Search Results (3,211)

Optimizing hop (Humulus lupulus L.) extraction protocols for maximum antibacterial efficacy remains an open methodological challenge in developing plant-based natural antimicrobials. We compared five extraction protocols—hot ethanol, cold ethanol, espresso/steam, hot water, and cold water—applied to four hop varieties (Citra, Lubelski, Magnat and Marynka), with a commercial supercritical CO₂ extract as a reference preparation. We characterized extracts by HPLC (α-acids, β-acids, iso-α-acids) and GC-MS (volatile profile of cold ethanol extracts) and determined antibacterial activity as minimum inhibitory concentration (MIC) against reference and clinically relevant multidrug-resistant (MDR) strains of Escherichia coli and Staphylococcus aureus. Friedman tests confirmed a statistically significant effect of extraction method on MIC values (p ≤ 0.004 for E. coli ATCC 25922, S. aureus ATCC 29213, and clinical MRSA). Ethanol-based protocols consistently produced the highest hop acid concentrations and the lowest MICs against S. aureus ATCC 29213 (0.125–0.250 mg/mL) and against clinical MRSA (as low as 0.016 mg/mL), compared with 1.0–15.0 mg/mL for aqueous and steam-based extracts. Clinical MRSA demonstrated increased susceptibility to selected ethanol extracts and to the CO₂ reference. MDR uropathogenic E. coli (UPEC) maintained high-level resistance (MIC 15 mg/mL) to all preparations except the CO₂ reference (MIC 6 mg/mL). Spearman correlation identified α-acid content as the dominant predictor of antibacterial activity (ρ = −0.927, p < 0.001 for S. aureus ATCC 29213). These results suggest ethanol-based and supercritical CO₂ extraction as optimal protocols for producing hop extracts with antibacterial properties targeting Gram-positive pathogens, including MRSA, and provide a rationale for their use as natural antimicrobials. Full article

Over the past decade, antifungal vaccinology has produced genuine proof of concept: adhesin-based candidates such as NDV-3A have completed Phase II human trials, and reverse-vaccinology pipelines now routinely generate multi-epitope constructs with high predicted population coverage against Candida albicans and the multidrug-resistant Candida auris. However, no antifungal vaccine has reached the market, and the reasons for this gap are rarely examined together in a single, critical account. This review argues that the bottleneck is not primarily antigen discovery, but a layered set of translational barriers: biological constraints inherent to a commensal, morphologically plastic pathogen; manufacturing and purity requirements that complicate subunit vaccine production; a historical bias in preclinical animal models toward chemically immunosuppressed, rather than genetically susceptible, hosts; an underutilization of key insights from veterinary medicine; and a fragmented regulatory and commercial landscape that structurally disincentivizes investment in niche, high-risk patient populations. We further examine emerging immunotherapeutic strategies—passive antibody engineering, cytokine-based adjuvant approaches, phytocompound-derived antifungals, and dual-action nanovaccines—as partial, rather than complete, solutions to the immunocompromised-host paradox that limits active immunization in the patients who need protection most. Finally, we situate Candida vaccine development within a One Health and global-equity framework, arguing that diagnostic infrastructure, HLA population diversity, and cold-chain economics must be addressed as part of vaccine design rather than as an afterthought. Full article

The COVID-19 pandemic redirected infection control and antimicrobial stewardship towards SARS-CoV-2, potentially increasing multidrug-resistant (MDR) bloodstream infections (BSIs). We compared MDR BSI epidemiology and outcomes in a non-COVID intensive care unit (ICU) before and after the pandemic. The MATURATE ICU study retrospectively included adults with MDR BSIs admitted to a non-COVID ICU during the pre-COVID-19 (1 January 2017–1 January 2020) and post-COVID-19 (1 January 2022–1 January 2025) eras. Clinical, microbiological and outcome data were compared. Survival analyses and multivariable logistic regression identified predictors of ICU mortality. Overall, 146 patients were included (74 pre-COVID-19 and 72 post-COVID-19). Pre-COVID-19 patients were older and had higher comorbidity burden and severity indices (all p ≤ 0.023). ICU stay after the first positive blood culture was longer in the post-COVID-19 period (p = 0.003). New organ dysfunction, acute kidney injury, and septic shock were more frequent pre-COVID-19, whereas cardiovascular events were more frequent post-COVID-19. ICU mortality was higher pre-COVID-19 (p < 0.001). Competing-risk analysis, treating ICU discharge alive as a competing event, demonstrated a significantly lower cumulative incidence of ICU death in the post-COVID-19 era (adjusted sHR 0.20, 95% CI 0.11–0.35; p < 0.001). In multivariable analysis, post-COVID-19 era independently predicted lower 28-day ICU mortality (adjusted OR = 0.11, 95% CI 0.04–0.28, p < 0.001), whereas higher CCI (adjusted OR = 1.31, 95% CI 1.04–1.69, p = 0.027) and SOFA (adjusted OR = 1.22, 95% CI 1.07–1.40, p = 0.003) independently predicted increased mortality. Despite the persistently high burden of antimicrobial resistance, improved post-COVID-19 survival suggests that, advances in ICU care and healthcare system recovery may have contributed to better outcomes. Full article

