Journal of Antimicrobial Chemotherapy最新文献

Objectives: To evaluate the synergistic effect of a ceftibuten and polymyxin B combination and to determine its capacity to overcome polymyxin B resistance in polymyxin/carbapenem-resistant (PC-R) Klebsiella pneumoniae.

Methods: To investigate the combination's antibacterial efficacy, antimicrobial susceptibility tests using broth microdilution methods, chequerboard assays and time-kill testing were performed. Antibiofilm activity was also assessed. The treatment's effect on the bacterial cell membrane was examined by quantifying intracellular protein leakage and conducting scanning electron microscopy. Haemocompatibility tests were conducted to evaluate toxicity. Additionally, an infection model was established using Swiss mice to assess in vivo antimicrobial activity.

Results: The ceftibuten/polymyxin B combination demonstrated synergistic effects against several PC-R strains of K. pneumoniae, as determined by the FIC index (FICI) values, which ranged from 0.15 to 0.37. This combination was efficacious, exhibiting bactericidal activity at twice the MIC. Ceftibuten/polymyxin B also demonstrated antibiofilm activity. Additionally, ceftibuten/polymyxin B neither damaged the bacterial membrane nor exhibited haemolytic activity. Based on these findings, the in vivo therapeutic potential was investigated and it was found that ceftibuten/polymyxin B significantly decreased the bacterial load in the peritoneal lavage fluid of mice, revealing its effectiveness in treating infections caused by PC-R K. pneumoniae.

Conclusions: The ceftibuten/polymyxin B combination exhibited synergistic effects in vitro and in vivo, and thus might be a promising therapeutic alternative for treating PC-R K. pneumoniae infections. As the combination was efficacious in preclinical models, researchers may further investigate its potential in clinical studies.

Background: To date, no research has compared longer-term outcomes (antibiotic provision; re-consultations; hospital admissions for quinsy; cost-effectiveness) following presentation with acute sore throat at general practice (GP) versus newer, pharmacy-led services.

Methods: A retrospective, longitudinal cohort study of sore throat consultations between 1 November 2018 and 28 February 2020 either with the Wales pharmacy-led sore throat test and treat (STTT) service or with a healthcare professional at GP. Individual-level pharmacy consultation data from the national Choose Pharmacy IT application were securely uploaded to the Secure Anonymised Information Linkage Databank and linked to routinely collected, anonymized, population-scale, individual-level, anonymized health and administrative data.

Results: Of 72 736 index consultations, 6495 (8.9%) were with STTT and 66 241 (91.1%) with GP. Antibiotic provision at the index consultation was 1382 (21%) with STTT and 25 506 (39%) with GP [adjusted odds ratio (AOR), 0.30; 95% CI, 0.27 to 0.32]. Antibiotic provision within 28 days of index occurred in 1820 (28%) STTT and 26 369 (40%) GP consultations (AOR, 0.44; 95% CI, 0.41 to 0.47). GP re-consultation rate within 28 days of index date was 21% (n = 1389) with STTT compared with 7.4% (n = 4916) with GP (AOR, 3.8; 95% CI, 3.5 to 4.1). Coding limitations may lead to overestimates of GP re-consultations rates in the STTT group. Hospital admissions for quinsy were rare in both STTT (n = 20, 0.31%) and GP (n = 274, 0.41%) (AOR, 0.68; 95% CI, 0.43 to 1.1). STTT was less costly than consultation with GP.

Conclusions: The pharmacy-led STTT service is safe, cost-effective, and contributes to antimicrobial stewardship.

Background: Mycoplasma genitalium, which causes sexually transmitted diseases, is increasingly resistant to key antibiotics such as macrolides and quinolones, posing a challenge for treatment.

Objectives: To assess the effectiveness of prolonged sitafloxacin and doxycycline combination therapy as a new alternative treatment strategy for highly drug-resistant M. genitalium strains.

