Journal of Antimicrobial Chemotherapy最新文献

Background: 'One Health' initiatives to tackle the rising risk of antimicrobial resistance (AMR) have flourished due to increasing detection of Enterobacterales producing extended-spectrum beta-lactamases (ESBLs) and carbapenemases (CPs).

Objectives: This study aimed to conduct an in-depth holistic analysis of Escherichia coli (Ec) and Klebsiella pneumoniae (Kp) isolates recovered from landfill-foraging white stork faecal samples and clinical isolates from a nearby hospital.

Methods: Faecal samples (n = 211) were collected from storks foraging at two landfills in Spain. Ec/Kp stork isolates were recovered on selective media and whole-genome sequencing (WGS), together with isolates obtained from the nearby hospital. These genomic data were compared with public genomes from different contexts (clinical, environmental, or animal hubs) to understand global transmission dynamics.

Results: A wide range of blaESBL/blapAmpC (blaCTX-M/blaSHV-12/blaDHA) were detected in 71 stork samples (33.6%), while blaCP (blaKPC/blaNDM/blaOXA-48/blaVIM) were identified in 28 (13.3%) samples. Clonal and plasmid transmissions were evidenced inside and between both landfills. Mapping against 10 624 public Ec/Kp genomes and from those of nearby hospital revealed that identical strains (<10 allelic differences with Ec-ST38/ST131 and Kp-ST512 lineages) and epidemic plasmids (full identity/coverage with IncN/blaKPC-2, IncF/blaKPC-3, IncX3/blaNDM-7, IncL/blaOXA-48) were found from clinical isolates in countries located along the storks' migration routes.

Conclusions: Storks may be contaminated by bacterial isolates from a likely human origin and become non-human reservoirs of critical genes, which can be dispersed over long distances. Identifying strains/plasmids along the stork's routes that are identical or closely related to those described here opens new perspectives for large-scale research to understand the AMR transmission dynamics.

Objectives: Hypofibrinogenaemia is a serious adverse reaction associated with tigecycline (TGC) therapy and may lead to the discontinuation of the treatment. This study aimed to explore the relevant factors of TGC-induced hypofibrinogenaemia and determine the thresholds of serum concentration as a predictive indicator of TGC-induced hypofibrinogenaemia.

Methods: A retrospective single-centre study was conducted on patients with severe infection who were treated with TGC. Clinical data and serum concentration parameters were extracted from the electronic medical records of these patients. Patients were divided into the hypofibrinogenaemia group (< 2.0 g/L) and the normal fibrinogen group (≥ 2.0 g/L) in order to evaluate risk factors associated with TGC-induced hypofibrinogenaemia. Logistic regression analysis and receiver operating characteristic curves were utilized to identify the risk factors associated with TGC-induced hypofibrinogenaemia and to establish plasma concentration thresholds as predictive indicators.

Results: A total of 114 patients were enrolled in this study, with 59.6% experiencing hypofibrinogenaemia. The multivariate regression analysis indicated that baseline fibrinogen level, trough concentration (Cmin), peak concentration (Cmax), the concentration at 6 h after the dosing (C6h) and the area under the concentration-time curve over a 24-h period (AUC0-24) were significantly associated with hypofibrinogenaemia (P < 0.05). Furthermore, it was found that AUC0-24 is the optimal predictor of TGC-induced hypofibrinogenaemia. The optimal cut-off for the AUC0-24 of TGC in ICU patients was determined to be 17.03 mg h/L.

Conclusions: TGC exposure is highly predictive of TGC-induced hypofibrinogenaemia. We recommend closely monitoring plasma concentrations of TGC in patients to ensure patient efficacy and safety.

Introduction: Pyrazinamide, one of the first-line antituberculosis drugs, displays variability in drug exposure that is associated with treatment response. A simple, low-cost assay may be helpful to optimize treatment. This study aimed to develop and validate a point-of-care assay to quantify the concentration of pyrazinamide in saliva.

Methods: All measurements were conducted using the nano-volume drop function on the mobile ultraviolet (UV) spectrophotometer (NP80, Implen, Germany). Assay development involved applying second derivative spectroscopy in combination with the Savitzky-Golay filter between wavelengths of 200-300 nm to increase spectral resolution. Assay validation included assessing selectivity, linearity, accuracy, precision, carry-over and matrix effects. Specificity was also analysed by evaluating the impact of co-administered medications on pyrazinamide results. Sample stability was measured at various temperatures up to 40°C.

