Effectiveness of a double-carbapenem combinations against carbapenem-resistant Gram-negative bacteria.
Ontology highlight
ABSTRACT:
SUBMITTER: Lu J
PROVIDER: S-EPMC9257860 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes. Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts. Results: Carbapenem-resistant (CR) Klebsiella pneumoniae (n=9) and CR Pseudomonas aeruginosa (n=7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN. Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts.
| S-EPMC8645865 | biostudies-literature
Project description:Infections by drug-resistant bacteria are life-threatening. As iron is a vital element for the growth of bacteria, iron-chelating agents (siderophores) can be used to arrest their multiplication. Exogenous siderophores - exochelin-MS and deferoxamine-B - were evaluated for their inhibitory activity against methicillin-resistant Staphylococcus aureus and metallo-β-lactamase producers - Pseudomonas aeruginosa and Acinetobacter baumannii - by disc diffusion, micro-broth dilution, and turbidimetric growth assays. The drug-resistant isolates were inhibited by the synergistic activity of siderophores and antibiotics. Minimum inhibitory concentration of exochelin-MS+ampicillin for different isolates was between 0.05 and 0.5 mg/mL. Minimum inhibitory concentration of deferoxamine-B+ampicillin was 1.0 mg/mL and greater. Iron-chelation therapy could provide a complementary approach to overcome drug resistance in pathogenic bacteria.
| S-EPMC5765970 | biostudies-literature
Project description:BACKGROUND:Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS:This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS:Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION:The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.
| S-EPMC6172649 | biostudies-other
Project description:Multidrug-resistant (MDR) Gram-negative bacteria have emerged as a serious threat to human and animal health. Bdellovibrio spp. and Micavibrio spp. are Gram-negative bacteria that prey on other Gram-negative bacteria. In this study, the ability of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus to prey on MDR Gram-negative clinical strains was examined. Although the potential use of predatory bacteria to attack MDR pathogens has been suggested, the data supporting these claims is lacking. By conducting predation experiments we have established that predatory bacteria have the capacity to attack clinical strains of a variety of ß-lactamase-producing, MDR Gram-negative bacteria. Our observations indicate that predatory bacteria maintained their ability to prey on MDR bacteria regardless of their antimicrobial resistance, hence, might be used as therapeutic agents where other antimicrobial drugs fail.
| S-EPMC3641118 | biostudies-other
Project description:BackgroundCarbapenem-resistant Gram-negative bacteria are a major clinical concern as they cause virtually untreatable infections since carbapenems are among the last-resort antimicrobial agents. β-Lactamases implicated in carbapenem resistance include KPC, NDM, and OXA-type carbapenemases. Antimicrobial combination therapy is the current treatment approach against carbapenem resistance in order to limit the excessive use of colistin; however, its advantages over monotherapy remain debatable. An alternative treatment strategy would be the use of carbapenem/β-lactamase inhibitor (βLI) combinations. In this study, we assessed the in vitro and in vivo phenotypic and molecular efficacies of three βLIs when combined with different carbapenems against carbapenem-resistant Gram-negative clinical isolates. The chosen βLIs were (1) Avibactam, against OXA-type carbapenemases, (2) calcium-EDTA, against NDM-1, and (3) Relebactam, against KPC-2.MethodsSix Acinetobacter baumannii clinical isolates were screened for bla OXA-23-like, bla OXA-24/40, bla OXA-51-like, bla OXA-58, and bla OXA-143-like, and eight Enterobacteriaceae clinical isolates were screened for bla OXA-48, bla NDM-1, and bla KPC-2. The minimal inhibitory concentrations of Imipenem (IPM), Ertapenem (ETP), and Meropenem (MEM) with corresponding βLIs for each isolate were determined. The efficacy of the most suitable in vitro treatment option against each of bla OXA-48, bla NDM-1, and bla KPC-2 was assessed via survival studies in a BALB/c murine infection model. Finally, RT-qPCR was performed to assess the molecular response of the genes of resistance to the carbapenem/βLI combinations used under both in vitro and in vivo settings.ResultsCombining MEM, IPM, and ETP with the corresponding βLIs restored the isolates' susceptibilities to those antimicrobial agents in 66.7%, 57.1%, and 30.8% of the samples, respectively. Survival studies in mice revealed 100% survival rates when MEM was combined with either Avibactam or Relebactam against bla OXA-48 and bla KPC-2, respectively. RT-qPCR demonstrated the consistent overexpression of bla OXA-48 upon treatment, without hindering Avibactam's activity, while bla NDM-1 and bla KPC-2 experienced variable expression levels upon treatment under in vitro and in vivo settings despite their effective phenotypic results.ConclusionNew carbapenem/βLI combinations may be viable alternatives to antimicrobial combination therapy as they displayed high efficacy in vitro and in vivo. Meropenem/Avibactam and Meropenem/Relebactam should be tested on larger sample sizes with different carbapenemases before progressing further in its preclinical development.