Stenotrophomonas maltophilia is an opportunistic, multidrug-resistant pathogen commonly associated with respiratory and bloodstream infections. Owing to extensive intrinsic and acquired antimicrobial resistance and limited pediatric-specific evidence, contemporary management relies heavily on extrapolation from adult data, underscoring the need to better characterize real-world treatment practices and outcomes in children. This was a retrospective, observational cohort that included hospitalized patients < 18 years of age with a positive S. maltophilia culture who received active antimicrobial therapy, excluding cases determined by the treating provider to represent colonization. Outcomes assessed included in-hospital mortality, adverse drug effects, and clinical success rates using descriptive statistics. Forty pediatric patients (median [IQR] age of 2.7 [0.7–7.9] years) were included. Respiratory infections accounted for 77.5% of cases, and sulfamethoxazole-trimethoprim monotherapy was the most common treatment regimen (70.0%). Five patients (12.5%) experienced in-hospital mortality, three patients (7.5%) experienced adverse effects related to treatment, and all patients exhibited clinical success. Larger, multicenter observational and prospective studies are warranted to strengthen evidence-based therapeutic approaches for pediatric patients with S. maltophilia infections. Full article

Background/Objectives: Listeria monocytogenes is a major foodborne pathogen of public health concern because of the severe outcomes associated with invasive listeriosis, its ability to persist throughout the food chain, and its capacity to form biofilms. In this study, the occurrence, antimicrobial resistance, antimicrobial resistance genes, and biofilm-forming capacity of L. monocytogenes from food of animal origin in Northern Kazakhstan were investigated, and the association between the biofilm phenotype and antimicrobial resistance was also assessed. Methods: A total of 1561 samples were analyzed. L. monocytogenes was isolated and identified according to ISO 11290-1 and confirmed by MALDI‒TOF MS. Antimicrobial susceptibility was determined by disk diffusion according to EUCAST recommendations. Resistance genes were detected by PCR, and biofilm formation was assessed using a crystal violet assay. Results:L. monocytogenes was detected in 34 (2.18%) samples. Resistance to at least one antimicrobial agent was observed in 18 (52.9%) isolates, with the highest resistance rate observed for trimethoprim–sulfamethoxazole (14/34, 41.2%). Multidrug resistance was detected in 8 (23.5%) isolates and was defined as resistance to at least three antimicrobial classes, including β-lactams, macrolides, and sulfonamides. The most frequently detected resistance genes were msrA (26.5%) and mefA (20.6%). All isolates formed biofilms, with 44.1% classified as strong producers and 55.9% as moderate producers. Strong biofilm formation was significantly associated with antimicrobial resistance (OR = 4.71, p = 0.045). Conclusions: L. monocytogenes was detected in 34 (2.18%) animal-origin food samples from Northern Kazakhstan. The isolates demonstrated antimicrobial resistance and biofilm-forming capacity, with a significant association between strong biofilm formation and antimicrobial resistance. These findings highlight the importance of continued microbiological surveillance of L. monocytogenes in animal-origin foods. Full article

