Genomic study substantiates the intensive care unit as a reservoir for carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has recently emerged as a notable public health concern, while the underlying drivers of CRKP transmission among patients across different healthcare facilities have not been fully elucidated. To explore the transmission dynamics of CRKP, 45 isolates were collected from both the intensive care unit (ICU) and non-ICU facilities in a teaching hospital in Guangdong, China, from March 2020 to August 2023. The collection of clinical data and antimicrobial resistance phenotypes was conducted, followed by genomic data analysis for these isolates. The mean age of the patients was 75.2 years, with 18 patients (40.0%) admitted to the ICU. The predominant strain in hospital-acquired CRKP was sequence type 11 (ST11), with k-locus type 64 and serotype O1/O2v1 (KL64:O1/O2v1), accounting for 95.6% (43/45) of the cases. The CRKP ST11 isolates from the ICU exhibited a low single nucleotide polymorphism (SNP) distance when compared to isolates from other departments. Genome-wide association studies identified 17 genes strongly associated with SNPs that distinguish CRKP ST11 isolates from those in the ICU and other departments. Temporal transmission analysis revealed that all CRKP isolates from other departments were genetically very close to those from the ICU, with fewer than 16 SNP differences. To further elucidate the transmission routes among departments within the hospital, we reconstructed detailed patient-to-patient transmission pathways using hybrid methods that combine TransPhylo with an SNP-based algorithm. A clear transmission route, along with mutations in potential key genes, was deduced from genomic data coupled with clinical information in this study, providing insights into CRKP transmission dynamics in healthcare settings.

Recent updates in treating carbapenem-resistant infections in patients with hematological malignancies.

INTRODUCTION: Patients with hematological malignancies (PHMs) are at increased risk for infections caused by carbapenem-resistant organisms (CROs) due to frequent exposure to broad-spectrum antibiotics and prolonged hospital stays. These infections result in high mortality and morbidity rates along with delays in chemotherapy, longer hospitalizations, and increased health care costs. AREAS COVERED: Treatment alternatives for CRO infections in PHMs. EXPERT OPINION: The best available treatment option for KPC and OXA-48 producers is ceftazidime/avibactam. Imipenem/cilastatin/relebactam and meropenem/vaborbactam remain as the alternative options. They can also be used as salvage therapy in KPC-positive Enterobacterales infections resistant to ceftazidime/avibactam, if in vitro susceptibility is shown. Treatment of metallo-ß-lactamase producers is an unmet need. Ceftazidime/avibactam plus aztreonam or aztreonam/avibactam seems to be the most reliable option for metallo-ß-lactamase producers. As a first-line option for carbapenem-resistant Pseudomonas aeruginosa infections, ceftolozane/tazobactam is preferable and ceftazidime/avibactam and imipenem/cilastatin/relebactam constitute alternative regimens. Although sulbactam/durlobactam is the most reliable option against carbapenem-resistant Acinetobacter baumannii infections, its utility as monotherapy and in PHMs is not yet known. Cefiderocol can be selected as a 'last-resort' option for CRO infections. New risk score models supported by artificial intelligence algorithms can be used to predict the exact risk of infections in previously colonized patients.

Clinical outcomes and risk factors of Acinetobacter baumannii meningitis in pediatric patients at a tertiary hospital in China.

Objectives: To summarize the clinical characteristics, outcomes and identify risk factors of Acinetobacter baumannii (AB) meningitis in children. Methods: This was a single-center, retrospective study. Children hospitalized between January 2016 and December 2021 who were diagnosed with AB meningitis were included. The clinical characteristics and outcomes were reviewed. Risk factors were determined using univariate analyses (chi-square and Mann-Whitney U tests). Results: Seventeen patients were included; 15 cases were secondary to neurosurgery, and two were neonates with primary bacterial meningitis. Common symptoms included fever, convulsions and nervous system abnormalities. Cerebrospinal fluid (CSF) tests typically showed increased white blood cell counts dominated by neutrophils, reduced glucose levels and elevated protein levels. Ten patients were successfully treated (successful treatment [ST] group); seven had failed treatment (failed treatment [FT] group). Univariate analyses revealed that mechanical ventilation, routine white cell counts in the peripheral blood, procalcitonin, protein in the CSF, septic shock and carbapenem-resistant AB (CRAB) differed significantly between the groups. Conclusion: AB meningitis in children has a high mortality rate. FT was associated with mechanical ventilation, septic shock, CRAB, lower peripheral leukocyte counts, higher protein levels in the CSF and procalcitonin. Larger studies are needed to identify independent risk factors for adverse outcomes.

