy, an emerging approach utilising viruses that specifically target bacteria, offers a potential solution to combat P. aeruginosa infections resistant to conventional antibiotics. This review examines the prevalence and disease burden of P. aeruginosa in CF and CSLD, explores the mechanisms behind antibiotic resistance, the promising role of bacteriophage therapy and clinical trials in this sphere.

Bacteriophages (phages) are emerging as a viable adjunct to antibiotics for the treatment of multidrug-resistant (MDR) bacterial infections. While intravenous phage therapy has proven successful in many cases, clinical outcomes remain uncertain due to a limited understanding of host response to phages. In this study, we conducted a comprehensive examination of the interaction between clinical-grade phages used to treat MDR Escherichia coli and Klebsiella pneumoniae infections, and human peripheral blood immune cells. Using whole transcriptome as well as proteomic approaches, we identified a strong inflammatory response to E. coli phage vB_EcoM-JIPh_Ec70 (herein, JIPh_Ec70) that was absent upon exposure to K. pneumoniae phage JIPh_Kp127. We confirmed that JIPh_Ec70's DNA recognition by the STING pathway was principally responsible for the activation of NF-kB and the subsequent inflammatory response. We further show that monocytes and neutrophils play a dominant role in phage uptake, primarily through complement-mediated phagocytosis. Significant differences in complement-mediated phagocytosis of JIPh_Kp127 and JIPh_Ec70 were observed, suggesting that reduced recognition, phagocytosis, and immunogenicity all contribute to the significantly decreased response to JIPh_Kp127. Our findings contribute to the progress of our understanding of the innate immune response to therapeutic phages and offer potential insights into how to improve the safety and effectiveness of phage therapy.

BACKGROUND:Due to the rise in antimicrobial resistance, there has been an increased interest in phage therapy to treat multidrug-resistant infections. In Australia, phage therapy is predominantly used in small clinical studies or for compassionate use; however, despite its potential expansion in modern medicine, the perception of phage therapy among medical professionals remains largely unknown. METHODS:We conducted a national survey of Australian infectious diseases and clinical microbiology advanced trainees and specialists using an online mailing list to assess their knowledge, areas of interest, and concerns around the use of phage therapy in clinical practice in Australia; with 92 eligible respondents. RESULTS:Most respondents believed that the current national plan for controlling antimicrobial resistance is inadequate and that phage therapy may be an effective solution; with 87 (97%) indicating that they would consider using phage therapy meeting established guidelines for purity and safety. There was a preference for bespoke therapy, with Gram-negative pathogens highlighted as priority targets. Alongside the phage therapy delivery protocols, therapeutic phage monitoring was considered important. Cystic fibrosis, lung-infections, prosthetic device/related infections, and infections among patients following transplantation and/or immunosuppression were highly ranked in terms of priorities for clinical syndromes. Accessibility was highlighted as a barrier to phage therapy, specifically, timely access (n = 66; 72%) and logistics of phage procurement and administration (n = 64; 70%). CONCLUSIONS:These results suggest the support of phage therapy among infectious diseases and clinical microbiology advanced trainees and specialists in Australia, and highlights areas of focus and priority in order to advance phage therapy.

The global rise in antibiotic resistance poses a critical threat to healthcare, with ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) leading the charge in nosocomial infections resistant to multiple drug classes. These pathogens, often impervious to last-line antibiotics, present immense clinical challenges. Their resilience is driven by several mechanisms, including capsule formation, biofilm production, β-lactamase, and efflux pump systems, which collectively enable immune evasion and antimicrobial resistance. The high mortality rate associated with ESKAPE pathogens stresses the urgent need for alternative therapeutic strategies. Phage therapy has emerged as a promising approach, utilising bacteriophages that specifically target bacterial surface receptors, including capsules, outer membrane proteins and certain efflux pumps, to infect and kill resistant strains while preserving the host microbiome. Recent clinical case studies demonstrate the success of phage therapy in treating infections caused by MDR Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, including phage-antibiotic combinations that have reversed resistance in previously untreatable infections. Despite promising case studies, challenges remain, including phage-resistant variants, regulatory hurdles, and scalable production. This review explores the transformative potential of phage therapy against ESKAPE pathogens, highlighting recent breakthroughs, current limitations, and future prospects. As the threat of antimicrobial resistance intensifies, phage therapy represents a critical tool in the fight against MDR ESKAPE pathogens.

