Published papers

Hydrogel is an attractive delivery vehicle for phages as it keeps the wound moist, acts as a protective barrier and facilitates wound healing process. The aim of this study was to formulate biologically stable phage hydrogels that enable controlled release of infective phages. Pseudomonas-targeting phages, PEV1 (myovirus) and PEV31 (podovirus) were formulated in hydrogels (109 PFU/g) consisting of non-ionic polymers, including hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyethylene oxide (PEO), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP). The formulations were evaluated for physical properties, in vitro release profiles, antibacterial activity, and storage stability. Controlled release of phages was observed in 7.5% PEO, 20% PVA and 75% PVP hydrogels with >108 PFU release within 8 h. Poor phage release (7 × 105–4 × 107 PFU) was observed in 5% HPMC, 5% HEC and 30% HPC gels. The biostability of the optimized hydrogels was phage-specific with less titer loss observed for PEV1 (0–0.8 log) than for PEV31 (0.3–1.4 log). Both phages remained stable in PEO, PVA and HPMC hydrogels with <1 log titer reductions when stored at 5 °C. This study showed that 7.5% PEO and 20% PVA hydrogel formulations could be promising therapeutic systems for delivering phages for the treatment of wound infections.

Bacteriophage (phage) therapy is a promising treatment strategy to combat antibiotic-resistant bacteria. Clinical reports from a century ago, as well as recent reports have revealed safety and efficacy of phage therapy for bacterial wound infections. However, the conventional liquid phage formulation and delivery platforms reported lack of dose control as it easily runs off from the infection site and it is impossible to determine total volume transfer. The aim of this study was to formulate phage liquids for topical delivery using a metered-dose spray. Two types of anti-Pseudomonas phages, PEV1 (myovirus) and PEV31 (podovirus) were formulated in 35% ethanol in water containing non-ionic polymers. The formulations were evaluated for physical properties, ease of spray, dripping upon spraying, drying time, in vitro release profiles, antibacterial activity, and storage stability. The optimized phage-polymer spray formulations were easily sprayable with minimal dripping and fast drying time. Phages were rapidly released from the formulation and inhibited the growth of Pseudomonas aeruginosa. Both PEV1 and PEV31 remained biologically stable in the optimized formulations during storage at 4 °C for eight weeks. This study showed the topical spray formulations containing non-ionic polymers in ethanol/water could be a promising and innovative therapeutic system for delivering phages.

Background: Fluoroquinolone (FQ) antimicrobials have antipyretic effects during the treatment of bacterial infections; however, it is not clear whether these are due to their antimicrobial activities or their hypothermic effects. In this study, we investigated the hypothermic effects of FQ antimicrobials (ciprofloxacin [CPFX], gatifloxacin [GFLX], and levofloxacin [LVFX]) on fever by evaluating rectal body temperature changes in a mouse model of non-bacterial fever. Methods: CPFX, GFLX, and LVFX were administered intraperitoneally to non-bacterial fever model mice induced by yeast. Rectal body temperature was measured up to 180 min after administration. Results: A decrease in rectal body temperature of up to 1.2 °C for CPFX, 3.4 °C for GFLX, and 1.0 °C for LVFX was observed. The decrease in temperature was induced by an increase in the plasma concentration of FQ antimicrobials, suggesting that they are responsible for the temperature reduction. Focusing on glucocorticoids, one thermoregulation mechanism, we investigated the substances responsible for the reduction in rectal body temperature induced by FQ antimicrobials. Aminoglutethimide (an inhibitor of glucocorticoid production) were premedicated, followed by intraperitoneal administration of GFLX in the yeast-induced fever mouse model, resulting in attenuated GFLX-induced hypothermic effects. Conclusions: These results suggest that certain antipyretic effects of CPFX, GFPX, and LVFX during fever may contribute to their hypothermic effects; certain mechanisms are glucocorticoid-mediated.