Characterization of pKPN945B, a novel transferable IncR plasmid from hypervirulent carbapenem-resistant Klebsiella pneumoniae, harboring blaIMP-4 and qnrS1.

Carbapenem-resistant Klebsiella pneumoniae producing metallo-ß-lactamase poses a major public health threat worldwide. Imipenemase often coexists with other resistance genes leading to the formation of multidrug-resistant bacteria. In this study, we describe the microbiological and genomic characteristics of the hypervirulent carbapenem-resistant K. pneumoniae ST20-K23 strain KPN945 harboring blaIMP-4 and qnrS1. The minimum inhibitory concentration of KPN945 against antimicrobials was determined by the broth microdilution method. The virulence of KPN945 was evaluated through string test, serum killing resistance, and Galleria mellonella larvae infection models. The transferability of pKPN945B was assessed using a conjugation test. The genome sequence characteristics of KPN945 were analyzed through whole genome sequencing, and a phylogenetic tree was constructed to evaluate the prevalence of imipenemase. Our findings showed that KPN945 was non-susceptible to ß-lactam antibiotics, highly resistant to serum killing, and highly lethal to G. mellonella larvae. The fusion plasmid pKPN945B carried by the isolate KPN945 belonged to the IncR incompatibility group and harbored multiple drug resistance genes such as blaIMP-4, blaCTX-M-14, qnrS1, and sul2. The most important point is that the IncR plasmid is a novel plasmid that arose by the accretion of parts from different plasmids, making it transferable and with a fitness cost. Globally, blaIMP-4 is the most prevalent imipenemase subtype, with the highest isolation rates in Asia, particularly China. The spread of blaIMP-4, especially the emergence of transferable plasmids, deserves our vigilance and prevention. Additionally, we should pay attention to the formation of hypervirulent K. pneumoniae mediated by non-virulent plasmids. IMPORTANCE: Up to now, IncR replicons carrying blaIMP-4 have not been reported, and the IncR plasmids described in previous studies have been found to be non-transferrable to other bacteria through conjugation. Moreover, there have been no extensive phylogenetic analyses of strains carrying blaIMP in the published papers. The lack of data in these studies is noteworthy because blaIMP appears in the novel transferable fusion plasmid IncR. Although the IncR plasmid has no tra operon, it can still be transferred to Escherichia coli EC600 or Klebsiella pneumoniae ATCC13883 (RIFR) without high fitness cost, but it only affects the MIC of imipenem. blaIMP integrates with other resistance mechanisms leading to the formation of multidrug-resistant strains. Notably, the high prevalence of blaIMP-4 in Asia and the presence of blaIMP-4 on novel transferable IncR plasmids suggest the urgent need to monitor the emergence of such plasmids and control their spread.

First report of ISKpn26 element mediating mgrB gene disruption in the ST1 colistin- and carbapenem-resistant Klebsiella pneumoniae cluster isolated from a patient with chest infection.

Colistin is used as a last-line therapy against carbapenem-resistant Klebsiella pneumoniae (CRKP). However, colistin resistance in Klebsiella pneumoniae is increasingly reported worldwide. This study aims to investigate the instrumental role of insertion sequence (IS) elements in colistin resistance through mgrB disruption in K. pneumoniae during treatment. Five clinical isolates of CRKP, designated KPN1~KPN5 were collected from the lower respiratory tract of a patient with chest infection before and after treatment with colistin. Antimicrobial susceptibility testing was performed using the broth microdilution method. Whole genome sequencing and bioinformatics were used to analyze the sequence types (STs), resistance genes, and genetic characteristics of the five isolates of K. pneumoniae. Antimicrobial susceptibility testing indicated that all five K. pneumoniae isolates were resistant to cephalosporins (ceftriaxone, ceftazidime, and cefepime), several carbapenems (imipenem, meropenem), cefoperazone-sulbactam, piperacillin-tazobactam, ciprofloxacin, and fosfomycin, whereas they were sensitive to amikacin and tigecycline. In addition, three of these isolates were resistant to colistin, with minimum inhibitory concentration values of >8 mg/L. Whole genome sequencing revealed that all five K. pneumoniae isolates belonged to sequence type 1 (ST1), which shared an identical blaKPC-2. Notably, disruption of mgrB by the ISKpn26 insertion sequence was shown to be the primary colistin resistance mechanism during the treatment. To our knowledge, this is the first report of ISKpn26 element mediating mgrB disruption in the ST1 colistin and CRKP obtained from a patient with chest infection in mainland China. This study provides new research ideas to explore the clinical drug resistance mechanism of CRKP and the critical need to monitor and understand resistance mechanisms to preserve the efficacy of last-line antibiotics such as colistin. IMPORTANCE: Of note, this chapter gives an update on colistin resistance in sequence type 1 Klebsiella pneumoniae, by focusing on the mgrB disrupted by ISKpn26 element.