Results: The calibration curve (7.5-200 mg/L) was linear (R2 = 0.9991). The overall accuracy (bias%) and precision (CV%) ranged from -0.66% to 5.15%, and 0.56% to 4.95%, respectively. Carry-over and matrix effects were both acceptable with a bias% of <±4% and CV% of <7.5%. Commonly co-administered medications displayed negligible interferences. Levofloxacin displayed analytical interference (bias% = -10.21%) at pyrazinamide concentrations < 25 mg/L, but this will have little clinical implications. Pyrazinamide was considered stable in saliva after 7 days in all storage conditions with a CV% of <6.5% and bias% of <±10.5% for both low- and high-quality control concentrations.

Conclusions: A saliva-based assay for pyrazinamide has been successfully developed and validated using the mobile UV spectrophotometer.

Objectives: To establish a formal diagnosis in infectious disease is not an easy task. Our aim was to characterize diagnostic uncertainty (DU) in patients for whom blood cultures were positive (PBC) and to determine its impact on both the antibiotic therapy and the outcome.

Methods: This was a prospective multicentre study including PBC for 6 months. The laboratory gave the PBC result to the infectious disease (ID) specialists in real time (24/7). The latter analysed all data from electronic patient charts and gave therapeutic advice to the physicians in charge of the patient to either initiate an antibiotic therapy, or to modify or to pursue continuing antimicrobial treatment. A DU was defined as no diagnosis of ID after thorough reading of the patient's chart, or more than two diagnoses despite two medical opinions obtained before PBC. An unfavourable outcome was defined by the occurrence of death during hospitalization.

Results: One hundred and nighty-nine PBCs were communicated to ID specialists, including 93 DUs (47%). In multivariate analysis, DU was associated with hospitalization in medical wards: [adjusted odds ratio (AOR) (95% CI): 6.94 (3.41-14.28)], the advice to initiate an antibiotic treatment: [3.89 (1.56-9.70)] and piperacillin-tazobactam use [3.75 (1.56-9.00)]; ICU requirement at initiation of care was a protective factor [0.38 (0.17-0.84)]. An unfavourable outcome was observed in 22 cases, and in a second logistic regression showed that DU was associated with the latter [AOR (95% CI): 5.07 (1.60-16.12)].

Conclusion: DUs were frequent during infections proved by PBC, and were associated with admission in medical wards, broad-spectrum antibiotic use and a high rate of unfavourable outcomes.

Background: The EASL cystic liver disease guideline states that drug penetration at the site of infection (liver cyst) is essential for successful treatment, but pharmacokinetic (PK) data on cyst penetration are limited.

Objectives: This study aims to investigate tissue penetration of four antibiotics in non-infected liver cysts and explores influencing factors.

Methods: We performed a prospective, randomized single-dose PK-study. Before percutaneous drainage of a non-infected liver cyst, an intravenous (IV) dose of either ciprofloxacin and piperacillin/tazobactam (group 1); or co-trimoxazole (trimethoprim/sulfamethoxazole) and doxycycline (group 2) was given. Cyst fluid was collected during drainage. Blood samples were obtained before, during and after drainage (within 12 h). Drug concentrations were measured with a validated LC-MS/MS. Primary outcome was liver cyst penetration, defined as the cyst-fluid-to-plasma concentration ratio (%) expressed as median (IQR).

Results: We included 20 patients, and 21 liver cysts were drained (group 1: n = 11, group 2: n = 10). Median drained cyst volume was 700 mL. Median time between infusion and drainage was 139 min (IQR 120-188 min). Median cyst-fluid-to-plasma concentration ratio was 4.2% (IQR 1.6%-8.9%) for ciprofloxacin, 0.3% (IQR 0.0%-1.3%) for piperacillin, 0.2% (IQR 0.0%-1.3%) for tazobactam, 12.2% (IQR 6.3%-16.1%) for trimethoprim, 0.4% (IQR 0.2%-3.8%) for sulfamethoxazole and 1.6% (IQR 0.9%-2.3%) for doxycycline. Time between trimethoprim infusion and cyst drainage was correlated with increased cyst-fluid-to-plasma concentration ratio (P < 0.01).

Conclusions: Trimethoprim and ciprofloxacin have the highest penetration ratios amongst antibiotics tested. We found that liver cyst penetration varies widely between drugs after a single IV dose.

Clinical trial number: NTR8499The trial was originally registered in the Netherlands Trial Register (ID: NL7290), which was converted to the International Clinical Trials Registry Platform in 2022.

Background: Antiretroviral therapy (ART) is recommended for all individuals with HIV infection, including those with acute HIV-1 infection (AHI). While recommendations are similar to those for chronic infection, efficacy data regarding treatment of acute HIV is limited.

Methods: This was a single arm, 96-week study of a once-daily integrase inhibitor (INSTI)-based regimen using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) in AHI. Primary endpoint was proportion of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL by treatment weeks 24 and 48, respectively. We also examined time to viral suppression and weight gain after treatment initiation. Outcomes and characteristics were compared with a historical AHI cohort using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).

