Antimicrobial resistance is a global public health threat, and the World Health Organization (WHO) has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed. The discovery and introduction of novel antibiotics are time-consuming and expensive. According to WHO’s report of antibacterial agents in clinical development, only 18 novel antibiotics have been approved since 2014. Therefore, novel antibiotics are critically needed. Artificial intelligence (AI) has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics. Here, we first summarized recently marketed novel antibiotics, and antibiotic candidates in clinical development. In addition, we systematically reviewed the involvement of AI in antibacterial drug development and utilization, including small molecules, antimicrobial peptides, phage therapy, essential oils, as well as resistance mechanism prediction, and antibiotic stewardship.

Background: The prevalence of infections due to carbapenem-resistant Acinetobacter baumannii (CRAB) is on the rise worldwide. Polymyxins are considered as last-resort drugs for CRAB infections, but there is still controversy regarding the efficacy and safety of polymyxins based therapies in CRAB infections. The present systematic review was designed to compare the efficacy and safety of polymyxins based therapies versus non-polymyxins based therapies in CRAB infections. Methods: We performed a systematic literature search in PubMed, Embase, CINAHL, Cochrane Library, and clinicaltrials.gov to identify eligible studies reporting the clinical outcomes of patients with CRAB infections. The meta-analysis employed a random-effects model to estimate the odds ratio (OR) and standardized mean difference (SMD) with 95% confidence interval (CI). The primary outcome was 1-month mortality for any cause. We also examined clinical response, microbiological response, length of stay in hospital, and adverse events. Results: Eleven eligible studies were analyzed (1052 patients in total), including 2 randomized clinical trials. Serious risk of bias was found in 8 out of the 11 studies. There was no statistically significant difference between polymyxins based therapies and non-polymyxins based therapies in 1-month mortality for any cause (OR, 0.95; 95% CI, 0.59 to 1.53), microbiological response (OR, 3.83; 95% CI, 0.90 to 16.29) and length of stay in hospital (SMD, 0.24; 95% CI, − 0.08 to 0.56). The pooled OR of clinical response indicated a significant difference in favor of polymyxin based therapies (OR, 1.99; 95% CI, 1.31 to 3.03). The pooled OR of adverse events showed that non-polymyxins based therapies were associated with fewer adverse events (OR, 4.32; 95% CI, 1.39 to 13.48). Conclusion: The performance of polymyxins based therapies was better than non-polymyxin based therapies in clinical response rate and similar to non-polymyxin based therapies in terms of 1-month mortality and microbiological response in treating CRAB infections. Due to the limitations of our study, we cannot draw a firm conclusion on the optimal treatment of CRAB infections, but polymyxins would be a relatively effective treatment for CRAB infections. Adequate and well-designed large scale randomized controlled trials are required to clarify the relative efficacy of polymyxins based and non-polymyxins based therapies.

MRX-8 is a novel polymyxin for carbapenem-resistant Gram-negative infections that has been recently evaluated in Phase I clinical trials. Herein, its pharmacokinetics (PK) and nephrotoxicity in rats are reported for the first time. This study aimed at pre-clinical PK and safety assessments. An LC-MS/MS method was developed to determine concentrations of MRX-8 and its major deacylation metabolite, MRX-8039, in rat plasma. Animals were administered a single dose of MRX-8 (2, 4, 6, and 8 mg/kg) or comparator polymyxin B (PMB) (4 and 8 mg/kg) to compare the kidney injury known for the polymyxin drug class. Nephrotoxicity was evaluated using serum creatinine, blood urea nitrogen (BUN) biomarkers, and renal histopathology. In rats, MRX-8 displayed linear PK within the range of 2–8 mg/kg, with approximately 4% of MRX-8 converted to MRX-8039. MRX-8 induced only mild increases in serum creatinine and BUN levels, with an apparent decrease in nephrotoxicity within 24 h, in contrast to PMB, which exhibited a significant and more persistent toxicity. Additional nephrotoxicity biomarkers (plasma NGAL and urinary NGAL, KIM-1, and TIMP-1) have confirmed attenuated MRX-8 kidney injury. Histopathology has revealed significantly greater cellular/tissue toxicity for PMB as compared to MRX-8 (variances of p = 0.008 and p = 0.048 vs. saline control, respectively). Thus, MRX-8 induces a mild and reversible kidney injury in rats compared to PMB. These data support a continued evaluation of the novel polymyxin in human trials.

Polymyxin B, a last resort for carbapenem-resistant gram-negative bacteria (CRGNB) infections, has infection site-specific pharmacokinetic/pharmacodynamic (PK/PD) properties. However, there is little clinical evidence to support optimal exposures of polymyxin B for different site infections. We performed a prospective, observational, multicenter study to evaluate the clinical outcomes and PK/PD of intravenous polymyxin B treatment for various site CRGNB infections. The main clinical outcomes were 14-day all-cause mortality and nephrotoxicity, and the secondary outcomes were 28-day mortality and clinical response. The area under curves (AUCs) of polymyxin B were determined, and their associations with clinical outcomes were analyzed by stratification based on the infection site. A total of 312 patients were ultimately enrolled from 10 research centers. The overall 14-day mortality was 29.5%, and those of patients with lower respiratory tract infection (LRTI), intra-abdominal infection (IAI), and bloodstream infection (BSI) were 32.3%, 19.7%, and 30.3%, respectively. The 28-day mortality rate was 38.1%, while LRTI patients had the highest mortality (41.4%) and IAI patients lowest (34.8%). The clinical response rate was 46.2%, which was similar among the subgroups. The overall AKI rate was 60.9%. An AUC greater than 50 mg∙h/L was related to lower mortality in IAI patients but not in LRTI patients, which led to a lower but not significant difference in the overall analysis. The AUC of polymyxin B was an independent risk factor for 14-day mortality in IAI patients, and the cutoff value was 76 mg∙h/L. The results would be helpful for personalized dosing and monitoring of polymyxin B. CLINICAL TRIALS: This study is registered with the Chinese Clinical Trial Registry as ChiCTR2200056667 .

Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study.