scholarly journals Clinical Efficacy of Combination Therapy for the Treatment of Severe Infections Caused by Carbapenem Resistant Gram-Negatives. A Systematic Review of Clinical Studies

2021 ◽  
Author(s):  
Alessia Savoldi ◽  
Elena CARRARA ◽  
Laura JV Piddock ◽  
Francois FRANCESCHI ◽  
Sally ELLIS ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Case Series ◽  
Carbapenem Resistance ◽  
Attributable Mortality ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Language Restriction ◽  
Therapeutic Recommendation

Abstract Background: The combination of antibiotics has become the clinicians’ preferred strategy for the treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) although the evidence supporting its use is weak. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods: Comparative and non-comparative observational studies, randomized control trials (RCTs) and case series were considered eligible with no language restriction. Studies were included if reporting microbiologically-confirmed sepsis caused by Acinetobacter baumannii, Enterobacterales/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcome and targeted antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected to explore feasibility of pooling data on antibiotic regimens. Results: A total of 6306 records were retrieved and 134 studies (11546 patients) were included [54 studies on Acinetobacter, 52 on Enterobacterales/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas]. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective and 17 (13%) case series. Forty-one studies (31%) were multicentric. Ninety-two distinct regimens were identified with 47 (51%, 5863 patients) not reporting any details on combination. 30-day mortality was assessed in 65 (48%) studies while attributable mortality was reported only in 19 (14%).The NMAs were not applicable for any of selected outcomes given the presence of too many disconnected components. Conclusion: The existing evidence is too weak for allowing formulating any evidence-based therapeutic recommendation for combination of antibiotics to treat CR-GNB sepsis. Future studies must clearly define number, type, dosages, and in vitro activity of each antibiotic included in the regimen to drive recommendations for using combination of antibiotics that might be reliably applied into clinical practice.

scholarly journals The role of combination therapy in the treatment of severe infections caused by carbapenem resistant gram-negatives: a systematic review of clinical studies

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alessia Savoldi ◽  
Elena Carrara ◽  
Laura J. V. Piddock ◽  
Francois Franceschi ◽  
Sally Ellis ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Case Series ◽  
Carbapenem Resistance ◽  
Attributable Mortality ◽  
Antibiotic Regimen ◽  
Qualitative Synthesis ◽  
Gram Negative ◽  
Carbapenem Resistant

Abstract Background Effective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods We systematically searched published literature from January 1945 until December 2018 for observational comparative and non-comparative studies and randomized trials examining any antibiotic option for CR-GNB. Studies were included if reporting microbiologically-confirmed infection caused by Acinetobacter baumannii, Enterobacteriaceae/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcomes, and definitive antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Each antibiotic regimen was classified as “defined” when at least the molecular class(es) composing the regimen was detailed. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected for quantitative synthesis to explore feasibility of pooling data on antibiotic regimens. Results A total of 6306 records were retrieved and 134 studies including 11,546 patients were included: 54 studies were on Acinetobacter, 52 on Enterobacteriaceae/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective, and 17 (13%) case series. Forty-one studies (31%) were multicentric. Qualitative synthesis showed an heterogeneous and scattered reporting of key-clinical and microbiological variables across studies. Ninety-two distinct antibiotic regimens were identified with 47 of them (51%, 5863 patients) not reporting any details on numbers, type, dosage and in vitro activity of the included antibiotic molecules. The NMAs could not be performed for any of the selected outcome given the presence of too many disconnected components. Conclusion The existing evidence is insufficient to allowing for the formulation of any evidence-based therapeutic recommendation for CR-GNB sepsis. Future studies must provide a standardized definition of antibiotic regimen to drive recommendations for using combination of antibiotics that can be reliably applied to clinical practice.

Carbapenem Resistance, Initial Antibiotic Therapy, and Mortality inKlebsiella pneumoniaeBacteremia: A Systematic Review and Meta-Analysis

2017 ◽  
Vol 38 (11) ◽  
pp. 1319-1328 ◽  
Author(s):  
Philipp P. Kohler ◽  
Cheryl Volling ◽  
Karen Green ◽  
Elizabeth M. Uleryk ◽  
Prakesh S. Shah ◽  
...  
Keyword(s):  
Systematic Review ◽  
Antibiotic Therapy ◽  
Meta Analysis ◽  
Carbapenem Resistance ◽  
Carbapenem Resistant ◽  
Initial Antibiotic Therapy ◽  
Meta Regression ◽  
The Difference ◽  
Meta Regression Analysis ◽  
The Impact