Methods: A prospective cohort study was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, from 1 January 2020 to 31 October 2022. Patients with M. genitalium urogenital or rectal infections and those who did not receive the initial sitafloxacin monotherapy were included. Patients were administered sitafloxacin and doxycycline for 21 days as salvage therapy. M. genitalium isolates were tested for parC, gyrA and 23S rRNA resistance-associated mutations.

Results: Twenty-seven patients received the combination therapy. All M. genitalium strains available for resistance analysis had parC (24/24) and macrolide resistance-associated (25/25) mutations, and 68% (17/25) had gyrA mutations. The overall cure rate was 77.8%. For strains with concurrent parC and gyrA mutations, the cure rate was 68.8% (P = 0.053) compared with that for monotherapy (37.5%).

Conclusions: Prolonged combination therapy is highly effective against M. genitalium strains with concurrent parC and gyrA mutations. Future research should focus on establishing the optimal treatment duration and monitoring the risk of resistance.

Background: The role of integrase strand transfer inhibitors (INSTI) in the cardiovascular risk of people with HIV is controversial.

Objectives: To assess the association of INSTI to subclinical atherosclerosis progression measured with the carotid intima-media thickness (cIMT).

Methods: Prospective study in virologically suppressed people with HIV receiving INSTI- or NNRTI-based regimens. cIMT was measured at baseline, 48 and 96 weeks. cIMT progression was analysed both as a continuous and categorical variable, defined as cIMT increase ≥ 10% and/or new carotid plaque. Adjustments through Cox proportional hazard regression and linear mixed models, and propensity score matching were conducted.

Results: 190 participants were recruited and 173 completed the 96 week follow-up. 107 (56.3%) were receiving an INSTI-containing, 128 (67.4%) a NNRTI-containing and 45 (23.7%) a NNRTI plus an INSTI-containing regimen. The overall median (IQR) 2-year change of cIMT was 0.029 (-0.041 to 0.124) mm; 87 (45.8%) participants experienced a cIMT increase ≥ 10%, of whom 54 (28.4%) developed a new carotid plaque. Adjusted Cox regression showed no differences between INSTI and NNRTI groups in the categorical 2-year progression of cIMT, both including or excluding participants receiving INSTI + NNRTI. Similar results were observed for the continuous cIMT increase through adjusted linear mixed models. Propensity score matching showed no significant differences in the 2 year cIMT change between treatment groups [0.049 mm (-0.031-0.103) in the INSTI group versus 0.047 mm (-0.023-0.115) in the NNRTI group; P = 0.647]. cIMT progression was associated with traditional cardiovascular risk factors.

Conclusions: INSTI-based regimens are not associated with increased progression of subclinical atherosclerosis when compared to NNRTI.

Background: Subcutaneous delivery of antibiotics is a practical alternative to IV administration. Meropenem is commonly used to treat infections caused by resistant Gram-negative organisms.

Methods: This was a prospective, crossover self-controlled study in 11 stable inpatients established on meropenem. Participants received a single dose of subcutaneous meropenem, in 50 mL normal saline via gravity feed. Venous blood sampling was performed at baseline, 0.5, 1, 2, 4 and 8 h following the subcutaneous and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were assessed.

Results: Subcutaneous meropenem was well tolerated. The bioavailability of subcutaneous administration was 81.5% (95% CI 71.6%-93.2%). Increasing BMI was associated with slower absorption from subcutaneous tissue. Compared with IV, subcutaneous administration resulted in lower peak and higher trough concentrations. Despite the lower bioavailability observed, the PTA for free drug concentrations greater than the MIC for more than 40% of the time between doses was higher for subcutaneous than IV administration at MIC values between 0.03 and 8 mg/L. Simulated subcutaneous doses of 1.5 g twice daily, or 3 g continuous 24 h infusion had improved PTA relative to standard IV dosing of 1 g three times daily.

Conclusions: Subcutaneous meropenem appears to be well tolerated and has a favourable pharmacokinetic profile. Either 1.5 g twice daily or 3 g as a 24 h subcutaneous infusion could be considered for future evaluation.