Background/Objectives: Antimicrobial resistance has been recognized as a major global health threat, with multidrug-resistant Acinetobacter baumannii identified as one of the most critical pathogens. To address the limitations of conventional antibiotics, phage therapy has been proposed as a complementary or alternative intervention. In this study, experimental data were integrated into a deterministic differential-equation-based model to capture phage–bacteria–antibiotic–host immune system interactions. Methods: The model extended a previous phage–host immune system synergy framework by incorporating phage–antibiotic synergy and a time-dependent reduction in phage adsorption as a phenomenological representation of population-level reduction in phage susceptibility. This formulation does not explicitly model the molecular mechanisms or evolutionary emergence of resistance. In vitro observations of phage-induced resensitization to ceftazidime informed model parameterization, while remaining parameters were estimated from experimental observations or literature values. Simulations evaluated bacterial dynamics under phage-only, antibiotic-only, and immunity-only conditions, as well as combined therapeutic scenarios. Results: Model predictions indicated the greatest bacterial reduction when phages, antibiotics, and host innate immunity acted together. Phage–antibiotic synergy further enhanced predicted bacterial clearance, particularly for ceftazidime-resistant populations, while a population-level reduction in phage susceptibility was predicted approximately 4 h post-infection, consistent with experimental observations. Combined scenarios involving continuous antibiotic infusion, phage plus host immunity, or low-dose antibiotic regimens predicted accelerated bacterial declines when synergistic interactions were active. Conclusions: This framework integrates experimental observations with mathematical modeling to explore therapeutic interactions and temporal changes in phage susceptibility, while assessing parameter sensitivity and guiding future experimental and preclinical studies. Full article

Over the past few years, considerable scholarly interest has been directed toward the synergistic application of natural compounds alongside conventional antibiotics to address infections stemming from multidrug-resistant (MDR) pathogens. The primary objective of this research is to investigate the efficacy of baicalin (BA), an extract obtained from Scutellaria baicalensis, when used in conjunction with oxacillin sodium (OXS). Specifically, the study evaluates their combined impact on biofilm formation and toxicity reduction in methicillin-resistant Staphylococcus aureus (MRSA) strain USA300. Furthermore, a murine peritonitis model induced by MRSA USA300 was developed to determine the therapeutic potential of this combination therapy against infection. Experimental data indicate that the co-administration of BA and OXS does not induce hemolysis in vitro. In comparison to treatments involving either BA or OXS alone, the combined regimen significantly enhances the accumulation of intracellular reactive oxygen species (ROS) within MRSA USA300. Additionally, this synergistic approach suppresses the production of extracellular polymeric substances (EPSs), decreases the overall protein content within the biofilm matrix, and impairs the metabolic functions of biofilm cells. The investigation also revealed that the synergistic application of BA and OXS intensifies the suppression of key virulence determinants, specifically lipase activity and staphyloxanthin production, while simultaneously downregulating the transcription of sarA (a global regulator of virulence). These findings substantiate the anti-virulence efficacy of the BA-OXS combination. In a murine model of peritonitis established using MRSA USA300, the healthy mice group, the MRSA USA300 group, the BA group, the OXS group, the combined group of BA and OXS, and the VAN group were set up, with eight mice in each group. The results showed that the combined therapy significantly mitigated body weight reduction, decreased the circulating counts of inflammatory cells, including leukocytes and lymphocytes, and suppressed the secretion of pro-inflammatory mediators such as TNF-α, IL-6, and IL-1β, thereby demonstrating potent anti-inflammatory properties. Furthermore, the co-administration of BA and OXS reduced bacterial burden in the abdominal organs of infected mice and alleviated associated histopathological injuries. Importantly, the treatment regimen exhibited no hepatorenal toxicity in the peritonitis mice, effectively maintaining normal levels. In the plasma of mice suffering from peritonitis, the concentration of malondialdehyde (MDA), a marker of oxidative stress, was reduced, while the activities of catalase (CAT) and superoxide dismutase (SOD) were elevated. This modulation contributes to anti-infective effects. These findings offer a theoretical foundation for subsequent investigations into the synergistic application of natural compounds and conventional antibiotics against MRSA. Full article