BACKGROUNDMortality associated with infections caused by carbapenem-resistantEnterobacteriaceae(CRE) is higher than mortality due to carbapenem-sensitive pathogens.OBJECTIVETo examine the association between mortality from bacteremia caused by carbapenem-resistant (CRKP) and carbapenem-sensitiveKlebsiella pneumoniae(CSKP) and to assess the impact of appropriate initial antibiotic therapy (IAT) on mortality.DESIGNSystematic review and meta-analysisMETHODSWe searched MEDLINE, EMBASE, CINAHL, and Wiley Cochrane databases through August 31, 2016, for observational studies reporting mortality among adult patients with CRKP and CSKP bacteremia. Search terms were related toKlebsiella, carbapenem-resistance, and infection. Studies including fewer than 10 patients per group were excluded. A random-effects model and meta-regression were used to assess the relationship between carbapenem-resistance, appropriateness of IAT, and mortality.RESULTSMortality was higher in patients who had CRKP bacteremia than in patients with CSKP bacteremia (15 studies; 1,019 CRKP and 1,148 CSKP patients; unadjusted odds ratio [OR], 2.2; 95% confidence interval [CI], 1.8–2.6; I2=0). Mortality was lower in patients with appropriate IAT than in those without appropriate IAT (7 studies; 658 patients; unadjusted OR, 0.5; 95% CI, 0.3–0.8; I2=36%). CRKP patients (11 studies; 1,326 patients; 8-year period) were consistently less likely to receive appropriate IAT (unadjusted OR, 0.5; 95% CI, 0.3–0.7; I2=43%). Our meta-regression analysis identified a significant association between the difference in appropriate IAT and mortality (OR per 10% difference in IAT, 1.3; 95% CI, 1.0–1.6).CONCLUSIONSAppropriateness of IAT is an important contributor to the observed difference in mortality between patients with CRKP bacteremia and patients with CSKP bacteremia.Infect Control Hosp Epidemiol2017;38:1319–1328

scholarly journals In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol

2020 ◽  
Vol 4 (1) ◽  
pp. e100055
Author(s):  
Elda Righi ◽  
Luigia Scudeller ◽  
Margherita Chiamenti ◽  
Kamilia Abdelraouf ◽  
Thomas Lodise ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
In Vivo Models ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
The Impact ◽  
Antibiotic Combination

ObjectiveThere is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria.Methods and analysisThis protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE’s risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias.DisseminationThis systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals.PROSPERO registration numberCRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104).

Systematic Review and Meta-analysis of Carbapenem Resistance of Acinetobacter baumannii in Iran

2020 ◽  
Vol 20 (5) ◽  
pp. 611-619
Author(s):  
Pegah Shakib ◽  
Zeinab Babaie Choolandaimy ◽  
Faranak Rezaie ◽  
Mahmood Bahmani ◽  
Somayeh Delfani
Keyword(s):  
Systematic Review ◽  
Acinetobacter Baumannii ◽  
Web Of Science ◽  
Meta Analysis ◽  
Carbapenem Resistance ◽  
Drug Resistant ◽  
Sample Collection ◽  
Carbapenem Resistant ◽  
Collection Period ◽  
Egger Test

Introduction: The prevalence of carbapenem resistance in Acinetobacter baumannii has been increasing worldwide, and therapeutic options are extremely limited. We performed a systematic review to evaluate the phenotypic and genotypic carbapenem resistance in A.baumannii reported in Iran. Methods: We systematically searched Pub Med, Web of Science Direct, and Google scholar databases to identify studies addressing the carbapenem resistance of A. baumannii. The selected papers were published between 2005 and 2016, but the sample collection period was between 2002 and 2016. To estimate the prevalence, the Der Simonian and Laird randomized models, a 95% confidence interval, was used. For the heterogeneity check, I2 test was used. The Egger test was used to check the propagation bias. Results: Analysis of data indicates that there was an increase in resistance to carbapenems from 4.5% in 2005 to a 100% prevalence rate in 2016 (65.4 (95% CI: 58.8 – 71.6). Conclusion: According to the results of this study, the rate of resistance to carbapenem in A.baumannii has been increasing in Iran. The presence of carbapenem-resistant isolates is a major concern, because carbapenem is the main drug used against Multi Drug Resistant (MDR) isolates.