Background: Scedosporium/Lomentospora species are ranked as the second most frequently isolated filamentous fungi from cystic fibrosis (CF) patients. Previously, we demonstrated that the minimum inhibitory concentration (MIC) for voriconazole and posaconazole increased when performed on a mucin-containing synthetic CF sputum medium (SCFM) compared to the standard medium, RPMI-1640. In this study, we have expanded the MIC comparison to four additional azoles and investigated characteristics linked to azole resistance in Scedosporium apiospermum, Scedosporium minutisporum, Scedosporium aurantiacum and Lomentospora prolificans.

Methods: MIC was assayed by CLSI protocol, efflux pump activity was assessed by rhodamine 6G and sterols were analysed by gas chromatography-mass spectrometry (GC-MS).

Results: Overall, MICs for fluconazole, itraconazole, voriconazole, posaconazole, miconazole and ketoconazole increased by least 2-fold when susceptibility tests were performed using SCFM compared to RPMI. The activity of efflux pumps was similar in both media; however, in RPMI, but not in SCFM, the activity was induced by voriconazole and fluconazole. Additionally, MICs for those antifungals decreased more noticeably in SCFM than in RPMI in the presence of the efflux pump inhibitor PaβN. The SCFM-grown cells presented fewer sterols in their composition, and consequently higher membrane fluidity, than RPMI-grown cells. GC-MS analysis demonstrated a remodulation in the sterol profile in SCFM- compared to RPMI-grown cells. Accordingly, when the MIC assay was performed in the presence of the membrane stressor NaCl (3%), the susceptibility to voriconazole and fluconazole increased more in SCFM- than RPMI-grown cells.

Conclusions: Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.

Objectives: The objective of this study was to identify and analyse the distribution characteristics, toxin genotyping and antimicrobial susceptibility of Clostridium perfringens and to investigate its resistance mechanisms and genetic characteristics.

Methods: The MICs of various antibiotics against C. perfringens were determined using the agar dilution method, and resistance genes and toxin genotypes were detected by PCR. Genetic relationships were analysed using MLST. WGS was conducted on the DNB system and PacBio platforms.

Results: Analysis of 36 strains of C. perfringens revealed that the major toxin types were types C and F, with 86.1% of the strains isolated from bile samples. Of these, 30.6% of the strains exhibited MDR, with resistance rates of 75.0%, 52.8% and 52.8% for penicillin, clindamycin and ampicillin, respectively; however, no resistance to metronidazole and carbapenems was observed. MLST analysis identified 29 STs, including 14 novel types. ST221 and ST498 were the dominant types. The WGS revealed that the most prevalent virulence factors are plc (100.0%), nagH (100.0%), colA (100.0%), nanJ (100.0%), entB (100%), nanH (97.0%), entA (97.0%) and nanI (90.9%). Among these factors, the primary determinants of tetracycline resistance are tetA (66.7%) and tetB (78.8%), which represent the most frequently detected antibiotic resistance genes.

Conclusions: This study indicates that the infection rate of C. perfringens is relatively high, with the majority of isolated strains exhibiting MDR. The observed high levels of antibiotic resistance, combined with the significant genetic diversity of these strains, suggest a potential public health risk.

Background and objectives: In Belgium, monitoring antibiotic consumption relies on reimbursement data, which is obtained with a time delay and does not account for over-the-counter or nonreimbursed products. This study aims to bridge this gap by comparing reimbursement and retail data for primary care to understand variations and assess the accuracy of current surveillance methods.

Method: Reimbursement data were obtained from the National Institute for Health and Disability Insurance, and retail data were obtained from IQVIA for the period 2013-22. The community consumption of systemic antibiotics was expressed in defined daily doses (DDD-WHO ATC/DDD Index 2023) per inhabitants per day (DID). Relative differences in DID (RDs) based on the two data sets were computed and validated through Bland-Altman plots and correlation analysis.

