Antimicrobial Agents and Chemotherapy最新文献

This study evaluated the safety and pharmacokinetics (PK) of a single dose of leritrelvir, a novel inhibitor of 3-chymotrypsin-like cysteine protease (3CLpro), in patients with hepatic impairment versus healthy participants with normal hepatic function. Eight participants with mild (Child-Pugh A) hepatic impairment, eight with moderate (Child-Pugh B) hepatic impairment, and eight healthy matched control participants were enrolled in this open-label, parallel clinical trial. After administration of leritrelvir of 400 mg, PK parameters were calculated and compared across groups. In total, 24 participants were enrolled and completed the study. Leritrelvir was generally well tolerated, with no serious adverse events or deaths reported during the study. Compared to the group with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for C_max, AUC_0-t, and AUC_0-∞ of leritrelvir in participants with mild hepatic impairment were 96.9% (69.3%, 135%), 92.2% (69.6%, 122%), and 92.1% (69.7%, 122%), respectively. For moderate hepatic impairment, the corresponding ratios were 91.6% (61.7%, 136%), 113% (80.0%, 160%), and 113% (80.0%, 159%). Leritrelvir exposures were comparable among the three groups. Overall, there was no clinically relevant difference in leritrelvir exposure in participants with hepatic impairment compared to normal controls. No dose adjustment is required for leritrelvir in patients with mild or moderate hepatic impairment.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06161259.

Tobramycin dosing in patients with cystic fibrosis (CF) is challenged by its high pharmacokinetic (PK) variability and narrow therapeutic window. Doses are typically individualized using two-sample log-linear regression (LLR) to quantify the area under the concentration-time curve (AUC). Bayesian model-informed precision dosing (MIPD) may allow dose individualization with fewer samples; however, the relative performance of these methods is unknown. This single-center retrospective analysis included adult patients with CF receiving tobramycin from 2015 to 2022. Tobramycin concentrations were predicted using LLR or Bayesian estimation with two population PK models (Hennig and Alghanem). Then, both methods were used to estimate the AUC for simulated patients. For Bayesian estimation, AUC estimation with flattened priors and limited sampling strategies were also assessed. Predictions were evaluated using normalized root mean square error (nRMSE), mean percent error (MPE), and accuracy. The data set included 70 treatment courses, with 32 not evaluable by LLR due to detection limits or timing issues. Bayesian estimation demonstrated worse accuracy (47.1%-50.7% vs 75.7%), higher MPE (24.2%-32.4% vs -2.4%), and higher nRMSE (35.0%-39.4% vs 24.8%) than LLR for peak concentrations but performed better on troughs (accuracy: 92.0%-92.9% vs 84.6%). Bayesian estimation with flattened priors and a single sample at 4 h was comparable to LLR performance, with better accuracy (42.9%-68.0% vs 41.1% LLR), comparable MPE (-2.3% to -3.7% vs -0.5%) and nRMSE (11.3%-21.6% vs 17.3%). Bayesian estimation with one concentration and flattened priors can match LLR prediction accuracy. However, popPK models must be improved to better estimate peak samples.