Mastitis severely hinders dairy farming, with Streptococcus agalactiae (S. agalactiae) serving as a major causative pathogen. Prolonged antibiotic administration promotes the emergence of multidrug-resistant strains, thereby compromising mastitis control. Consequently, novel natural antibacterial agents are urgently needed. In this study, bacteriostatic assays identified the MIC of rosmarinic acid (RA) against S. agalactiae as 8 mg/mL. At the MIC, RA reduced the adhesion capacity of S. agalactiae by 16.6% and inhibited biofilm formation by 25.09%. RA also disrupted bacterial membrane architecture and markedly downregulated the expression of virulence factors. A mouse model of mastitis treated with varying doses of RA (25, 50, and 100 mg/kg) indicated that RA attenuated pathological damage to the mammary duct architecture and ameliorated inflammatory responses in S. agalactiae-infected mice. ELISA revealed that RA significantly reduced pro-inflammatory mediators, including IL-1α, IL-1β, IL-6, and TNF-α. RT-qPCR results indicated that mRNA expression levels of TLR2, NF-κB, AKT, and PI3K were substantially reduced following RA treatment, whereas apoptosis-related genes p53, RUNX1, and Bim exhibited distinct expression patterns. Western blotting analysis further indicated that RA modulated the phosphorylation of Bim, RUNX1, and p53 in mastitis tissues, suppressed the TLR2/NF-κB inflammatory signaling pathway, and regulated the PI3K/AKT cascade. By targeting multiple pathways, RA suppressed S. agalactiae proliferation and attenuated mammary gland inflammation, highlighting its potential as a green therapeutic agent for sustainable animal husbandry. Full article

Candidozyma auris is an emerging multidrug-resistant fungal pathogen, which causes high mortality and nosocomial outbreaks worldwide. Macrophages are key innate immune cells that clear fungi through phagocytosis, reactive oxygen species, and cytokine secretion. Mannan, a major fungal cell wall polysaccharide, has immunomodulatory properties and can interact with receptors such as C-type lectins and Toll-like receptors 2/4, which are associated with nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling in macrophages. However, its role in host defense against C. auris remains unclear. In this study, the effects of mannan against C. auris infection were evaluated using Ana-1 macrophages and murine models. Cell Counting Kit-8 assay, neutral red uptake, and fluorescence microscopy assay showed that mannan with safety concentrations of 0–160 μg/mL significantly increased the phagocytosis activity of Ana-1 macrophages, and following pre-stimulation of Ana-1 macrophages with mannan for 1 h, the phagocytic ability of these macrophages to C. auris was significantly enhanced at 30 min, and the killing ability was significantly higher than that of the control group at 4 h. Transcriptomic analysis combined with real-time quantitative PCR and Western blotting showed that mannan enhanced the immune response of Ana-1 macrophages, which was associated with changes in GPCR-related PI3K/NF-κB signaling, and improved their killing activity against C. auris. In vivo efficacy was further validated in mice and zebrafish via fungal burden, histopathology, and immune cell recruitment assays, which confirmed that mannan can effectively prevent C. auris bloodstream infection. These findings provide insights into mannan’s immunomodulatory mechanisms and support its potential in developing new antifungal immunotherapies for C. auris infection. Full article

Hydroquinine, a cinchona alkaloid, has demonstrated antibacterial activity against multidrug-resistant pathogens, with previous transcriptomic data implicating the arginine deiminase (ADI) pathway. However, its potential molecular target engagement remains to be fully characterized. This study aimed to investigate potential molecular targets of hydroquinine within the ADI pathway utilizing an Escherichia coli BL21 heterologous expression model. We integrated computational molecular docking as a hypothesis-generating tool, in silico-guided site-directed mutagenesis, and continuous broth microdilution growth kinetics profiling. Phenotypic profiling of the ADI-pathway transformants revealed that heterologous expression of the arginine/ornithine antiporter (AOA, encoded by arcD) was associated with growth tolerance under sub-inhibitory hydroquinine pressure. Serving strictly to nominate candidate binding residues, molecular docking predicted that the quinoline and quinuclidine moieties of hydroquinine may interact with residues Trp301 and Glu150 within the predicted AOA binding region. Consistent with these computational predictions, site-directed mutagenesis supported the contribution of these residues to the observed hydroquinine-associated phenotype. E. coli BL21 variants harboring the W301V and E150I arcD mutations lost the observed growth tolerance and exhibited significantly reduced maximum specific growth rates under sub-inhibitory hydroquinine stress. Furthermore, baseline growth defects in untreated mutants indicated potential fitness costs associated with these substitutions. In conclusion, this study provides preliminary insights into AOA as a potential target within a surrogate heterologous host, highlighting bacterial transport systems as candidate targets for future investigation of cinchona alkaloid-based antibacterial development. Full article