| S-EPMC6503214 | biostudies-literature
Project description:Cefiderocol is a novel catechol-substituted siderophore cephalosporin that binds to the extracellular free iron, and uses the bacterial active iron transport channels to penetrate in the periplasmic space of Gram-negative bacteria (GNB). Cefiderocol overcomes many resistance mechanisms of these bacteria. Cefiderocol is approved for the treatment of complicated urinary tract infections, hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in the case of adults with limited treatment options, based on the clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In the CREDIBLE-CR trial, a higher all-cause mortality was observed in the group of patients who received cefiderocol, especially those with severe infections due to Acinetobacter spp. Further phase III clinical studies are necessary in order to evaluate cefiderocol´s efficacy in the treatment of serious infections.
| S-EPMC8683016 | biostudies-literature
Project description:BackgroundCarbapenem-resistant gram-negative bacteria (CRGNB) continue to present a global healthcare crisis. We aimed to identify emerging trends of CRGNB over nearly 2 decades and describe the impact of CRGNB on patient outcomes.MethodsPatients from whom CRGNB were isolated between 2000 and 2017 were included in the study. Carbapenem resistance was defined by the most recent breakpoints and applied across the study period. Patient demographics, clinical characteristics, and outcomes were retrieved from the electronic health record.ResultsA total of 94 888 isolates from 64 422 patients were identified; 9882 (10%) isolates from 4038 patients were carbapenem-resistant. Pseudomonas aeruginosa was the most common CRGNB each year. The second most common CRGNB emerged in waves over time. Carbapenem daily defined doses increased in parallel with CRGNB rates (R2 = 0.8131). The overall 30-day mortality rate was 19%, which decreased from 24% in 2000 to 17% in 2017 (P = .003; R2 = .4330). Among patients with CRGNB bloodstream infections (n = 319), overall 30- and 90-day mortality rates were 27% and 38%, respectively. Charlson score (adjusted odds ratio [aOR], 1.11 per point), intensive care unit residence (aOR, 7.32), and severe liver disease (aOR, 4.8.4) were independent predictors of 30-day mortality, while receipt of transplantation was associated with lower rates of death (aOR, 0.39). Among patients admitted between 2011 and 2017 (n = 2230), 17% died during hospitalization, 32% were transferred to long-term care facilities, and 38% were discharged home.ConclusionsCRGNB emerged in waves over time, causing high rates of mortality. Despite increasing rates of CRGNB, overall patient outcomes have improved, suggesting that recognition and novel therapeutics have made a major impact.