Praziquantel alone is insufficient for the control of schistosomiasis due to poor efficacy against juvenile worms and increasing concerns about the risk of drug resistance. We compared the efficacy and safety of praziquantel combined with four different artemisinin-based combinations to praziquantel alone in treating Schistosoma mansoni infection in Kenyan children. In this randomized, open-label, five-arm, head-to-head, non-inferiority trial, children (aged 9-15 years) with S. mansoni infection according to duplicate Kato Katz thick smears from a stool sample in the Mwea irrigation scheme of central Kenya, were enrolled. Participants were randomly assigned (1:1:1:1:1) via a computer-generated block randomization procedure to receive a single oral dose of praziquantel (PZQ) (40 mg/kg/day) alone or in combination with a 3-day course (4 mg/kg of artesunate) of artesunate plus sulfalene-pyrimethamine (As + SP), artesunate plus amodiaquine (As + AQ), artesunate plus mefloquine (As + MQ) or dihydroartemisinin-piperaquine (DHAP). Laboratory technicians were masked to treatment allocation, but participants, clinicians, and study nurses were not. The primary outcomes were the cure rate and frequency of adverse events, which were assessed 6 weeks after treatment in the available case population using a per-protocol analysis. The non-inferiority margin was set at -10% for the risk difference in cure rates between combination therapy and PZQ alone. Between 12 September 2018 and 11 January 2019, 540 participants were assigned to receive PZQ alone (n = 108), PZQ plus As + SP (n = 108), PZQ plus As + AQ (n = 108), PZQ plus As + MQ (n = 108), or PZQ plus DHAP (n = 108). Primary outcome data were available for 523 (96.9%) participants. The cure rate was 82.5% (85/103) in PZQ alone, 81.7% (85/104) in PZQ plus As + SP, 76.2% (80/105) in PZQ plus As + AQ, 88.7% (94/106) in PZQ plus As + MQ, and 85.7% (90/105) in PZQ plus DHAP arm. Non-inferiority was declared for PZQ plus As + MQ (difference 6.2 [95% confidence interval: -3.3 to 15.6]) and PZQ plus DHAP (3.2 [-6.7 to 13.1]) but not for PZQ plus As + SP (-0.8 [-11.2 to 9.6]) or PZQ plus As + AQ (-6.3 [-17.3 to 4.6]). Adverse events were reported by 26% (138/540) of participants, including abdominal pain, headache, and vomiting. There were no serious adverse events. Alternatives to praziquantel should include praziquantel plus artesunate-mefloquine or praziquantel plus dihydroartemisinin-piperaquine. However, further multicentre trials are needed in different epidemiological settings and population groups to confirm these findings.CLINICAL TRIALSThis study is registered with the Pan-African Clinical Trials Registry under PACTR202001919442161.

Omadacycline, an aminomethylcycline tetracycline, has a low propensity to cause Clostridioides difficile infection (CDI) in clinical trials. Omadacycline exhibited a reduced bactericidal effect compared with vancomycin on key microorganisms implicated in bile acid homeostasis and short-chain fatty acids (SCFAs), key components of CDI pathogenesis. The purpose of this study was to assess bile acid and SCFA changes in stool samples from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers, who were given oral omadacycline or vancomycin for 10 days. Daily stool samples were assessed for bile acids and SCFA concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bile acids changed significantly over time for all subjects (P < 0.01 for each bile acid), with vancomycin causing a larger change in the primary bile acids, cholic acid (P < 0.001) and chenodeoxycholic acid (P < 0.001), and a reduced change in the secondary bile acid, lithocholic acid (P < 0.001). The secondary bile acid ursodeoxycholic acid was reduced less by vancomycin than by omadacycline (P < 0.001). All SCFA concentrations were reduced from baseline with a larger effect observed with vancomycin for isobutyric acid (P = 0.0034), propionic acid (P = 0.0012), and acetic acid (P = 0.047). Microbial changes associated with the use of vancomycin versus omadacycline were also associated with changes in bile acid homeostasis and SCFA concentrations. Oral omadacycline produced a distinctive metabolomic profile compared with vancomycin when administered to healthy subjects. The metabolic findings help further our understanding of the lower CDI risk properties of omadacycline and warrant phase 2 investigations using omadacycline as a CDI antibiotic.

Importance: The purpose of this study was to assess bile acid and SCFA changes in stool samples obtained from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers given a 10-day oral course of omadacycline or vancomycin. Vancomycin caused a larger change in the primary bile acids and SCFA concentrations compared with omadacycline. The metabolic findings help further our understanding of the mechanistic basis for the lower-risk properties of omadacycline causing CDI and warrant phase 2 investigations using omadacycline as a CDI antibiotic.

Clinical trials: This study is registered with ClinicalTrials.gov as NCT06030219.