Effectiveness of combination therapy with intrathecal or intraventricular administration of polymyxin B for hospital-acquired central nervous system infections caused by carbapenem-resistant Acinetobacter baumannii: a retrospective study.

OBJECTIVES: To evaluate the therapeutic regimen, efficacy and safety of intrathecal or intraventricular (ITH/IVT) administration of polymyxin B for hospital-acquired central nervous system (CNS) infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). METHODS: A retrospective study was performed on patients with CNS infections caused by CRAB treated with ITH/IVT combination therapy. The primary study outcome was the clinical efficacy after treatment. Secondary outcomes were bacterial clearance rate and safety of therapy. RESULTS: In total, 35 patients who received ITH (13[37.1%]) or IVT (22[62.9%]) polymyxin B as combination therapy were included. The median duration of ITH/IVT polymyxin B therapy was 9 days (interquartile ranges, 7-11). The overall clinical cure and bacterial clearance rate was 77.1% and 85.7%, respectively. No adverse effects deemed related with ITH/IVT polymyxin B were recorded. Clinical failure was independently associated with the initial Acute Physiology and Chronic Health Evaluation II (≥ 15) (odds ratio [OR], 1.24; 95% confidence interval [CI]: 1.05-1.42; P = 0.038) and Glasgow Coma Scale scores (≤ 8) (OR, 0.69; 95% CI: 0.49-0.88; P = 0.029). Early administration (within 4 days) of ITH/IVT polymyxin B therapy can support significantly higher clinical cure rate (OR, 0.65; 95% CI: 0.49-1.12; P < 0.001), and potentially reduce the length of treatment and the adverse effects. CONCLUSIONS: ITH/IVT administration of polymyxin B is a valid alternative for the treatment of CNS infections caused by CRAB. Early use of ITH/IVT polymyxin B can lead to higher clinical success.

Diagnostic Test Precision of Modified Carbapenem Inactivation Method and Carbapenemase Nordmann-Poirel Test for Phenotypic Detection of Carbapenemase Production in Enterobacterales: A Systematic Review.

Carbapenem-resistant Enterobacterales, particularly those that produce carbapenemases, pose a significant public health concern due to very limited treatment options. The timely identification of carbapenemase-producing Enterobacterales (CPE) is essential for putting in place efficient infection control measures and selecting appropriate antimicrobial therapies, thereby improving the clinical outcome of the patient. The purpose of this systematic review is to compare the diagnostic accuracy and practicality between two phenotypic tests, namely the modified carbapenem inactivation method (mCIM) and carbapenemase Nordmann-Poirel (Carba NP) test, in detecting carbapenemase production by Enterobacterales and thereby aiding the clinician in making a decision to choose an appropriate test for their phenotypic detection. This systematic review involved combining sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, diagnostic odds ratio with 95% confidence interval (CIs), Forest plot for sensitivity and specificity, and plotting suitable summary receiver operating characteristic curve with the area under the curve. Of the 20 studies included in this review, the overall effect sizes of Carba NP and mCIM with 95% CIs were as follows: sensitivity, 91% (86-96%) and 97% (95-99%); specificity, 93% (88-97%) and 97% (93-100%); PPV, 97% and 98%; NPV, 79% and 90%; accuracy, 93% and 97%; diagnostic odds ratio, 1487.8879 and 8527.5541; and AUC, 0.85 and 1, respectively. In conclusion, the mCIM method showed superior sensitivity (97%), specificity (97%), and accuracy compared to the Carba NP test in detecting carbapenemase production, even though both these methods had a few technical limitations. The Carba NP test is rapid, affordable, and dependable, whereas mCIM is more accurate and cost-effective but time-consuming. We propose that both tests can be reliably used for screening of carbapenemase production in Enterobacterales, as endorsed by the Clinical and Laboratory Standards Institute even in resource-limited clinical laboratories, in the order of prioritizing the mCIM method first and then followed by the Carba NP test when situation demands expedited results.