| S-EPMC8662792 | biostudies-literature
Project description:IntroductionInfections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) are a significant cause of mortality and represent a serious challenge to health systems. The early identification of mortality predictors could guide appropriate treatment and follow-up. We aimed to identify the factors associated with 90-day all-cause mortality in patients with CR-GNB infections.MethodsWe conducted a cohort study from 1 January 2019 to 30 April 2022. The primary outcome was death from any cause during the first 90 days after the date of the first CR-GNB-positive culture. Secondary outcomes included infection relapse, invasive mechanical ventilation during follow-up, need for additional source control, acute kidney injury, Clostridioides difficile infection, and all-cause hospital admission after initial discharge. Bivariate and multivariate Cox-proportional hazards models were constructed to identify the factors independently associated with 90-day all-cause mortality.ResultsA total of 225 patients with CR-GNB infections were included. Death occurred in 76 (34%) cases. The most-reported comorbidities were immunosuppression (43%), arterial hypertension (35%), and COVID-19 (25%). The median length of stay in survivors was 18 days (IQR 10-34). Mechanical ventilation and ICU admission after diagnosis occurred in 8% and 11% of cases, respectively. Both infection relapse and rehospitalisation occurred in 18% of cases. C. difficile infection was diagnosed in 4% of cases. Acute kidney injury was documented in 22% of patients. Mechanical ventilation after diagnosis, ICU admission after diagnosis, and acute kidney injury in the first ten days of appropriate treatment were more frequently reported among non-survivors. In the multivariate analysis, age (HR 1.19 (95%CI 1.00-1.83)), immunosuppression (HR 1.84 (95%CI 1.06-3.18)), and septic shock at diagnosis (HR 2.40 (95% 1.41-4.08)) had an independent association with death during the first 90 days after the CR-GNB infection diagnosis. Receiving antibiogram-guided appropriate treatment was independently associated with a lower risk of death (HR 0.25 (95%CI 0.14-0.46)).ConclusionsThe presence of advanced age, immunosuppression, septic shock at diagnosis, and inappropriate treatment are associated with higher 90-day all-cause mortality in hospitalised patients with infections due to CR-GNB. Recognition of the risk factors for adverse outcomes could further assist in patient care and the design of interventional studies that address the severe and widespread problem that is carbapenem resistance.
| S-EPMC10375996 | biostudies-literature
Project description:Carbapenem-resistant organisms (CRO) are a major global public health threat. Enterobacterales hydrolyze almost all β-lactams through carbapenemase production. Infections caused by CRO are challenging to treat due to the limited number of antimicrobial options. This leads to significant morbidity and mortality. Over the last few years, several new antibiotics effective against CRO have been approved. Some of them (e.g., plazomicin or imipenem-cilastatin-relebactam) are currently approved for use only by adults; others (e.g., ceftazidime-avibactam) have recently been approved for use by children. Recommendations for antibiotic therapy of CRO infections in pediatric patients are based on evidence mainly from adult studies. The availability of pediatric pharmacokinetic and safety data is the cornerstone to broaden the use of proposed agents in adults to the pediatric population. This article provides a comprehensive review of the current knowledge regarding infections caused by CRO with a focus on children, which includes epidemiology, risk factors, outcomes, and antimicrobial therapy management, with particular attention being given to new antibiotics.
| S-EPMC7038253 | biostudies-literature
Project description:Infections caused by multidrug-resistant Gram-negative bacteria have emerged as a major threat to public health worldwide. The high mortality and prevalence, along with the slow pace of new antibiotic discovery, highlight the necessity for new disease management paradigms. Here, we report on the development of a multiantigenic nanotoxoid vaccine based on macrophage membrane-coated nanoparticles for eliciting potent immunity against pathogenic Pseudomonas aeruginosa. The design of this biomimetic nanovaccine leverages the specific role of macrophages in clearing pathogens and their natural affinity for various virulence factors secreted by the bacteria. It is demonstrated that the macrophage nanotoxoid is able to display a wide range of P. aeruginosa antigens, and the safety of the formulation is confirmed both in vitro and in vivo. When used to vaccinate mice via different administration routes, the nanotoxoid is capable of eliciting strong humoral immune responses that translate into enhanced protection against live bacterial infection in a pneumonia model. Overall, the work presented here provides new insights into the design of safe, multiantigenic antivirulence vaccines using biomimetic nanotechnology and the application of these nanovaccines toward the prevention of difficult-to-treat Gram-negative infections.
| S-EPMC6711367 | biostudies-literature