Background: The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines and myocarditis/pericarditis in the Japanese population has not been systematically investigated. This study was aimed at clarifying the association between SARS-CoV-2 mRNA vaccines (BNT162b2 and mRNA-1273) and myocarditis/pericarditis as well as influencing factors by using the Japanese Adverse Drug Event Report database. Methods: Reporting odds ratios (RORs) and 95 % confidence intervals (95 % CIs) for the association between the vaccines and myocarditis/pericarditis were calculated using data from the database (April 2004–December 2023). Age, sex, onset time, and outcomes in symptomatic patients were evaluated. Results: The total number of reports was 880,999 (myocarditis: 1846; pericarditis: 761). The adverse events associated with the vaccines included myocarditis (919 cases) and pericarditis (321 cases), with the ROR [95 % CIs] being significant for both (myocarditis: 30.51 [27.82–33.45], pericarditis: 21.99 [19.03–25.40]). Furthermore, the ROR [95 % CIs] of BNT162b2 and mRNA-1273 were 15.64 [14.15–17.28] and 54.23 [48.13–61.10], respectively, for myocarditis, and 15.78 [13.52–18.42] and 27.03 [21.58–33.87], respectively, for pericarditis. Furthermore, most cases were ≤30 years or male. The period from vaccination to onset was ≤8 days, corresponding to early failure type based on analysis using the Weibull distribution. Outcomes were recovery or remission for most cases; however, they were severe or caused death in some cases. Conclusion: In the Japanese population, SARS-CoV-2 mRNA vaccination was significantly associated with the onset of myocarditis/pericarditis. The influencing factors included age of ≤30 years and male. Furthermore, although most adverse events occurred early after vaccination, overall outcomes were good.

Background Isavuconazole (ISA) is a treatment option for invasive fungal infections (IFIs) and is known for a favorable safety profile compared with other antifungal agents. However, comprehensive evidence regarding its efficacy and safety remains limited. Objectives This study aimed to assess the efficacy and safety of ISA compared with other antifungal agents through a systematic review and meta-analysis restricted to randomized controlled trials (RCTs), to provide more reliable estimates of its clinical effects. Methods Following Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted using PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov to identify RCTs comparing ISA with other antifungal agents. The primary outcomes were clinical response and mortality. Secondary outcomes included the incidence of adverse events, including serious, drug-related, and organ-specific toxicities. A subgroup analysis was conducted focusing on filamentous fungal infections, comparing ISA and voriconazole. Results Three RCTs met the inclusion criteria. No statistically significant differences were observed between ISA and comparator agents in terms of clinical response, mortality, or total and organ-specific adverse events. A trend toward fewer adverse events was noted in the ISA group. In the subgroup analysis, ISA and voriconazole showed similar efficacy and overall safety; however, the incidence of both drug-related adverse events and hepatobiliary disorders was significantly lower in the ISA group. Conclusions ISA demonstrated efficacy comparable to that of other antifungal agents, with a favorable safety profile in patients with IFIs, including filamentous fungal infections. This meta-analysis of RCTs provides high-quality evidence to support antifungal drug selection in clinical practice.

Introduction: Nacubactam is a novel β-lactamase inhibitor with intrinsic antibacterial activity that shows therapeutic potential against carbapenemase-producing Enterobacterales when administered with β-lactam antibiotics. Pharmacokinetics/pharmacodynamics (PK/PD) analyses based on drug concentrations at the site of infection are recommended to better evaluate antibiotic efficacy. A new PD index, the instantaneous minimum inhibitory concentration (MICi), which dynamically reflects the changing susceptibility of β-lactams during co-administration with β-lactamase inhibitors, has recently been proposed. This study aimed to assess the efficacy of cefepime combined with nacubactam in a murine model of pneumonia using MICi-based PK/PD analysis in the lung epithelial lining fluid (ELF). Methods: In vitro pharmacodynamic testing using the checkerboard method was conducted with two β-lactamase-producing Klebsiella pneumoniae strains. In vivo PK and PD studies were performed in neutropenic mice using both β-lactamase-producing and non-producing strains. Drug concentrations in plasma and ELF were measured, and MICi-based PK/PD analysis was conducted. Results: In vitro, the MIC of cefepime decreased in a concentration-dependent manner with increasing nacubactam. In the murine model of pneumonia, cefepime monotherapy resulted in bacterial changes of 0.12–4.30 log10 CFU/lung, while the combination therapy reduced bacterial counts by −5.93 to −0.234 log10 CFU/lung. The percentage of time that free cefepime concentrations exceeded MICi (T > MICi) was highly correlated with bacterial reduction. The target T > MICi for maximal effect was estimated to be 29.3 %. Conclusions: These findings support the utility of MICi-based PK/PD analysis for optimizing combination antibiotic therapy in pneumonia.