In vitro activities of the essential antimicrobial agents including aztreonam/avibactam, eravacycline, colistin, and other comparators against carbapenem-resistant bacteria with different carbapenemase genes: a multicenter study in China, 2021.

OBJECTIVE: Carbapenem-resistant bacteria (CRB), including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Enterobacterales (CRE), pose a considerable threat to public health in China. Eravacycline, aztreonam/avibactam, and colistin are important antimicrobial agents for the treatment of serious infections caused by CRB. The study aims to evaluate the prevalence of CRB strains and the susceptibility of commonly used clinical antimicrobial agents against the strains with different carbapenemase genes . METHODS: We collected 7,194 gram-negative bacteria (GNB) strains from different regions of China and identified 924 carbapenem-resistant strains. All strains were from infections with confirmed diagnoses. Antimicrobial susceptibility testing, covering 21 antimicrobial agents including aztreonam/avibactam, eravacycline, colistin, and other comparators, was performed using the broth microdilution method. Carbapenemase genes (blaKPC, blaNDM, blaOXA, blaIMP, and blaVIM) were screened by PCR amplification and sequence analysis. All statistical analyses were performed using Statistical Package for the Social Sciences version 23.0 software. RESULTS: The isolation rates of CRE, CRAB, and CRPA were 6.31% (332/5265), 62.95% (440/699), and 15.20% (152/1000), respectively. The predominant carbapenemase in carbapenem-resistant Escherichia coli (CRECO) was NDM, while in CRKP it was KPC. All CRAB produced OXA-23 and 85.52 % of CRPA did not produce any of the following carbapenemases: NDM, KPC, VIM, IMP and OXA. Aztreonam/avibactam, colistin, and eravacycline exhibited high antimicrobial activity against different species producing various carbapenemases. Compared to ceftazidime/avibactam, aztreonam/avibactam demonstrated superior antimicrobial activity, particularly pronounced in CRECO and strains producing metallo-beta-lactamases (MBLs). In comparisons between tigecycline and eravacycline, the latter maintained higher antimicrobial activity across different species. Antimicrobial agents exhibited varying levels of activities when against strains with different resistance mechanisms. CONCLUSIONS: Our results support the fact that using aztreonam/avibactam, eravacycline, and colistin to treat infections caused by CRB offers significant advantages. These fingdings will guide clinical practice and optimize antimicrobial administration.

Comparison of cefiderocol and colistin-based regimens for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: There are multiple antibiotic regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) in clinical practice. We conducted this meta-analysis to compare the efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections. METHODS: Two authors independently searched the PubMed, Web of Science, Embase, and Cochrane databases from their establishment to April 15, 2024, to search for randomized controlled trials (RCTs) or cohort studies, and compared the clinical efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections. The Newcastle Ottawa Scale (NOS) checklist was used to evaluate the quality of the included studies. The primary outcome was all-cause mortality, and subgroup analysis was conducted on the basis of the site of infection and the risk of bias in the studies. Trial sequential analysis (TSA) was then conducted. RESULTS: Six observational studies were included, with 251 cases in the cefiderocol-based group and 372 cases in the colistin-based group. Compared to the colistin-based group, the cefiderocol-based group had lower all-cause mortality (RR = 0.71, 95% CI: 0.54-0.92, P = 0.01) and 30-day mortality (RR = 0.64, 95% CI: 0.43-0.95, P = 0.03). However, for the 14-day and 28-day mortality rates, there was no statistically significant difference between two groups. According to the subgroup analysis, among patients with bloodstream infection (BSI), the cefiderocol-based group had lower all-cause mortality, but it did not reduce the mortality of ventilator-associated pneumonia (VAP) patients. The result of TSA showed that our conclusions are reliable. There was no significant statistical difference in the microbiological cure rate, clinical cure rate, or duration of hospitalization. In addition, the cefiderocol-based group did not have an increased incidence of acute kidney injury (AKI). CONCLUSIONS: Compared with the colistin-based regimens, the cefiderocol-based regimens were significantly associated with a lower risk of mortality in CRAB-infected patients, especially for patients with BSI. However, they did not show any advantages in terms of the clinical cure rate or microbiological cure rate, nor did they reduce the incidence of AKI. PROSPERO REGISTRATION NUMBER: CRD42023487213.

