Sohei Harada

OBJECTIVE: Infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) have a poor prognosis, particularly in immunocompromised patients. While carbapenemase production is the primary resistance mechanism in CRKP, other mechanisms may contribute synergistically to carbapenem resistance. Here, we describe a case in which extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae, initially susceptible to carbapenems, acquired carbapenem resistance without carbapenemase production following ceftolozane-tazobactam exposure. METHODS: Whole-genome sequencing was performed on ESBL-producing K. pneumoniae strains detected during the clinical course to investigate the relationship between the genetic characteristics and antimicrobial susceptibility, particularly to ceftolozane-tazobactam and carbapenems. Changes in the transcription levels of the beta-lactamase genes were also analyzed using reverse transcription quantitative PCR (RT-qPCR). RESULTS: Active surveillance stool culture before cord blood transplantation (CBT) identified colonization with an ESBL-producing K. pneumoniae strain. Febrile neutropenia occurred on day 7 after CBT and was treated empirically with ceftolozane-tazobactam. Fatal bacteremia developed on day 30 after CBT due to a carbapenemase-negative isolate resistant to both ceftolozane-tazobactam and carbapenems. Whole-genome sequencing analysis revealed that K. pneumoniae ST307 strains harboring blaCTX-M-15, blaSHV-28, and blaTEM-1B acquired a nonsense mutation in ompK36 following ceftolozane-tazobactam exposure. RT-qPCR analysis documented a significant increase in blaSHV-28 transcription after ceftolozane-tazobactam exposure. CONCLUSIONS: This case demonstrates that K. pneumoniae without carbapenemase production can acquire carbapenem resistance through a combined resistance mechanisms following exposure to non-carbapenem antibiotics. Antimicrobial stewardship must be implemented comprehensively, not focused solely on specific antibiotics.

Background Bloodstream infections (BSIs) caused by extended-spectrum β-lactamase-producingEnterobacterales (ESBL-E) are associated with increased morbidity and mortality, yet the optimal empiric treatment strategy remains uncertain. We aimed to identify prognostic factors for early clinical response and 30-day mortality in patients with ESBL-E bacteremia and to evaluate the impact of the appropriateness of empiric antimicrobial therapy. Methods We conducted a retrospective cohort study at a 916-bed tertiary care hospital in Tokyo, Japan, including all patients with ESBL-E bacteremia between April 2018 and March 2023. Clinical, microbiological, and therapeutic data were extracted from electronic medical records. Independent variables were selected based on prior literature, including age, sex, Charlson Comorbidity Index (CCI), quick sequential organ failure assessment (qSOFA) score, infection setting, invasive device use, C-reactive protein (CRP) level, and appropriateness of empiric antimicrobial therapy. Logistic regression was used to identify predictors of clinical improvement within 72 hours and 30-day all-cause mortality. Results A total of 138 patients were included, with a median age of 72.7 years; 83% of infections were caused by Escherichia coli. The urinary tract was the most common source of infection (58%). Approximately half of the infections were hospital-acquired (49%), and 46% were community-acquired. Appropriate empiric therapy, defined according to Clinical and Laboratory Standards Institute (CLSI) criteria, was administered in 60% of cases. Logistic regression analysis revealed that a qSOFA score ≥2 was significantly associated with reduced clinical improvement at 72 hours (odds ratio (OR), 0.29; 95% confidence interval (CI), 0.11-0.76) and with increased 30-day mortality (OR, 9.42; 95%CI, 2.27-39.11). Conversely, community-acquired infection was independently associated with reduced mortality risk (OR, 0.25; 95%CI, 0.06-0.94). Appropriateness of empiric antimicrobial therapy was not significantly associated with either early clinical response or 30-day mortality in multivariable analysis. In subgroup analysis of patients with a qSOFA score ≥2, inappropriate empiric therapy tended to be associated with higher 30-day mortality (OR, 7.22; 95%CI, 0.74-107.88), though this did not reach statistical significance. Conclusion Among patients with ESBL-E bacteremia, a qSOFA score ≥2 at the time of blood culture collection was the strongest independent predictor of both poor early clinical response and higher 30-day mortality, regardless of empiric antimicrobial appropriateness. These findings suggest that patient severity at presentation may outweigh the impact of initial antimicrobial selection in determining outcomes. However, potential for clinical deterioration with inappropriate therapy in high-risk patients underscores the need for timely, effective empiric coverage in those with suspected sepsis and elevated qSOFA scores. Risk stratification using qSOFA may support tailored empiric therapy decisions, helping to balance effective patient care with antimicrobial stewardship. Prospective, multicenter studies are warranted to validate these results and refine treatment strategies in the era of increasing antimicrobial resistance.