Results: Thirty-three participants with AHI were enrolled with 31 available for analyses. Most were African American (61%) and men who have sex with men (73%). Median age was 26 (IQR 22-42). Demographics were similar between the two AHI cohorts. By Week 24, 100% in the INSTI and 99% in the NNRTI cohort were <200 copies/mL; by Week 48, 100% in both cohorts were <50 copies/mL. Time to viral suppression was shorter in the INSTI cohort (median 54 versus 99 days). Mean weight change was similar with a 3.6 kg increase in the INSTI cohort and 2.4 kg in the NNRTI cohort at 96 weeks.

Conclusions: INSTI-based ART during AHI resulted in rapid and sustained viral suppression. Over 96 weeks, weight increased in the INSTI-based cohort but was similar to weight increase in a historical NNRTI-based AHI cohort.

Background: Tigecycline is an antimicrobial agent with a broad spectrum of activity against both Gram-positive and Gram-negative bacteria. However, mobile tigecycline resistance gene clusters, such as tnfxB-tmexCD-toprJ, have spread globally. The prevalence of tigecycline-resistant Enterobacterales in clinical settings in Japan is unknown.

Objectives: To investigate the tnfxB-tmexCD-toprJ gene cluster in the genome sequences of Enterobacterales clinical isolates in Japan.

Methods: We investigated the tnfxB-tmexCD-toprJ cluster from the genome sequences of 5143 Enterobacterales isolates collected from 175 hospitals around Japan between 2019 and 2020 as part of a national genomic surveillance program for antimicrobial-resistant bacteria.

Results: The tnfxB1-tmexCD1-toprJ1 cluster was detected in two Klebsiella pneumoniae isolates in 2019. One isolate possessed a 299.4 kb IncFIB(K) plasmid, pJBBGAAF19431, and the other possessed a 224.9 kb IncHI1B/IncFIB(K) hybrid plasmid, pJBEAACG19501, co-carrying multiple antimicrobial resistance genes, including extended-spectrum β-lactamase genes, blaOXA-1 and blaCTX-M-27, respectively, along with tnfxB1-tmexCD1-toprJ1. The genetic context of the tnfxB1-tmexCD1-toprJ1-surrounding structure on pJBBGAAF19431 was similar to that of a K. pneumoniae plasmid pHNAH8I-1 from a chicken in China in 2017, and the cluster was embedded in an apparently intact mobile DNA element: strand-biased circularizing integrative element. The tnfxB1-tmexCD1-toprJ1 on pJBEAACG19501 was embedded in a Tn3 family transposon related to TnAs1. The plasmid pJBEAACG19501 was highly similar to that of K. pneumoniae, isolated from humans in China in 2021.

Conclusions: tmexCD-toprJ was present in Japan as of 2019. Even in Japan, where the clinical use of tigecycline is significantly rare, tmexCD-toprJ-harbouring multidrug-resistant Enterobacterales is a public health threat and requires continuous monitoring.

Background: Carbapenemase-producing Enterobacterales (CPE) pose difficult therapeutic challenges. We aimed to characterize antimicrobial resistance profiles of CPE in our centre.

Methods: All non-duplicate CPE isolates between 1 August 2020 and 31 August 2023 in a large teaching trust in England were retrospectively studied. Cefiderocol antimicrobial susceptibility testing (AST) was performed using disc diffusion, ceftazidime/avibactam using disc diffusion and gradient diffusion, and ceftazidime/avibactam aztreonam synergy using the double disc diffusion method. EUCAST version 14.0 breakpoints were used.

Results: A total of 158 CPE from 136 patients were isolated. Most patients were colonized with CPE, but only 16.9% had active infections. Thirty-day all-cause mortality was 10.3%, increasing to 13% for patients with infections and to 18.2% for bacteraemias. OXA-48 was the most prevalent carbapenemase (48.1%), followed by NDM (38%). All isolates exhibited MDR profiles, with high levels of resistance to meropenem (41.1%). Resistance to cefiderocol was found in 69.7% of NDM-producing isolates, with a further 18.2% in the area of technical uncertainty. Ceftazidime/avibactam and aztreonam synergy was seen in 87.5% of isolates, whereas colistin and fosfomycin susceptibility remained high (98.1% and 97.2%, respectively). All OXA-48-producing isolates were susceptible to ceftazidime/avibactam, and 15.3% were resistant to cefiderocol. No patients had been exposed to cefiderocol beforehand, whereas three had been exposed to ceftazidime/avibactam. The most common risk factor for CPE isolation was travel and receiving healthcare abroad, especially in Asia.

Conclusions: We found high rates of resistance to cefiderocol in CPE isolates without prior cefiderocol exposure. Our results prohibit empirical use of cefiderocol for the treatment of CPE infections in our setting.

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.