Ceftazidime/avibactam alone or in combination with an aminoglycoside for treatment of carbapenem-resistant Enterobacterales infections: a retrospective cohort study.

BACKGROUND: Ceftazidime/avibactam is one of the preferred treatment options for carbapenem-resistant Enterobacterales (CRE). However, the benefit of combining ceftazidime/avibactam with another antibiotic remains unclear. OBJECTIVES: To identify variables associated with treatment failure during the use of ceftazidime/avibactam for CRE infections and assess the effect of combining an aminoglycoside with ceftazidime/avibactam. METHODS: This was a retrospective cohort study of patients with a positive CRE culture treated with ceftazidime/avibactam between 2015 and 2021 in 134 Veterans Affairs (VA) facilities. The primary outcome was 30-day mortality and the secondary outcome was in-hospital mortality. A subanalysis in patients who received an aminoglycoside was also performed. RESULTS: A total of 303 patients were included. The overall 30-day and in-hospital mortality rates were 12.5% and 24.1%, respectively. Age (aOR 1.052, 95% CI 1.013-1.093), presence in the ICU (aOR 2.704, 95% CI 1.071-6.830), and receipt of an aminoglycoside prior to initiation of ceftazidime/avibactam (aOR 4.512, 95% CI 1.797-11.327) were independently associated with 30-day mortality. In the subgroup of patients that received an aminoglycoside (n=77), their use in combination with ceftazidime/avibactam had a 30-day mortality aOR of 0.321 (95% CI, 0.089-1.155). CONCLUSIONS: In veterans treated with ceftazidime/avibactam for CRE infections, increased age, receipt of an empiric aminoglycoside, and presence in the ICU at the time of index culture were associated with higher 30-day mortality. Among patients who received an aminoglycoside, their use in combination with ceftazidime/avibactam trended toward protectiveness of 30-day mortality, suggesting a potential role for this combination to treat CRE infections in patients who are more severely ill.

Biological studies of the activity of Manuka honey against Carbapenem-resistant Enterobacterales (CRE) bacteria.

OBJECTIVES: To evaluate the potency of Manuka honey UMF +15 against Carbapenem-resistant Enterobacterales (CRE). Bacterial resistance is a worldwide problem that is increasing year by year, especially Carbapenem resistance. Alternatives to antibiotics are needed to both reduce costs, and to reduce the spread of antibiotic resistance, with the ultimate goal of saving lives. METHODS: The efficacy of Manuka honey UMF +15 was tested by 2 methods; Well diffusion assay and minimum bactericidal concentration (MBC) against twenty Carbapenem-resistant isolates which collected from Makkah city hospitals during three months of study from 1st of September 2023 up to 1st of December 2023. RESULTS: The growth of all isolates of Carbapenem-resistant Enterobacterales (CRE) was severely inhibited by low concentrations of Manuka honey, affecting 25% of isolates at 15% and 75% of isolates at 18% of Manuka honey. In addition, using the honey at different concentrations in a well diffusion assay resulted, as expected, in a variable zone diameter, ranging from large zones(14mm) to small zones (2 mm) according to the concentration of the honey. CONCLUSION: This study shows the remarkable antibacterial activity of Manuka honey and suggests that this natural remedy might be used in the future as an alternative treatment option against Carbapenem-resistant Enterobacterales (CRE); however, further clinical trials should be performed to corroborate our initial findings.

Clinical outcomes and safety of polymyxin B versus tigecycline combination therapy for pneumonia of carbapenem-resistant Klebsiella pneumoniae: a retrospective cohort study.

PURPOSE: Infection by carbapenem-resistant Klebsiella pneumoniae (CRKP) has high mortality. There is no clear optimal therapeutic choice for pneumonia caused by CRKP. The aim of this study was to compare the clinical outcomes and safety of the standard doses of polymyxin B-based regimens vs tigecycline-based regimens and to identify risk factors for mortality. METHODS: This retrospective cohort study included patients with pneumonia caused by CRKP between January 1, 2020 and December 31, 2022. The primary outcomes were 7-day bacterial eradication rate and 14- and 28-day all-cause mortality. The secondary outcome was incidence of acute kidney injury. RESULTS: Seventy-three patients were included in this study, 29 in the polymyxin B-based combination therapy group and 44 in tigecycline-based combination therapy group. There were no significant differences between the two groups in terms of the 7-day bacterial eradication rate (31.03% vs 20.45%, p = 0.409), the 14-day all-cause mortality (37.93% vs 22.73%, p = 0.160), and the incidence of acute kidney injury (14.29% vs 6.82%, p = 0.526). The 28-day all-cause mortality in the polymyxin B-based therapy group was higher than in the tigecycline-based group (75.86% vs 45.45%, p = 0.010). Binary logistic regression analysis revealed that male and previous use of carbapenems were independent factors associated with 28-day all-cause mortality for patients treated with polymyxin B (p < 0.05). CONCLUSIONS: Polymyxin B-based combination therapy at the standard dose should be used with caution for patients with CRKP-induced pneumonia, especially for men who used carbapenems prior to CRKP detection.