Ethambutol is used to treat tuberculosis (TB) in individuals living with HIV. Low concentrations of ethambutol have been reported in patients dosed with the World Health Organization (WHO)-recommended first-line regimen. We analyzed the pharmacokinetics of ethambutol in 61 HIV-positive individuals diagnosed with drug-sensitive TB enrolled in the tuberculosis and highly active antiretroviral therapy (TB-HAART) study. Participants started on TB treatment and were randomized to early or later introduction of efavirenz-based antiretroviral treatment. We explored potential covariate effects and evaluated the current WHO dosing recommendations for ethambutol in drug-susceptible and multidrug-resistant (MDR)-TB. A two-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption best described the pharmacokinetics of ethambutol. Clearance was estimated to be 40.3 L/h for a typical individual with a fat-free mass (FFM) of 42 kg. The Antib-4 formulation had 26% higher bioavailability and slower mean transit time by 37% compared with Rifafour. Simulations showed that individuals in the lower weight bands (<55 kg) who were administered ethambutol at WHO-recommended doses had relatively low drug exposures. These individuals would need doses of 825 mg if their body weight is <37.9 kg and 1,100 mg if it is between 38 and 54.9 kg to achieve the reference maximum concentrations of 2-6 mg/L and an area under the concentration-time curve (0-24) of 16-29 mg·h/L. To achieve these targets in MDR-TB treatment, a dose increment of 400 mg (extra tablet) would be required for individuals in the lower weight band (<46 kg). Our dose adjustments are consistent with the literature and can be recommended for consideration by the WHO for first-line drug-susceptible and MDR-TB treatment.

Drug development for congenital toxoplasmosis is challenging since first-line therapy has a high rate of adverse effects and exhibits suboptimal efficacy. Bumped kinase inhibitors (BKIs), targeting protein kinases with small gatekeeper residues, have been found to be effective against Toxoplasma gondii. The efficacy of BKI-1748 administered later than 2 days post-infection (p.i.), a scenario that may better reflect its real-world use as a therapeutic candidate, has not been investigated in T. gondii-infected pregnant sheep. For this purpose, 19 pregnant sheep were assigned to three experimental groups. Group 1 (G1, n = 8) and group 2 (G2, n = 8) were dosed orally with 10 TgShSp1 sporulated oocysts at 90 days of gestation (dg). Animals from group 3 (G3, n = 3) were simultaneously mock dosed with phosphate-buffered solution (PBS). In G1, BKI-1748 was administered orally from day 7 p.i. (fever and increased serum IFNγ levels) onward, maintaining drug exposure for 20 days (10 doses at 15 mg/kg every 2 days). Treated animals (G1) exhibited significantly lower rectal temperatures (on days 8 and 9 p.i.), serum IFNγ levels (on day 10 p.i.), and specific IgG levels when compared with non-treated animals (G2). At delivery, significantly higher percentages of healthy lambs were found in infected/treated sheep in G1 (73.3%) and in uninfected sheep in G3 (80%) compared with infected/untreated sheep in G2 (31.3%). Concerning congenital transmission, parasite DNA was neither detected in placenta nor target tissues (brain and lungs) from the fetuses/lambs in G1(infected/treated) and G3 (uninfected). By contrast, parasite DNA was detected in all placentas and lambs from G2 (infected/untreated), except for one sheep that aborted on day 13 p.i.

Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp; Nsp12). Here, we conducted viral resistance analyses from the Phase 3 PINETREE trial of remdesivir in nonhospitalized participants at risk of severe COVID-19. Nasopharyngeal swabs (collected at baseline [Day 1], Days 2, 3, 7, and 14) were eligible for analysis if their viral load was above the lower limit of quantification for the RT-qPCR assay (2228 copies/mL). The SARS-CoV-2 genome was sequenced for all remdesivir participants and 50% of placebo participants (baseline, Days 3, 7, and 14) and for participants who progressed to COVID-19-related hospitalization or all-cause death (all time points). Emergent substitutions in Nsp12 and other replication complex proteins were phenotyped using site-directed mutagenesis in a SARS-CoV-2 subgenomic replicon system. Overall, emergent Nsp12 substitutions were detected in 8/115 (7.0%) remdesivir participants and 7/129 (5.4%) placebo participants (1 substitution overlap between groups). Based on a structural analysis, none of the emergent Nsp12 substitutions were in direct contact with the incoming nucleoside triphosphate substrate, the RNA, or the RNA template 5' overhang. One substitution (A376V) showed reduced susceptibility to remdesivir (12.6-fold change in remdesivir half-maximal concentration [EC₅₀]); it also showed reduced fitness when introduced in the SARS-CoV-2 replicon and virus in vitro. Other substitutions had <1.1-fold change in remdesivir EC₅₀. None of the emergent substitutions in Nsp8, Nsp10, Nsp13, or Nsp14 (remdesivir, 10/115 [8.7%]; placebo, 10/129 [7.8%]) showed reduced remdesivir susceptibility. In conclusion, emergent substitutions in the SARS-CoV-2 RdRp complex with reduced remdesivir susceptibility were uncommon, indicating a high barrier to remdesivir resistance.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04501952.

