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Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections.

ABSTRACT: Antimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern due to the lack of effective and safe alternative treatment options. Carbapenem-resistant gram-negative bacteria of clinical relevance include the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and more recently, Stenotrophomonas maltophilia. Colistin and tigecycline have been used as first-line agents for the treatment of infections caused by these pathogens; however, there are uncertainties regarding their efficacy even when used in combination with other agents. More recently, several new agents with activity against certain carbapenem-resistant pathogens have been approved for clinical use or are reaching late-stage clinical development. They include ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, eravacycline, and cefiderocol. In addition, fosfomycin has been redeveloped in a new intravenous formulation. Data regarding the clinical efficacy of these new agents specific to infections caused by carbapenem-resistant pathogens are slowly emerging and appear to generally favor newer agents over previous best available therapy. As more treatment options become widely available for carbapenem-resistant gram-negative infections, the role of antimicrobial stewardship will become crucial in ensuring appropriate and rationale use of these new agents.

SUBMITTER: Doi Y

PROVIDER: S-EPMC6853760 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections.

Doi Yohei Y

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20191101 Suppl 7

Antimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern due to the lack of effective and safe alternative treatment options. Carbapenem-resistant gram-negative bacteria of clinical relevance include the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and more recently, Stenotrophomonas maltophilia. Colistin and tigecycline have been used as first-line agents for the treatment of infect ...[more]

PMID: 31724043

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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.

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: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:Purpose:Carbapenems are considered the most efficient antibiotic used in the treatment of nosocomial infections. Carbapenem-resistant Gram-negative rods are becoming a serious hazard in hospitals threatening public health. The aim of the current study was to investigate the prevalence of carbapenem-resistant Gram-negative pathogens incriminated in healthcare-associated infections, along with antimicrobial resistance profiles, carbapenemase and metallo-?-lactamase production, and their molecular characterization. Methods:A total of 186 clinical specimens were collected from 133 patients at various hospitals in Cairo, Egypt. The obtained specimens were subjected to bacteriological examination, antimicrobial susceptibility testing, detection of carbapenemase production using the modified Hodge test (MHT), the metallo-?-lactamase production using the EDTA combined disc test (CDT), and PCR-based detection of the bla KPC and bla GES resistance genes. The identification of the highly resistant retrieved isolates was then confirmed by 16S rRNA gene sequencing. Results:The most common isolated Gram-negative species was Klebsiella pneumoniae (40.9%), followed by Acinetobacter baumannii (18.8%), Pseudomonas aeruginosa (17.3%), Escherichia coli (15.4%), Enterobacter aerogenes (5.3%), and Proteus mirabilis (2.4%). The prevalence of carbapenem-resistant isolates was 36.1% (n=75). However, 86.5% of the recovered clinical isolates were susceptible to colistin. The MHT revealed that 33.6% (n=70) of the tested strains were positive for carbapenemase production, while the CDT showed that 33.17% (n=69) of the examined strains were metallo-?-lactamase producers. The PCR revealed that 98.6% (74/75) of the tested strains possessed the bla KPC gene; moreover, 97.3% (73/75) of the examined strains harbored the bla GES gene. Conclusion:This study displayed the emergence of carbapenem-resistant Gram-negative pathogens incriminated in healthcare-associated infections. The accurate identification of carbapenem-resistant bacterial pathogens is pivotal for the treatment of patients, in addition to propelling appropriate contamination control measures to restrain the fast spread of such pathogens. Colistin showed a potent in vitro antimicrobial activity against the carbapenem-resistant strains.

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Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections.

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Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections.

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