The global rise in antibiotic resistance poses a critical threat to healthcare, with Acinetobacter baumannii emerging as a significant pathogen due to its multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. These infections, often impervious to last-line antibiotics, present immense clinical challenges. Mechanisms such as capsule formation, biofilm production, β-lactamase, and efflux pump systems drive its resilience, enabling immune evasion and antimicrobial resistance. Phage therapy offers a targeted approach by exploiting bacterial surface receptors, such as capsules or efflux pump components, to infect and kill resistant strains while preserving the host microbiome. Recent clinical studies highlight its potential to resolve severe MDR infections, including targeting efflux pumps to restore antibiotic efficacy. However, challenges such as phage-resistant variants, regulatory hurdles, and scalable production remain. This review examines the transformative potential of phage therapy against A. baumannii, addressing breakthroughs, obstacles, and future directions as a critical tool against MDR pathogens.

Respiratory infections pose significant challenges to global health, impacting millions of individuals annually. Understanding the molecular mechanisms underlying the pathogenicity of these infections is crucial for developing effective interventions. RNA sequencing provides insights into a patient's global transcriptome changes, facilitating the identification of host gene signatures in response to infection and potential therapeutic targets. Here we present an extensive whole blood transcriptome dataset from a demographically diverse cohort of 502 patients with infections including COVID-19, seasonal coronavirus, influenza A or influenza B, sepsis, septic shock, and co-infections (Viral/Viral, Bacterial/Viral, Bacterial/Viral/Fungal, Viral/Fungal, Viral/ Viral/Fungal). The cohort size and depth of data showcase its potential to unravel respiratory infection pathogenesis for the development of better diagnostics, treatments, and preventive strategies for respiratory infections and future global health crises.

Abstract Background The incidence, risks and organisms causing bloodstream infections (BSI) differ between children and adults due to distinct comorbidities, procedures and antibiotic exposures. Age-specific data are required to inform targeted interventions, empiric treatment and guideline development. We aimed to compare the incidence, risk factors and resistance patterns of bacteria causing BSI in children and adults (2020-21). Methods The Australian Group on Antimicrobial Resistance (AGAR) is a national hospital-based BSI surveillance program reporting on Staphylococcus aureus, Enterococcus spp. and key gram-negative pathogens. Results Data from 25,958 isolates were assessed (children: 1,679; adults: 24,279). The most common organisms in children and adults were Escherichia coli (20.9 vs 39.1%) and S. aureus (36.2 vs 20.9%). E. faecalis and non-typhoidal Salmonella spp. were more frequent in children (7.3% and 4.4% of surveyed organisms in children vs 5.1% and 0.5% in adults). BSI were more often community onset (69.0% children; 76.4% adults). 30-day mortality was significantly lower in children (3.3% vs 9.8%). Enterobacterales resistance was more common in children: e.g. to gentamicin/tobramycin (11.6% of child isolates; 8.5%, adult isolates; rate ratio [RR]: 1.4 [95%CI: 1.1-1.7]) and piperacillin-tazobactam resistance (11.2%; 8.6%; RR: 1.3 [1.0-1.6]). However, there was no difference observed in Enterobacterales resistance to cephalosporins, ciprofloxacin, meropenem or multi-drug resistance status. AMR prevalence in Pseudomonas and Acinetobacter spp isolates were also similar between children and adults. Methicillin-resistant S. aureus isolates were less common in children (13.2 vs 17.7%; RR: 0.7 [0.6-0.9]). Rates of clindamycin and cotrimoxazole resistance in S. aureus were similar to adults. Children had a lower proportion of E. faecium infections (24.1 vs 39.8%) and the rate of vancomycin-resistant E. faecium in children was half that in adults (19.5 vs 37.2%; RR; 0.5, [0.2-1.0]). Conclusion Analysis of national AMR data identifies unique trends in children. Ongoing clinical surveillance, targeted prevention, antimicrobial stewardship strategies and research to evaluate AMR drivers in children are required. Disclosures All Authors: No reported disclosures