Omadacycline is a novel antimicrobial belonging to the tetracycline class. It has the ability to evade both efflux and ribosomal methylation types of resistance and therefore has an expanded spectrum compared to other tetracycline agents. Omadacycline is active against a number of multidrug-resistant bacteria, including macrolide and doxycycline-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, and several enteric gram-negative bacilli. It also has activity against many nontuberculous mycobacterium (NTM) species. It is available both orally and intravenously, which allows for feasible switch therapy. This review will assess the antimicrobial activity, pharmacology, safety, and clinical efficacy of omadacycline and present the opinions of the authors on where to position omadacycline for clinical practice.

Brucellosis has therapeutic challenges due to 3%-15% relapses/therapeutic failures (R/TF) after antibiotic treatment. Therefore, determining the antibiotic concentration in tissues, the physiopathological parameters, and the R/TF after treatment is relevant. After exploring different antibiotic quantities, we found that a combined dose of 100 µg/g of doxycycline (for 45 days) and 7.5 µg/g of streptomycin (for 14 days), respectively, achieved therapeutic levels of more than fourfold minimum inhibitory concentrations (MICs) against Brucella abortus in the spleen, liver, bone marrow, and plasma of mice, causing minimal pathophysiological effects. After 30 days of infection, mice received antibiotics, and hematological, histopathological, biochemical, and immunological analyses were performed. After antibiotic therapy, the pathological, hematological, immunological, and physiological profiles paralleled those described in human brucellosis. Treatment lowered antibody titers, reduced proinflammatory cytokines, and reduced inflammation in the target organs for a protracted period. No bacteria were detected in tissues 8 weeks after treatment, suggesting complete recovery. However, despite high doxycycline and streptomycin concentrations in tissues, relapses appeared in 100% of the animals after 182 days post-infection, estimated by the bacterial counts and PCR from organs. This proportion contrasts with the 15% R/TF observed in humans after antibiotic treatments. None of the B. abortus isolated from relapses showed augmented MICs or mutations coding for antibiotic resistance in chromosomal-relevant regions. We discuss whether our findings constitute a general phenomenon or differences in the exhaustive screening method for bacteria detection related to the murine model. Along these lines, we envision likely mechanisms of bacterial persistence in tissues after antibiotic treatment.

Peptide-based therapeutics are gaining attention for their potential to target various viral and host cell factors. One notable example is Pep19-2.5 (Aspidasept), a synthetic anti-lipopolysaccharide peptide that binds to heparan sulfate proteoglycans (HSPGs) and has demonstrated inhibitory effects against certain bacteria and enveloped viruses. This study explores, for the first time, the effectiveness of Pep19-2.5 against a non-enveloped virus, using pseudoviruses of the oncogenic human papillomavirus type 16 (HPV16) as a model. HPV16 infects epithelial cells of the skin and mucosa by using multiple cell surface receptors with initial attachment to HSPGs. Pharmacological inhibition with Pep19-2.5 in HeLa and HaCaT cells resulted in a concentration-dependent reduction of HPV16 PsV infection, with near-complete blockade observed at higher concentrations. The half-maximal inhibitory concentration (IC₅₀) was determined to be 116 nM in HeLa cells and 183 nM in HaCaT cells, highlighting its potent antiviral activity. Our results demonstrate that Pep19-2.5 not only inhibits HPV16 PsV binding to the cell surface but also significantly reduces infection when administered post-binding. Imaging analyses revealed Pep19-2.5-dependent release of large cell-associated crowds of viral particles, suggesting interference with the transfer to secondary receptor molecules. This was corroborated by the effectiveness of Pep19-2.5 in an HSPG-negative cell line, indicating that the peptide disrupts virus binding to both primary and secondary interaction partners. Based on these findings, we propose that the antimicrobial effect of Pep19-2.5 is not limited to HSPG-dependent infections. Additionally, Pep19-2.5 may be a valuable tool for dissecting specific steps in the viral entry process.