Antibacterial activity of ibezapolstat against antimicrobial-resistant clinical strains of Clostridioides difficile.

Antimicrobial resistance is emerging in clinical strains of Clostridioides difficile. Ibezapolstat (IBZ) is a DNA polymerase IIIC inhibitor that has completed phase II clinical trials. IBZ has potent in vitro activity against wild-type, susceptible strains but its effect on C. difficile strains with reduced susceptibility to metronidazole (MTZ), vancomycin (VAN), or fidaxomicin (FDX) has not been tested. The primary objective of this study was to test the antibacterial properties of IBZ against multidrug-resistant C. difficile strains. The in vitro activity, bactericidal, and time-kill activity of IBZ versus comparators were evaluated against 100 clinical strains of which 59 had reduced susceptibility to other C. difficile antibiotics. Morphologic changes against a multidrug resistance strain were visualized by light and scanning electron microscopy. The overall IBZ MIC50/90 values (µg/mL) for evaluated C. difficile strains were 4/8, compared with 2/4 for VAN, 0.5/1 for FDX, and 0.25/4 for MTZ. IBZ MIC50/90 values did not differ based on non-susceptibility to antibiotic class or number of classes to which strains were non-susceptible. IBZ bactericidal activity was similar to the minimum inhibitory concentration (MIC) and maintained in wild-type and non-susceptible strains. Time-kill assays against two laboratory wild-type and two clinical non-susceptible strains demonstrated sustained IBZ activity despite reduced killing by comparator antibiotics for IBZ and VAN non-susceptible strains. Microscopy visualized increased cell lengthening and cellular damage in multidrug-resistant strains exposed to IBZ sub-MIC concentrations. This study demonstrated the potent antibacterial activity of IBZ against a large collection of C. difficile strains including multidrug-resistant strains. This study highlights the therapeutic potential of IBZ against multidrug-resistant strains of C. difficile.

Fecal Pharmacokinetics and Gut Microbiome Effects of Oral Omadacycline Versus Vancomycin in Healthy Volunteers.

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS: Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P < .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS: Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION: NCT06030219.

Caring for the whole person: transgender-competent HIV pre-exposure prophylaxis as part of integrated primary healthcare services in Vietnam.

INTRODUCTION: Although HIV prevalence among transgender women who have sex with men in Vietnam is high (16-18%), uptake of pre-exposure prophylaxis (PrEP) is low compared to other populations. When PrEP was initiated in 2017, gender-affirming healthcare was largely unavailable. Lack of access to competent, stigma-free healthcare is a well-documented barrier to transgender women's uptake of PrEP and primary healthcare (PHC). We aimed to demonstrate the utility of a PrEP quality improvement intervention in pinpointing and addressing barriers to PrEP use among transgender women in Vietnam. METHODS: We applied a real-world participatory continuous quality improvement (CQI) and Plan-Do-Study-Act (PDSA) methodology to ascertain barriers to PrEP uptake among transgender women and determine priority actions for quality improvement. A CQI team representing transgender women leaders, key population (KP)-clinic staff, public-sector HIV managers and project staff applied PDSA to test solutions to identified barriers that addressed the primary quality improvement outcome of the monthly change in PrEP uptake among transgender women and secondary outcomes, including month-3 PrEP continuation, the impact of offering PHC on PrEP uptake and unmet PrEP need. We utilized routine programmatic data and a descriptive cross-sectional study enrolling 124 transgender women to measure these outcomes from October 2018 to September 2021. RESULTS: Five key barriers to PrEP uptake among transgender women were identified and corresponding solutions were put in place: (1) offering gender-affirming care training to KP-clinics and community-based organizations; (2) integrating gender-affirming services into 10 KP-clinics; (3) offering PHC through five one-stop shop (OSS) clinics; (4) implementing a campaign addressing concerns related to hormone use and PrEP interactions; and (5) developing national HIV and transgender healthcare guidelines. New PrEP enrolment and month-3 PrEP continuation increased significantly among transgender women. Of 235 transgender women who initially sought healthcare other than PrEP at OSS clinics, 26.4% subsequently enrolled in PrEP. About one-third of transgender women reported unmet PrEP need, while two-thirds indicated an interest in long-acting cabotegravir. CONCLUSIONS: Offering gender-competent, integrated PHC can increase PrEP enrolment and continuation, and can be an entry-point for PrEP among those seeking care within PHC clinics. More work is needed to expand access to transgender women-led and -competent healthcare in Vietnam.

Interstrains comparison of the antimicrobial effect and mode of action of a Vietnamese Cinnamomum cassia essential oil from leaves and its principal component against Listeria monocytogenes.