KPC variants conferring resistance to ceftazidime-avibactam in Pseudomonas aeruginosa strains.

BACKGROUND: This study aimed to characterize three KPC variants (KPC-33, KPC-100, and KPC-201) obtained from a clinical isolate of Pseudomonas aeruginosa (#700), along with two induced strains C109 and C108. METHODS: Genomic DNAs of #700 (ST235), C109 (ST463), and C108 (ST1076) were sequenced using Illumina and Oxford Nanopore technologies. The transferability and stability of the plasmid was assessed through conjugation experiments and plasmid stability experiments, respectively. Minimum inhibitory concentrations of bacterial strains were determined using broth microdilution methods. In vitro induction was performed using ceftazidime-avibactam (CZA) at concentrations of 6/4 µg/ml. Linear genomic alignments were visualized using Easyfig, and protein structure modeling of the novel KPC variant (KPC-201) was conducted using PyMol. RESULTS: The plasmids carrying the KPC variants in the three CZA-resistant strains (C109, C108, and #700) had sizes of 39,251 bp (KPC-100), 394,978 bp (KPC-201), and 48,994 bp (KPC-33). All three plasmids belonged to the IncP-like incompatibility (Inc) groups, and the plasmid exhibited relatively high plasmid stability, KPC-33 and KPC-201-harboring plasmids were successfully transferred to the recipient strain P. aeruginosa PAO1rifR. The genetic environments of the three blaKPC genes differed from each other. The mobile elements of the three blaKPC genes were as follows, TnAS1-IS26-ΔISKpn27-blaKPC-33-ISKpn6-IS26, IS6-ΔISKpn27-blaKPC-100-ISKpn6-IS26-Tn3-IS26, and IS6100-ISKpn27-blaKPC-201-ISKpn6-TnAS1. Notably, the length of ΔISKpn27 upstream of the blaKPC-33 and blaKPC-100 genes were remarkably short, measuring 114 bp and 56 bp, respectively, deviating significantly from typical lengths associated with ISKpn27 elements. Moreover, the novel KPC variant, KPC-201, featured a deletion of amino acids LDR at positions 161-163 in KPC-3, resulting in a looser pocket structure contributing to its avibactam resistance. CONCLUSIONS: KPC-201, identified as a novel KPC variant, exhibits resistance to CZA. The presence of multiple mobile elements surrounding the blaKPC-variant genes on stable plasmids is concerning. Urgent preventive measures are crucial to curb its dissemination in clinical settings.

High drug-pathogen mismatch in the management of invasive carbapenem-resistant Enterobacteriaceae infections at a tertiary hospital in Nigeria.

Objectives: This study aims to provide lacking data on antibiotics and treatment strategies used in the management of carbapenem-resistant Enterobacteriaceae (CRE) infections in Nigeria. Methods: A cross-sectional study was carried out at the University College Hospital in Ibadan. CRE isolated from routine culture of specimens from hospitalized patients from December 2021 to September 2022 was identified. Treatment information and other data were collected from the patients' medical records. Results: The hospital laboratory isolated CRE from 55 patients during the study period and 27 (49.1%) of them had data available for the study. The most frequently isolated CRE was Klebsiella spp. (13 of 27, 48.1%). Of the 24 patients who received empiric antibiotics, only two (8.3%) of their CRE isolates were susceptible. After receiving culture results, 18 (66.7%) patients were treated with at least one antibiotic, to which resistance was documented. Only three (11.1%) patients overall commenced or remained on an antibiotic, to which their CRE isolate was susceptible. Conclusions: Despite culture data, we found a high prevalence of drug-pathogen mismatch in CRE treatment, including new or persistent use of antibiotics, to which resistance was documented. Antimicrobial stewardship efforts need to be strengthened to specifically address CRE treatment and effective antibiotics need to be made accessible.