Results: The sales of antibiotics declined from 22.89 DID (2013) to 20.50 (2022), with a steep drop during the COVID-19 pandemic-from 21.31 DID in 2019 to 16.55 DID in 2020-and a subsequent rebound. Reimbursement data slightly underestimated consumption compared to retail data, with RDs ranging from 2% (2013) to 9% (2022) when including quinolones and from 2% to 4% when excluding them. Bland-Altman plots showed high agreement between reimbursement and retail estimates, identifying quinolones as outliers.

Conclusion: Our findings suggest that reimbursement data are generally reliable for monitoring antibiotic consumption, but incorporating retail data is crucial for accurate assessments. The use of retail data can facilitate timely interventions and inform public health strategies to effectively address antimicrobial resistance.

Introduction: Antimicrobial resistance (AMR) is a global issue that needs addressing. While antibiotic stewardship has improved often by restricting antibiotic use, some antibiotics that are still sold legally over the counter (OTC), notably in sore throat medications. Recent findings suggest OTC antibiotics could trigger cross-resistance to antibiotics used in clinical treatments, whether systemic or topical. Here we investigated the impact of three antibiotics contained in OTC sore throat medicines on emerging AMR in vitro.

Methods: Bacterial pathogens were exposed to a bactericidal concentration of an aminoglycoside in the presence or absence of a during-use concentration of bacitracin, gramicidin or tyrothricin in a time-kill assay. Damage to the bacterial membrane was also investigated by measuring potassium leakage and membrane potential alteration post-OTC antibiotic exposure.

Results: Gramicidin (15 µg/mL) significantly decreased the bactericidal activity of amikacin, tobramycin or gentamicin in Acinetobacter baumannii. It also decreased gentamicin bactericidal activity in Enterobacter cloacae, Escherichia coli and Klebsiella pneumoniae, while tyrothricin decreased the aminoglycoside efficacy in E. cloacae and E. coli. Gramicidin significantly decreased bacterial membrane potential and caused significant potassium leakage.

Conclusion: Gramicidin and to some extent tyrothricin impacted aminoglycoside efficacy by affecting membrane potential, which is essential for aminoglycosides uptake. Thus, some OTC antibiotics can interfere with aminoglycoside activity, which could in turn affect treatment efficacy. Although the likelihood of OTC antibiotics and aminoglycosides being used at the same time might not be common, this research highlights one potential reason for OTC antibiotics' usage to result in treatment failure and their contribution to AMR development.

Objectives: We compared the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) in our cohort of treatment-naive people with HIV (PWH).

Methods: In a multicentre cohort of treatment-naive PWH starting a first-line regimen with either dolutegravir plus lamivudine or BIC/FTC/TAF, Kaplan-Meier survival analysis was used to estimate time to virological failure (VF) and time to treatment discontinuation (TD), whereas Cox regression was used to evaluate predictors of VF and TD. Changes in CD4+ cell count were assessed via non-parametric tests, and linear regression analyses were performed to explore predictors of CD4+ cell count changes.

Results: One hundred and seventy individuals were included: 66 started dolutegravir plus lamivudine (DTG group) and 104 started BIC/FTC/TAF (BIC group). During follow-up, we observed two VFs in the DTG group [1.7 per 100 person-years of follow-up (PYFU)] and two in the BIC group (1.7 per 100 PYFU). Estimated probability of remaining free from VF at Week 144 was 95.9% in the DTG group and 95.2% in the BIC group (log-rank P = 0.955). Four TDs were observed in the DTG group (3.4 per 100 PYFU) and 21 in the BIC group (17.6 per 100 PYFU). Estimated probability of maintaining the study regimen at Week 144 was 90.3% in the DTG group and 70.0% in the BIC group; individuals in the BIC group had a higher probability of TD (log-rank P = 0.003). In both groups, the CD4+ count improved significantly during follow-up.

Conclusions: Our study shows that both strategies are effective and safe, with few VFs and TDs due to tolerability issues.