Urinary tract infections (UTIs) represent a major global health burden, traditionally defined as microbial invasion of a sterile urinary tract, but now increasingly understood as a state of microbial dysbiosis involving disruption of the urinary microbiome. This review aims to synthesize current knowledge on the molecular mechanisms, etiological agents, clinical classification, and emerging therapeutic strategies in UTIs. The analysis integrates recent advances in microbiome research, molecular pathogenesis, and clinical guidelines. Uropathogenic Escherichia coli (UPEC) remains the predominant pathogen, utilizing virulence factors such as adhesins and intracellular bacterial community formation to establish persistent infection, while other organisms including Klebsiella pneumoniae, Proteus mirabilis, and Enterococcus faecalis contribute to disease complexity. The emergence of multidrug-resistant organisms, particularly among ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), poses significant therapeutic challenges through mechanisms such as β-lactamase production, efflux pumps, and biofilm formation. Clinically, evolving classification systems emphasize infection localization rather than host factors, improving diagnostic and therapeutic precision. Diagnostic strategies rely on clinical assessment, urinalysis, and urine culture, while treatment increasingly incorporates antimicrobial stewardship principles. Emerging approaches, including immunoprophylaxis, bacteriophage therapy, and microbiome-targeted interventions, demonstrate promising results. In conclusion, UTIs are complex, multifactorial diseases requiring integrated molecular, clinical, and therapeutic approaches, with future advancements likely driven by precision medicine and artificial intelligence. Full article

Background/Objectives: Shiga toxin-producing Escherichia coli (STEC) are important zoonotic pathogens associated with gastrointestinal infections and hemolytic–uremic syndrome (HUS). Increasing serotype diversity, emergence of hybrid strains, and growing antimicrobial resistance complicate surveillance and treatment. This review summarizes recent data on STEC isolated from major animal reservoirs between 2020 and 2026. Methods: We comparatively analyzed peer-reviewed, open-access studies investigating STEC from cattle, sheep, goats, poultry, wildlife, and related animal products. We extracted and evaluated data on serotypes, virulence genes, hybrid pathotypes, and antimicrobial resistance determinants. Results: High serotype diversity was observed across all reservoirs, with non-O157 STEC frequently predominating over O157:H7. Ruminant isolates commonly carried stx2 and additional virulence determinants associated with severe human disease, confirming cattle and small ruminants as major reservoirs of highly pathogenic STEC. Poultry-associated isolates showed greater variability in virulence profiles but frequently exhibited high rates of multidrug resistance. Hybrid strains combining virulence traits characteristic of multiple E. coli pathotypes were increasingly reported. Livestock-associated STEC commonly carried resistance determinants against β-lactams, tetracyclines, sulfonamides, quinolones, and polymyxins, whereas wildlife isolates generally showed lower rates of resistance. Conclusions: Animal-associated STEC populations demonstrate increasing genomic diversity, pathogenic potential, and antimicrobial resistance. The growing prevalence of non-O157 and hybrid strains highlights the limitations of traditional serotype-focused surveillance and emphasizes the need for integrated One Health monitoring strategies. Full article