Ceftazidime-avibactam: Combination therapy versus monotherapy in the challenge of pneumonia caused by carbapenem-resistant Klebsiella pneumoniae.

This research focused on evaluating the clinical results of patients suffering from pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP), who received treatment with either ceftazidime-avibactam (CZA) alone or in combination with other antibiotics. From January 2020 to December 2023, we retrospectively analyzed CRKP-related pneumonia patients treated in two Chinese tertiary hospitals. Mortality was measured at 14 and 30 days as the primary outcome. Secondary outcomes included the 14-day microbiological cure rate and the 14-day clinical cure rate. Factors contributing to clinical failure were evaluated via both univariate analysis and multivariate logistic regression. To account for confounding factors, propensity score matching (PSM) was utilized. Among the 195 patients with CRKP infections, 103 (52.8 %) received CZA combination therapy, and 92 (47.2 %) patients received CZA monotherapy. The combination therapy group exhibited superior clinical and microbiological cure rates compared to the monotherapy group, with a 14-day clinical cure rate of 60.1 % vs. 45.7 % (P = 0.042) and a 14-day microbiological cure rate of 72.8 % vs. 58.6 % (P = 0.038), respectively. Combination therapy reduced mortality rates at 14 days (7.8 % vs. 17.4 %, P = 0.041), but not at 30 days (14.6 % vs. 25.0 %, P = 0.066). Even after using PSM, the group treated with the CZA combination continued to had a lower mortality rate at 14 days (5.9 % vs. 17.6 %, P = 0.039). The 14-day clinical cure rate for the combination therapy group was 63.2 %, and the 14-day microbial cure rate was 77.9 %. Both of these statistics were notably greater than those observed in the monotherapy group. Furthermore, the multivariate logistic regression model indicated a significant link between combination therapy and a decrease in clinical failure. Carbapenems were noted to be the most effective class of concomitant agents. Our findings indicate that patients with pneumonia due to CRKP benefit from combination treatment of CZA rather than monotherapy; administering carbapenem in combination with CZA in the early stages could provide considerable survival benefits.

Epidemiological, Phylogenetic, and Resistance Heterogeneity Among Acinetobacter baumannii in a Large U.S. Deep South Healthcare system.

Background: Acinetobacter baumannii (Ab) disease in the United States is commonly attributed to outbreaks of 1 or 2 monophyletic carbapenem resistance (CR) Ab lineages that vary by region. However, there is limited knowledge regarding CRAb epidemiology and population structures in the U.S. Deep South, and few studies compare contemporary CR and carbapenem-susceptible (Cs) Ab, despite relative prevalence of the latter. Methods: We performed a multiyear analysis of 2462 Ab cases in a large healthcare system in Birmingham, AL, and 89 post-2021 Ab isolates were sequenced and phenotyped by antibiotic susceptibility tests. Results: Although the cumulative CR rate was 17.7% in our cohort, rates regularly increased in winter months as result of seasonal changes in case incidence of CsAb, specifically. Genotyped CRAb belonged to clonal group (CG) 1, CG2, CG108, CG250, or CG499, with local clones of CG108, CG250, and CG499 persisting over multiple months. There was no clonal expansion of any CsAb lineage. Among CRAb isolates, levels of ß-lactam antibiotic resistance and the repertoire of related genetic resistance determinants, which included the novel CR-conferring FtsI A515V polymorphism, differed according to CG. CG108 and CG499 isolates displayed specific heteroresistance to sulbactam and trimethoprim/sulfamethoxazole, respectively, which resulted in discrepant susceptibility results in microbroth versus agar-based antibiotic susceptibility tests modalities. Conclusions: We report an unusually high degree of CRAb phylogenetic diversity principally driven by emergent U.S. lineages harboring novel resistance elements that must be incorporated into diagnostic, surveillance, and preclinical research efforts.

Guidelines for Antibacterial Treatment of Carbapenem-Resistant Enterobacterales Infections.

This guideline aims to promote the prudent use of antibacterial agents for managing carbapenem-resistant Enterobacterales (CRE) infections in clinical practice in Korea. The general section encompasses recommendations for the management of common CRE infections and diagnostics, whereas each specific section is structured with key questions that are focused on antibacterial agents and disease-specific approaches. This guideline covers both currently available and upcoming antibacterial agents in Korea.

Characterization of the Chromosomally Located Metallo-ß-Lactamase Genes blaIMP-45 and blaVIM-2 in a Carbapenem-Resistant Pseudomonas aeruginosa Clinical Isolate.

