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Treatment of Infections Due to MDR Gram-Negative Bacteria.

ABSTRACT: The treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections in critically ill patients presents many challenges. Since an effective treatment should be administered as soon as possible, resistance to many antimicrobial classes almost invariably reduces the probability of adequate empirical coverage, with possible unfavorable consequences. In this light, readily available patient's medical history and updated information about the local microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB infections and firmly guiding empirical treatment choices, with the aim of avoiding both undertreatment and overtreatment. Rapid diagnostics and efficient laboratory workflows are also of paramount importance both for anticipating diagnosis and for rapidly narrowing the antimicrobial spectrum, with de-escalation purposes and in line with antimicrobial stewardship principles. Carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii are being reported with increasing frequencies worldwide, although with important variability across regions, hospitals and even single wards. In the past few years, new treatment options, such as ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, plazomicin, and eravacycline have become available, and others will become soon, which have provided some much-awaited resources for effectively counteracting severe infections due to these organisms. However, their optimal use should be guaranteed in the long term, for delaying as much as possible the emergence and diffusion of resistance to novel agents. Despite important progresses, pharmacokinetic/pharmacodynamic optimization of dosages and treatment duration in critically ill patients has still some areas of uncertainty requiring further study, that should take into account also resistance selection as a major endpoint. Treatment of severe MDR-GNB infections in critically ill patients in the near future will require an expert and complex clinical reasoning, of course taking into account the peculiar characteristics of the target population, but also the need for adequate empirical coverage and the more and more specific enzyme-level activity of novel antimicrobials with respect to the different resistance mechanisms of MDR-GNB.

SUBMITTER: Bassetti M

PROVIDER: S-EPMC6477053 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Treatment of Infections Due to MDR Gram-Negative Bacteria.

Bassetti Matteo M Peghin Maddalena M Vena Antonio A Giacobbe Daniele Roberto DR

Frontiers in medicine 20190416

The treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections in critically ill patients presents many challenges. Since an effective treatment should be administered as soon as possible, resistance to many antimicrobial classes almost invariably reduces the probability of adequate empirical coverage, with possible unfavorable consequences. In this light, readily available patient's medical history and updated information about the local microbiological epidemiology remain cri ...[more]

PMID: 31041313

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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.

Project description:ObjectivesMultidrug-resistant (MDR) Gram-negative bacterial infections have limited treatment options due to the impermeability of the outer membrane. New therapeutic strategies or agents are urgently needed, and combination therapies using existing antibiotics are a potentially effective means to treat these infections. In this study, we examined whether phentolamine can enhance the antibacterial activity of macrolide antibiotics against Gram-negative bacteria and investigated its mechanism of action.MethodsSynergistic effects between phentolamine and macrolide antibiotics were evaluated by checkerboard and time-kill assays and in vivo using a Galleria mellonella infection model. We utilized a combination of biochemical tests (outer membrane permeability, ATP synthesis, ΔpH gradient measurements, and EtBr accumulation assays) with scanning electron microscopy to clarify the mechanism of phentolamine enhancement of macrolide antibacterial activity against Escherichia coli.ResultsIn vitro tests of phentolamine combined with the macrolide antibiotics erythromycin, clarithromycin, and azithromycin indicated a synergistic action against E. coli test strains. The fractional concentration inhibitory indices (FICI) of 0.375 and 0.5 indicated a synergic effect that was consistent with kinetic time-kill assays. This synergy was also seen for Salmonella typhimurium, Klebsiella pneumoniae, and Actinobacter baumannii but not Pseudomonas aeruginosa. Similarly, a phentolamine/erythromycin combination displayed significant synergistic effects in vivo in the G. mellonella model. Phentolamine added singly to bacterial cells also resulted in direct outer membrane damage and was able to dissipate and uncouple membrane proton motive force from ATP synthesis that, resulted in enhanced cytoplasmic antibiotic accumulation via reduced efflux pump activity.ConclusionsPhentolamine potentiates macrolide antibiotic activity via reducing efflux pump activity and direct damage to the outer membrane leaflet of Gram-negative bacteria both in vitro and in vivo.

Project description:BACKGROUND:Experience in real clinical practice with ceftazidime-avibactam for the treatment of serious infections due to gram-negative bacteria (GNB) other than carbapenem-resistant Enterobacterales (CRE) is very limited. METHODS:We carried out a retrospective multicenter study of patients hospitalized in 13 Italian hospitals who received ?72 h of ceftazidime-avibactam for GNB other than CRE to assess the rates of clinical success, resistance development, and occurrence of adverse events. RESULTS:Ceftazidime-avibactam was used to treat 41 patients with GNB infections other than CRE. Median age was 62 years and 68% of them were male. The main causative agents were P. aeruginosa (33/41; 80.5%) and extended spectrum beta lactamase (ESBL)-producing Enterobacterales (4/41, 9.8%). Four patients had polymicrobial infections. All strains were susceptible to ceftazidime-avibactam. The most common primary infection was nosocomial pneumonia (n = 20; 48.8%), primary bacteremia (n = 7; 17.1%), intra-abdominal infection (n = 4; 9.8%), and bone infection (n = 4; 9.8%). Ceftazidime-avibactam was mainly administered as a combination treatment (n = 33; 80.5%) and the median length of therapy was 13 days. Clinical success at the end of the follow-up period was 90.5%, and the only risk factor for treatment failure at multivariate analysis was receiving continuous renal replacement therapy during ceftazidime-avibactam. There was no association between clinical failures and type of primary infection, microbiological isolates, and monotherapy with ceftazidime-avibactam. Only one patient experienced recurrent infection 5 days after the end of treatment. Development of resistance to ceftazidime-avibactam was not detected in any case during the whole follow-up period. No adverse events related to ceftazidime-avibactam were observed in the study population. CONCLUSIONS:Ceftazidime-avibactam may be a valuable therapeutic option for serious infections due to GNB other than CRE.

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.

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Treatment of Infections Due to MDR Gram-Negative Bacteria.

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Treatment of Infections Due to MDR Gram-Negative Bacteria.

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