Mortality associated with Blastomyces dermatitidis infection: A systematic review of the literature and meta-analysis

2019 ◽  
Vol 58 (1) ◽  
pp. 1-10
Author(s):  
Alex Carignan ◽  
Mélina Denis ◽  
Claire Nour Abou Chakra
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Meta Analysis ◽  
Random Effect ◽  
Random Effect Model ◽  
Case Series ◽  
Case Fatality ◽  
Attributable Mortality ◽  
Blastomyces Dermatitidis ◽  
Immunocompromised Patients

Abstract Published case fatality in blastomycosis patients ranges between 4% and 78%. This study aimed to assess mortality associated with blastomycosis and identify its associated risk factors. We conducted a systematic review of publications related to Blastomyces dermatitidis available in PubMed and Scopus databases. Studies that reported data on blastomycosis mortality and that were published from inception through February 2018 were assessed and included in the analysis. Using the R meta package, a random-effect model meta-analysis was used to calculate pooled and stratified estimates of case-fatality proportions and risk ratios. Of 1553 publications, we included 20 studies reporting on a total of 2820 cases of blastomycosis between 1970 and 2014 and three case series reports with 10, 21, and 36 patients. The mean or median ages ranged from 28 to 59 years. Mortality was defined as attributable mortality caused by blastomycosis in 13 studies. Among 14 studies with a standard error ≤0.05, the overall pooled mortality was 6.6% (95% confidence interval [CI], 4.9–8.2) with 57% heterogeneity. The mortality rate was 37% (95% CI, 23–51) in immunocompromised patients and 75% (95% CI, 53–96) in patients who developed an acute respiratory distress syndrome (ARDS) (n = 3 studies each). ARDS was the only identified risk factor in general patients (risk ratio = 10.2). The overall mortality was significantly higher in studies involving immunocompromised patients and ARDS patients. Our analysis showed considerable heterogeneity among studies. Inconsistent mortality definitions may have contributed to the observed heterogeneity. Further research is needed to assess potential risk factors for mortality.

scholarly journals Cefiderocol: A Novel Siderophore Cephalosporin Defeating Carbapenem-resistant Pathogens

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S519-S520 ◽  
Author(s):  
Robert A Bonomo
Keyword(s):  
Late Stage ◽  
Transport Mechanism ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Clinical Development ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Active Transport Mechanism

AbstractCefiderocol, a novel siderophore cephalosporin in late-stage clinical development, utilizes a “Trojan horse” active transport mechanism to enter bacteria and has proven in vitro activity against carbapenem-resistant gram-negative pathogens, including those with major carbapenem-resistance mechanisms, and stability against all carbapenemases.

scholarly journals Convalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative Analysis (Preprint)

2020 ◽  
Author(s):  
Henry Peng
Keyword(s):  
Systematic Review ◽  
Clinical Studies ◽  
Case Reports ◽  
Meta Analysis ◽  
Case Series ◽  
Future Research ◽  
In Vitro Testing ◽  
Screening Process ◽  
Prevention And Treatment

BACKGROUND The coronavirus disease (COVID-19) pandemic caused by a novel coronavirus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread quickly worldwide. Currently, no vaccine or specific therapeutics are available to prevent and/or treat COVID-19. Convalescent plasma (CP) obtained from patients following resolution of COVID-19 infection and development of antibodies against the virus is an attractive option for either prophylactic or therapeutic treatment, since antibodies may have direct or indirect antiviral activities and immunotherapy has proven effective in principle, and in many clinical reports. OBJECTIVE We sought to characterize the latest advances and evidence in the use of CP for COVID-19 through a systematic review and quantitatively analysis, identify knowledge gaps in this setting, and offer recommendations and directives for future research. METHODS PubMed, Web of Science and Embase were continuously searched for studies assessing the use of CP for COVID-19 including clinical studies, commentaries, reviews, guidelines/protocols and in vitro testing of CP antibodies. Screening process and data extraction were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality appraisal of all clinical studies was conducted using an universal tool independent on study designs. Meta-analysis of case-controlled and randomized controlled trials (RCTs) was conducted using a random-effects model. RESULTS Substantial literature has been published covering various aspects of CP therapy for COVID-19. Of the references included in this review, a total of 243 eligible studies including 64 clinical studies, 79 commentary articles, 46 reviews, 19 guidance and protocols, 35 in vitro testing of CP antibodies, matched the criteria. Positive results have been mostly observed so far when utilising CP for the treatment of COVID-19. There are remarkable heterogeneities in the CP therapy with respect to patient demographics, donor antibody titers, time and dose of CP administration. The studies assessing the safety of CP treatment reported low incidence of adverse events. Most clinical studies in particular case reports and case series had poor quality. Only one RCT was of high quality. Randomized and non-randomized data were found in two and 11 studies, respectively and included for meta-analysis suggesting that CP could reduce mortality and increase viral clearance. Despite promising pilot studies, the benefits of CP treatment can only be clearly established through carefully designed RCTs. CONCLUSIONS There is developing support for CP therapy particularly for patients who are critically ill or mechanically ventilated and resistant to antivirals and supportive care. These studies provide important lessons that should inform the planning of well-designed RCTs to generate more robust knowledge for the efficacy of CP in COVID-19 patients. Future research is necessary to fill the knowledge gap regarding prevention and treatment of COVID-19 patients with CP while vaccines and other treatment are being developed.