Cystic fibrosis (CF) is the most prevalent serious inherited disease in Australia, imposing significant health risks. CF is characterized by chronic lung inflammation and recurrent pulmonary infections that increase morbidity and premature mortality rates. The emergence of antimicrobial resistance (AMR) places further challenges on the treatment and management of CF, necessitating research into alternative strategies for treatment of bacterial infections. Bacteriophage therapy, involving bacterial-specific viruses, is a potential avenue for AMR infections in patients with CF. Existing literature supports the feasibility of phage therapy in CF but there has been a gap in investigating attitudes of the CF community including affected individuals and their caregivers, regarding phage therapy. Understanding perspectives and needs of the CF community is essential for successful implementation and acceptance of novel therapies including phage therapy. We conducted a survey that encompasses responses from 112 consumers from across Australia, comprising people living with CF (38.4%), parents of affected children (49.6%), carers (6.4%), and family members (3%). The findings showed a significant reliance on antibiotics with 51.4% requiring oral, 43.4% nebulized, and 11.4% intravenous antibiotics within the preceding 2 weeks. Respondents highlighted the availability of new treatments, duration of hospitalizations and costs associated with treatment as important priorities to address. Despite an awareness of phage therapy among 62.4% of respondents, 86.4% expressed interest in obtaining more information, primarily from medical staff (66.7%). Notably, 96.0% of respondents expressed willingness to participate in phage therapy trials. The results of this survey highlighted the CF community’s strong interest in advanced therapeutic approaches, specifically phage therapy. The findings reveal a notable recognition and acceptance of phage therapy as a viable treatment option for pulmonary infections associated with CF. This study addresses UN Sustainable Development Goal 3: Good Health and Wellbeing by advancing knowledge on alternative therapeutic strategies for managing AMR in CF. By exploring community attitudes towards bacteriophage therapy, the research promotes informed development and implementation of innovative, targeted treatments for CF-associated infections. These findings support the sustainable management of AMR, fostering better health outcomes and reducing reliance on traditional antibiotics, thereby contributing to long-term health resilience.

The Australian Group on Antimicrobial Resistance (AGAR) performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric gram-negative pathogens. From 1 January 2024 to 31 December 2024, fifty-five hospitals across Australia participated in the Australian Gram-negative Surveillance Outcome Program (GnSOP). A total of 10,340 isolates, comprising Enterobacterales (9,376; 90.9%), Pseudomonas aeruginosa (804; 7.7%) and Acinetobacter species (160; 1.4%), were tested using commercial automated methods. The results were analysed using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2025). Key resistances reported are to the third-generation cephalosporin ceftriaxone in 14.9% of Escherichia coli and 10.5% of Klebsiella pneumoniae complex isolates. Resistance rates to ciprofloxacin were 15.4% for E. coli; 9.7% for the K. pneumoniae complex; 3.8% for the Enterobacter cloacae complex; and 8.8% for P. aeruginosa. Resistance rates to piperacillin–tazobactam were 7.5%, 10.3%, 25.2%, and 13.6% for the same four species/complexes, respectively. Thirty-nine Enterobacterales isolates from 38 patients were shown to harbour a carbapenemase gene: 21 with a blaNDM gene (blaNDM-5 [8]; blaNDM-1 [7]; blaNDM-7 [6]); eight with blaIMP-4; four with a blaOXA-181-like gene (blaOXA-181 [2]; blaOXA-484 [1]; blaOXA-1205 [1]); three with a blaOXA-48-like gene (blaOXA-48 [2]; blaOXA-244); two with blaKPC-2; and one with blaNDM-5 + blaOXA-484. Carbapenemase genes were also detected in two P. aeruginosa isolates (blaNDM-1 [1]; blaGES-5 [1]).