Objective: Characterization of the multidrug resistance (MDR) region in P. aeruginosa strain PA59 revealed the presence of antibiotic resistance genes, including blaIMP-45 and blaVIM-2, within a complex genetic landscape of mobile genetic elements. Methods: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) strains were isolated from Shanghai Changhai Hospital. Polymerase chain reaction (PCR) was used to detect the ß-lactamase genes in the isolated strains. Strains carrying two or more genes were subjected to whole-genome sequencing (WGS) and in-depth bioinformatics analysis. Results: A total of 94 CRPA strains were isolated, among which PA59 was determined to carry blaIMP-45 and blaVIM-2 genes. Compared with single-gene positive or other blaIMP and blaVIM dual-gene positive strains reported, PA59 exhibited a broader range of drug resistance. We discovered a multidrug resistant (MDR)-related region composed of various mobile elements in the PA59 chromosome. This region carried many resistance genes, including the target genes blaIMP-45 and blaVIM-2. By further comparing the mobile elements GI13 and Ph08, we speculated that this integron structure carrying blaIMP-45 and blaVIM-2 was initially integrated into the genomic island or prophage, forming a more complex genetic structure, and then further integrated into the PA59 chromosome through plasmids. Phylogenetic tree analysis showed limited sequence similarity between PA59 and other CRPA strains. Conclusions: This study identified PA59 as the first reported P. aeruginosa strain carrying both blaIMP-45 and blaVIM-2 on the chromosome. The assembly and annotation of the PA59 genome provide valuable insights into the genomic diversity and gene content of this clinically important pathogen, aiding the development of effective strategies against antibiotic resistance.

Risk factors for infection after carbapenem-resistant Acinetobacter baumannii colonization.

PURPOSE: Predicting infection risk in carbapenem-resistant Acinetobacter baumannii (CRAB) colonized patients may help in improving timely appropriate antibiotic therapy. This study aims to explore risk factors for developing infections in hospitalized patients with previous CRAB colonization. METHODS: We performed an observational retrospective cohort study at ASST Sette Laghi-Varese Hospital between January 2020 and December 2022. All consecutive adult (> 18 years old) hospitalized patients with documented colonization by CRAB at any anatomical site or with CRAB infections preceded by CRAB colonization were included. Univariate and multivariate analyses were performed to investigate infection risk factors. RESULTS: Overall, 144 patients were included in the study: 104 colonized only and 40 infected patients. Colonization and infection rates significantly changed over the years (2020-2022, p < 0.001). The incidence of infections in CRAB carriers was 27.8% (40/144). Median time from colonization to infection was 4 days (IQR 1-8.5). Overall, inhospital mortality was 32.7% and 55.0% in colonized only and infected patients, respectively. At the multivariable logistic regression cardiovascular disease (OR 5.83, 95% CI 1.12-30.43, p = 0.037), COVID-19 (OR 3.72, 95% CI 1.16-11.91, p = 0.027) and intensive care unit (ICU) admission (OR 8.83, 95% CI 2.94-26.51, p < 0.001) were risk factors independently associated with cardiovascular disease CRAB infection after colonization. CONCLUSIONS: We observed an increased infection risk in patients colonized with CRAB with cardiovascular disease, COVID-19 and admitted in ICU setting. Additional evidence is needed to identify predictors of infection in colonized patients.

Innovative Treatment of Carbapenem-Resistant Pseudomonas aeruginosa Pneumonia with Carrimycin: A Case Report.

Carbapenem-resistant Pseudomonas aeruginosa is a common multidrug-resistant bacterium encountered in clinical practice. This pathogen causes pneumonia, which is difficult to treat owing to the limited choice of antimicrobial drugs, resulting in a relatively high mortality rate. Carrimycin is a new macrolide antibiotic with broad-spectrum antibacterial and potential immunomodulatory effects. Herein, we report a case of severe pneumonia caused by carbapenem-resistant Pseudomonas aeruginosa that presented with septic shock and Acute Respiratory Distress Syndrome (ARDS). Initially, we used piperacillin-tazobactam and ceftazidime-avibactam but without satisfactory results. Finally, we administered carrimycin in combination with piperacillin-tazobactam; the patient's condition improved, and he was successfully weaned off the ventilator. Therefore, the combined use of carrimycin should be considered for patients infected with carbapenem-resistant Pseudomonas aeruginosa who do not respond to conventional anti-infection treatments.