Here, we report the draft genome sequence of Stenotrophomonas maltophilia TUM26315, which exhibits resistance to cefiderocol and to aztreonam combined with ceftazidime-avibactam, despite no prior exposure. The isolate belonged to genomic group 6 and carried blaL1B and blaL2B β-lactamase genes. It also had a frameshift mutation in the cirA gene.

Daptomycin is an alternative agent for invasive infections caused by Corynebacterium species in patients with intolerance to vancomycin. Although it has recently been recognized that treatment failure with daptomycin due to the emergence of resistant strains during treatment is not uncommon in Corynebacterium striatum infections, it has been unclear whether there is a similar risk in Corynebacterium jeikeium infections. In the presenting case, daptomycin treatment for C. jeikeium endocarditis in a liver transplant recipient with neutropenia failed due to the rapid emergence of the resistant strain. Whole-genome sequencing analysis of blood culture isolates confirmed that a mutation in the pgsA gene, which is also involved in the development of daptomycin resistance in C. striatum, emerged after daptomycin exposure. This case demonstrated that there is a risk of treatment failure due to the emergence of daptomycin-resistant strains even in C. jeikeium infections caused by daptomycin-susceptible strains, particularly in immunocompromised patients and in biofilm infections with high bacterial burden.

UNLABELLED: Among Corynebacterium species, Corynebacterium striatum is relatively frequently involved in invasive human infections. In this study, we collected clinical information from patients diagnosed with C. striatum infection at a single cancer center and performed antimicrobial susceptibility testing and whole-genome sequencing of the causative strains. Of the 51 patients with C. striatum infections, 15 (29.4%) had postoperative intra-abdominal infections, eight (15.7%) had postoperative skin and soft tissue infections of the neck, and eight (15.7%) had osteoarticular infections. In 15 patients, C. striatum was detected concomitantly with other bacteria. The median duration of antimicrobial therapy was 25 days, with 43 patients (84.3%) showing clinical improvement by day 14. The crude mortality up to 90 days post-diagnosis was 15.7%. Vancomycin was the most commonly used definitive therapy, and 40 patients (78.4%) received multiple antimicrobial agents. Oral minocycline was often administered in patients requiring long-term treatment. Antimicrobial susceptibility testing of 53 strains, including two strains from follow-up cultures from the same patient, showed that most strains were susceptible to daptomycin and tetracyclines. However, non-susceptibility was noted in two strains (3.8%) for daptomycin and four strains (7.5%) for tetracyclines, each associated with psgA2 mutation and tet(W) carriage. Core-genome single-nucleotide polymorphism analysis of the strains and epidemiological reviews of the source patients identified three suspected clusters of nosocomial transmission involving seven patients. This study demonstrated that C. striatum can cause a range of infections in patients with underlying diseases, such as malignancy, and that nosocomial spread of this pathogen may also occur. IMPORTANCE: The use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, employed for bacterial species identification in this study, has enhanced the recognition of Corynebacterium striatum as an important human pathogen in clinical microbiology laboratories. Our study demonstrated that C. striatum is associated with various healthcare-associated infections, including those requiring prolonged antimicrobial therapy, and that nosocomial transmission of this pathogen can result in the development of infections. In addition, several agents other than vancomycin, such as teicoplanin, tetracyclines, and trimethoprim/sulfamethoxazole, have demonstrated favorable activities. The results of this study indicate the need for further research on the mechanisms and modes of nosocomial transmission of C. striatum, as well as the clinical efficacy of alternative agents to vancomycin, particularly those suitable for prolonged treatment, given the potential side effects associated with vancomycin use.