BACKGROUND:Concerns about the rise in antimicrobial resistance have led to renewed interest in phage therapy worldwide, but perceptions among relevant medical professionals in Korea remain largely unknown.MATERIALS AND METHODS:We conducted a semi-quantitative online survey to evaluate the Korean infectious disease specialists' perception of phage therapy.RESULTS:We sent out the link to the questionnaire to 380 subjects and received 91 replies, with 90/91 respondents identifying as Korean infectious diseases specialists or trainees. Ten out of 91 (11.0%) respondents scored themselves as well-informed about phage therapy. The majority (93.4%) of respondents would consider using phage therapy if the safety of the phage formulation is guaranteed, and 80% of respondents would consider participating in clinical trials with phage therapy given adequate support. The biggest concern was uncertainty about safety (73.6%) and efficacy (65.9%). Acinetobacter baumannii was ranked as a high priority for phage therapy research, as were bone and joint infections.CONCLUSION:Korean infectious diseases specialists are receptive to phage therapy, but a better understanding of safety, efficacy and clinical trials are warranted to progress phage therapy within the Korean healthcare system.

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A real-world study of 100 diverse cases facilitated by a single centre for individualized bacteriophage therapy demonstrates feasibility and provides new hope for refractory and resistant bacterial infections.

Background and Aims: Blood and urine are the most common culture testing for sepsis patients. This study aimed to compare clinical characteristics and outcomes of sepsis patients by blood and urine culture positivity and to identify factors associated with positive cultures. Methods: This retrospective study included patients aged >= 16 years with sepsis identified by the Sepsis-3 criteria presenting to the emergency department at four hospitals between 2017 and 2019 in Australia. Patient clinical outcomes were in-hospital mortality, intensive care unit (ICU) admission, hospital length of stay, and representation following discharge. Four culture groups were defined based on the positivity of blood cultures (BC) and urine cultures (UC) ordered within 24 h of triage. Results: Of 4109 patient encounters with sepsis, 2730 (66%) were nonbacteremic, urine culture-negative (BC-UC-); 767 (19%) nonbacteremic, urine culture-positive (BC-UC+); 359 (9%) bacteremic, urine culture-negative (BC+UC-); and 253 (6%) bacteremic, urine culture-positive (BC+UC+). Compared with BC-UC- patients, BC+UC- patients had the highest risk of ICU admission (adjusted odds ratio [AOR] 95% CI: 1.60 [1.18-2.18]) while BC-UC+ patients had lowest risk (adjusted odds ratio [AOR]: 0.56 [0.41-0.76]). BC+UC- patients had the highest risk of 3-day representation (AOR: 1.51 [1.02-2.25]) and second longest hospital stay (adjusted relative risk 1.17 [1.03-1.34]). Antibiotic administration before sample collection for culture was associated with lower odds of positive blood or urine culture results (AOR: 0.38, p < 0.0001). Conclusions: Enhanced clinical care should be beneficial for nongenitourinary sepsis patients (BC+UC-) who had the highest comparative risk of adverse clinical outcomes. Every effort needs to be made to collect relevant culture samples before antibiotic administration, to follow up on culture results, and tailor treatment accordingly.

Bacteriophages (phages) are estimated to be the most abundant microorganisms on Earth. Their presence in human blood suggests that they can translocate from non-sterile sites such as the gastrointestinal tract where they are concentrated. To examine phage translocation ex vivo, we adapted a primary colonoid monolayer model possessing cell diversity and architecture, and a thick layer of mucus akin to the colonic environment in vivo. We show that the colonoid monolayer is superior to the Caco-2 cell-line model, possessing intact and organized tight junctions and generating a physiologically relevant mucus layer. We showed, using two different phages, that translocation across the colonoid monolayer was largely absent in differentiated monolayers that express mucus, unlike Caco-2 cultures that expressed little to no mucus. By stimulating mucus production or removing mucus, we further demonstrated the importance of colonic mucus in preventing phage translocation. Finally, we used etiological drivers of gut permeability (alcohol, fat, and inflammatory cytokines) to measure their effects on phage translocation, demonstrating that all three stimuli have the capacity to amplify phage translocation. These findings suggest that phage translocation does occur in vivo but may be largely dependent on colonic mucus, an important insight to consider in future phage applications.