The antibacterial activity of a Cinnamomum cassia essential oil (EO) and of its main component trans-cinnamaldehyde (90% w/w) was examined against five Listeria monocytogenes strains. The minimal inhibitory concentrations (MICs) of C. cassia EO against the five L. monocytogenes strains were identical (250 µg ml-1 ), while the minimal bactericidal concentrations (MBCs) ranged between 800 and 1200 µg ml-1 . In order to study if this EO and trans-cinnamaldehyde altered the five strains at the membrane level, fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) was measured in presence of different concentrations (1/2MIC, MIC, 2MIC) of these antibacterial agents. A concentration-dependent increase of fluorescence anisotropy of DPH in their presence reflecting a rigidification of the membrane was observed for the five strains. This modification of the membrane fluidity was associated with a perturbation of the selective membrane permeability, as a perturbation of the gradient between intracellular and extracellular pH was also observed.

From conventional to disruptive: upturning the HIV testing status quo among men who have sex with men in Vietnam.

INTRODUCTION: HIV prevalence among men who have sex with men (MSM) in Vietnam is increasing, while annual HIV testing uptake has remained consistently low, posing a significant challenge to reaching the 90-90-90 goals. Barriers to MSM seeking HIV testing include concerns regarding confidentiality and lack of convenient testing options. Two new HIV testing strategies-HIV lay provider and HIV self-testing (HIVST)-were piloted alongside intensive social media outreach to increase access to and uptake of HIV testing among MSM not actively engaged in services. METHODS: We measured the proportion of first-time MSM HIV testers opting for HIV lay or self-testing, and factors that were associated with first-time testing, as part of a larger HIV lay and self-testing study among key populations in Vietnam. We also assessed MSM satisfaction with HIV lay or self-testing, and testing location and provider preferences. Finally, we calculated linkage to care cascade among MSM that were diagnosed and enrolled in anti-retroviral therapy (ART) services. RESULTS: Among MSM that sought HIV lay and self-testing, 57.9% (n = 320) and 51.3% (n = 412) were first-time testers respectively. In the final adjusted models, the odds of being a first-time tester and opting for HIV lay testing were higher among MSM who were young, had lower levels of income and had never exchanged sex for money; for HIVST, the odds of being a first-time HIV tester were higher among MSM that had attained lower levels of education. HIV lay and self-testing resulted in higher detection of new HIV cases (6.8%) compared to conventional HIV testing among key populations (estimated at 1.6% in 2016), while MSM linked to testing through social media interventions presented with even higher HIV-positivity (11%). Combined, 1655 HIV cases were diagnosed and more than 90% were registered for ART services. CONCLUSIONS: Our findings suggest that MSM-delivered HIV testing and self-testing, promoted through online or face-to-face interactions, offer important additions to MSM HIV testing services in Vietnam, and could significantly contribute to epidemic control by increasing HIV testing among harder-to-reach and higher-risk MSM, effectively enrolling them in ART, and reducing onward transmission.

Synergistic action of rapid chilling and nisin on the inactivation of Escherichia coli.

The effect of rapid and slow chilling on survival and nisin sensitivity was investigated in Escherichia coli. Membrane permeabilization induced by cold shock was assessed by uptake of the fluorescent dye 1-N-phenylnapthylamine. Slow chilling (2 degrees C min(-1)) did not induce transient susceptibility to nisin. Combining rapid chilling (2,000 degrees C min(-1)) and nisin causes a dose-dependent reduction in the population of cells in both exponential and stationary growth phases. A reduction of 6 log of exponentially growing cells was achieved with rapid chilling in the presence of 100 IU ml(-1) nisin. Cells were more sensitive if nisin was present during stress. Nevertheless, addition of nisin to cell suspension after the rapid chilling produced up to 5 log of cell inactivation for exponentially growing cells and 1 log for stationary growing cells. This suggests that the rapid chilling strongly damaged the cell membrane by disrupting the outer membrane barrier, allowing the sensitization of E. coli to nisin post-rapid chilling. Measurements of membrane permeabilization showed a good correlation between the membrane alteration and nisin sensitivity. Application involving the simultaneous treatment with nisin and rapid cold shock could thus be of value in controlling Gram negatives, enhancing microbiological safety and stability.

Rates of chilling to 0 degrees C: implications for the survival of microorganisms and relationship with membrane fluidity modifications.

The effects of slow chilling (2 degrees C min(-1)) and rapid chilling (2,000 degrees C min(-1)) were investigated on the survival and membrane fluidity of Escherichia coli, of Bacillus subtilis, and of Saccharomyces cerevisiae. Cell death was found to be dependent on the physiological state of cell cultures and on the rate of temperature downshift. Slow temperature decrease allowed cell stabilization, whereas the rapid chilling induced an immediate loss of viability of up to more than 90 and 70% for the exponentially growing cells of E. coli and B. subtilis, respectively. To relate the results of viability with changes in membrane physical state, membrane anisotropy variation was monitored during thermal stress using the fluorescence probe 1,6-diphenyl-1,3,5-hexatriene. No variation in the membrane fluidity of all the three microorganisms was found after the slow chilling. It is interesting to note that fluorescence measurements showed an irreversible rigidification of the membrane of exponentially growing cells of E. coli and B. subtilis after the instantaneous cold shock, which was not observed with S. cerevisiae. This irreversible effect of the rapid cold shock on the membrane correlated well with high rates of cell inactivation. Thus, membrane alteration seems to be the principal cause of the cold shock injury.