Background/Objectives: Bovine mastitis is a common infection in cattle causing significant economic losses globally in the dairy industry. While bacterial profiles and antimicrobial resistance (AMR) patterns are generally consistent worldwide, comprehensive epidemiological and AMR data from Kazakhstan are lacking. This study characterized mastitis-associated bacterial isolates and their AMR profiles from a single commercial Simmental dairy herd in the Akmola Region, Kazakhstan. Milk samples from 41 cows with clinical mastitis and documented treatment histories were collected. Methods: Bacterial identification was performed using MALDI-TOF MS, and antimicrobial susceptibility was tested phenotypically following EUCAST criteria. Whole genome sequencing (WGS) on a subset of isolates analyzed resistance and plasmid content using AMRFinderPlus v3.11.14 and Abricate v1.4.0, with the ResFinder and PlasmidFinder databases, respectively. Results: All samples yielded bacterial growth, resulting in 58 isolates across 11 species and five genera, from which Staphylococci predominated (50.0%), followed by Streptococci (28.0%), Escherichia coli (19%), one Aerococcus (1.72%) and one Corynebacterium (1.72%) strain. Phenotypic resistance to at least one antimicrobial class was found in 65.5% of tested isolates. Tetracycline resistance was the most frequent (71.7% of tested isolates), with multidrug resistance detected in 6.9%. WGS of a randomly selected subset of 33 isolates revealed that 27 (82%) carried at least one acquired AMR gene, predominantly tetracycline resistance genes (26/33), followed by lincosamide/macrolide (12 and 11 isolates) and aminoglycoside resistance genes (9 isolates). Plasmid replicon screening identified plasmid replicons in 21 of the 33 sequenced isolates, mainly of the repUS43 and repUS76 staphylococcal replicon families, suggesting a potential role of plasmids in AMR gene dissemination within the herd. Conclusions: This study offers a comprehensive phenotypic and genomic characterization of mastitis-associated pathogens and their AMR determinants within this single herd, highlighting the co-circulation of tetracycline, lincosamide/macrolide, and aminoglycoside resistance genes. As this study was limited to a single dairy herd, these findings should be regarded as descriptive, farm-level observations rather than being representative of the Akmola Region or Kazakhstan more broadly. These findings support farm-level mastitis surveillance that combines species identification, phenotypic AMR testing, and targeted molecular screening. Full article

Vibrio parahaemolyticus is an important foodborne and aquaculture-associated pathogen, and its increasing antimicrobial resistance threatens shrimp production, seafood safety, and public health. Although bacteriophages have emerged as a potential solution to the growing challenge of antimicrobial resistance, whether antibiotic resistance is associated with phage tolerance remains unclear. This study characterized antimicrobial resistance profiles and resistance genes in Vibrio parahaemolyticus isolates from Zhanjiang shrimp aquaculture farms and evaluated their association with bacteriophage susceptibility. A total of 132 isolates were tested against 18 antibiotics, while molecular and phage-related analyses were performed on 132 isolates. High resistance was observed against kanamycin (95.5%), sulfamethoxazole (94.7%), cefazolin (78.8%), imipenem (78.8%), amoxicillin (70.5%), and ampicillin (65.2%). Multidrug resistance was detected in 131/132 isolates (99.24%), indicating an extensive resistance burden. PCR analysis showed high detection rates of aphA (100.00%), sul1 (99.24%), blaTEM (98.48%), blaOXA (73.48%), blaCTX-M (53.03%), qnrA (45.45%), tetA (37.88%), and tetB (21.21%). Phage response analysis showed that 70.45% and 68.18% of isolates were phage-resistant at 4 h and 5 h, respectively. Genes potentially associated with phage–host interactions were also detected, with luxS showing the highest frequency (85.61%). Association analysis revealed significant links between tetA, tetB, blaOXA, and bacteriophage responses. These findings suggest that antimicrobial resistance and reduced phage susceptibility can co-occur among V. parahaemolyticus isolates recovered from shrimp farms in Zhanjiang, highlighting the need for regional resistance surveillance and careful phage selection. Full article

The rise of multidrug-resistant (MDR) pathogens in the pediatric population represents a significant global health challenge, compounded by a historically stagnant antibiotic pipeline for children. While several novel antibiotics have been approved for adults in recent decades, pediatric labeling is often deferred due to the complexities of developmental pharmacology and due to a certain precautionary prudence in introducing new drugs onto the market for this population. This review explores the landscape of the most recent antibiotics, including advanced cephalosporins (ceftaroline, cefiderocol, and ceftobiprole), novel beta-lactam/beta-lactamase inhibitor combinations (e.g., ceftazidime/avibactam, meropenem/vaborbactam), and long-acting lipoglycopeptides. We analyze their approval trials, pediatric-specific PK/PD profiles, and the balance between on-label use and evidence-based off-label prescriptions. Furthermore, we emphasize the role of antimicrobial stewardship through the “3 D’s” rule and the evolution of Therapeutic Drug Monitoring (TDM) from reactive safety controls to proactive, model-informed precision dosing (MIPD). Finally, we advocate for a multidisciplinary synergy between pediatricians and pharmacologists as the cornerstone for optimizing outcomes and preserving the efficacy of the future antibiotic pipeline. Full article