Introduction Pseudomonas aeruginosa is an organism well known for causing significant morbidity and mortality in people living with chronic lung conditions such as cystic fibrosis. We describe the safety, tolerability, and potential efficacy of bronchoscopic and nebulised bacteriophage administration, offering insights into a potential breakthrough for the treatment of chronic infections particularly in children and adolescents. Method A 12-year-old female (F12) and a 17-year-old male (M17), both diagnosed with cystic fibrosis and chronic P. aeruginosa lung infection, underwent bacteriophage treatment (BT). The administration involved bronchoscopic instillation and subsequent nebulisation. This was performed concurrently with intravenous antibiotics and regular physiotherapy delivered in an in-patient setting for 14 days. Microbiological, clinical, and lung function assessments were conducted to assess this treatment modality. Results No adverse events (fever, localised reaction, wheeze or bronchospasm) occurred during BT. F12 demonstrated a 4% increase, while M17 showed a 5% improvement in FEV1% from their best FEV1% over the past three years following BT. A 12% (F12) and an 8% (M17) improvement from baseline FEV1% was observed. For F12 P. aeruginosa was not isolated from her sputum despite 12 previous hospitalisations for intravenous antibiotics. Conclusion Bronchoscopic and nebulised routes of bacteriophage administration were well-tolerated in these two adolescents. This early report underscores the potential of this treatment modality and encourages clinicians and researchers to actively explore this innovative approach.

BACKGROUND:Viral respiratory tract infections are frequently complicated by secondary bacterial infections. This study aimed to use machine learning to predict the risk of bacterial superinfection in SARS-CoV-2-positive individuals. METHODS:In this prospective, multicentre, observational cohort study done in nine centres in six countries (Australia, Indonesia, Singapore, Italy, Czechia, and France) blood samples and RNA sequencing were used to develop a robust model of predicting secondary bacterial infections in the respiratory tract of patients with COVID-19. Eligible participants were older than 18 years, had known or suspected COVID-19, and symptoms of a recent respiratory infection. A control cohort of participants without COVID-19 who were older than 18 years and with no infection symptoms was also recruited from one Australian centre. In the pre-analysis phase, data were filtered to include only individuals with complete blood transcriptomics and patient data (ie, age, sex, location, and WHO severity score at the time of sample collection). The dataset was then divided randomly (4:1) into a training set (80%) and a test set (20%). Gene expression data in the training set and control cohort were used for differential expression analysis. Differentially expressed genes, along with WHO severity score, location, age, and sex, were used for feature selection with least absolute shrinkage and selection operator (LASSO) in the training set. For LASSO analysis, samples were excluded if gene expression data were not obtained at study admission, no longitudinal clinical information was available, a bacterial infection at the time of study admission was present, or a fungal infection in the absence of a bacterial infection was detected. LASSO regression was performed using three subsets of predictor variables: patient data alone, gene expression data alone, or a combination of patient data and gene expression data. The accuracy of the resultant models was tested on data from the test set. FINDINGS:Between March, 2020, and October, 2021, we recruited 536 SARS-CoV-2-positive individuals and between June, 2013, and January, 2020, we recruited 74 participants into the control cohort. After prefiltering analysis and other exclusions, samples from 158 individuals were analysed in the training set and 47 in the test set. The expression of seven host genes (DAPP1, CST3, FGL2, GCH1, CIITA, UPP1, and RN7SL1) in the blood at the time of study admission was identified by LASSO as predictive of the risk of developing a secondary bacterial infection of the respiratory tract more than 24 h after study admission. Specifically, the expression of these genes in combination with a patient's WHO severity score at the time of study enrolment resulted in an area under the curve of 0·98 (95% CI 0·89-1·00), a true positive rate (sensitivity) of 1·00 (95% CI 1·00-1·00), and a true negative rate (specificity) of 0·94 (95% CI 0·89-1·00) in the test cohort. The combination of patient data and host transcriptomics at hospital admission identified all seven individuals in the training and test sets who developed a bacterial infection of the respiratory tract 5-9 days after hospital admission. INTERPRETATION:These data raise the possibility that host transcriptomics at the time of clinical presentation, together with machine learning, can forward predict the risk of secondary bacterial infections and allow for the more targeted use of antibiotics in viral infection. FUNDING:Snow Medical Research Foundation, the National Health and Medical Research Council, the Jack Ma Foundation, the Helmholtz-Association, the A2 Milk Company, National Institute of Allergy and Infectious Disease, and the Fondazione AIRC Associazione Italiana per la Ricerca contro il Cancro.