scholarly journals Contemporary occurrence and aetiology of chronic leg ulcers in Africa: a systematic review and meta-analysis protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. e026868 ◽  
Author(s):  
Celestin Danwang ◽  
Joel Noutakdie Tochie ◽  
Temgoua Ngou Mazou ◽  
Rolf Nyah Tuku Nzalie ◽  
Jean Joel Bigna
Keyword(s):  
Systematic Review ◽  
Global Economy ◽  
Meta Analysis ◽  
Grey Literature ◽  
Case Series ◽  
Published Data ◽  
Leg Ulcers ◽  
Cross Sectional ◽  
Language Restriction ◽  
Chronic Leg Ulcers

IntroductionChronic leg ulcers are known as a major and snowballing threat to public health and the global economy. In Africa, there is controversy on the dearth of studies reporting the epidemiology of chronic leg ulcers. The present systematic review and meta-analysis aim at synthesising the prevalence, incidence and aetiologies of this ailment in this continent from contemporary data.Methods and designWe will include cohort studies, case–control, cross-sectional studies and case series with more than 30 participants. Electronical databases including African Journals Online, MEDLINE, Excerpta Medica Database and Web of knowledge, and grey literature will be searched for relevant abstracts of studies published and unpublished between 1 January, 2000, and 28 February, 2019, without language restriction. The review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Each study included in this review will be assessed for methodological quality. Clinically homogenous studies will be pooled using random-effects meta-analysis. Visual inspection of funnel-plots and the Egger’s test will be used to investigate publication bias. Meta-regression and subgroup analyses will be performed to investigate the possible sources of heterogeneity.Ethics and disseminationThe present study will be based on published data; therefore, ethical approval is not required. Result of the review will be presented at conferences, to relevant health authorities and will be published in a biomedical peer-reviewed journal.Protocol registration numberCRD42018108250.

Mechanical thrombectomy in pediatric stroke: systematic review, individual patient data meta-analysis, and case series

2019 ◽  
Vol 24 (5) ◽  
pp. 558-571 ◽  
Author(s):  
Kartik Bhatia ◽  
Hans Kortman ◽  
Christopher Blair ◽  
Geoffrey Parker ◽  
David Brunacci ◽  
...  
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Mechanical Thrombectomy ◽  
Case Reports ◽  
Meta Analysis ◽  
Case Series ◽  
Neurological Outcomes

OBJECTIVEThe role of mechanical thrombectomy in pediatric acute ischemic stroke is uncertain, despite extensive evidence of benefit in adults. The existing literature consists of several recent small single-arm cohort studies, as well as multiple prior small case series and case reports. Published reports of pediatric cases have increased markedly since 2015, after the publication of the positive trials in adults. The recent AHA/ASA Scientific Statement on this issue was informed predominantly by pre-2015 case reports and identified several knowledge gaps, including how young a child may undergo thrombectomy. A repeat systematic review and meta-analysis is warranted to help guide therapeutic decisions and address gaps in knowledge.METHODSUsing PRISMA-IPD guidelines, the authors performed a systematic review of the literature from 1999 to April 2019 and individual patient data meta-analysis, with 2 independent reviewers. An additional series of 3 cases in adolescent males from one of the authors’ centers was also included. The primary outcomes were the rate of good long-term (mRS score 0–2 at final follow-up) and short-term (reduction in NIHSS score by ≥ 8 points or NIHSS score 0–1 at up to 24 hours post-thrombectomy) neurological outcomes following mechanical thrombectomy for acute ischemic stroke in patients < 18 years of age. The secondary outcome was the rate of successful angiographic recanalization (mTICI score 2b/3).RESULTSThe authors’ review yielded 113 cases of mechanical thrombectomy in 110 pediatric patients. Although complete follow-up data are not available for all patients, 87 of 96 (90.6%) had good long-term neurological outcomes (mRS score 0–2), 55 of 79 (69.6%) had good short-term neurological outcomes, and 86 of 98 (87.8%) had successful angiographic recanalization (mTICI score 2b/3). Death occurred in 2 patients and symptomatic intracranial hemorrhage in 1 patient. Sixteen published thrombectomy cases were identified in children < 5 years of age.CONCLUSIONSMechanical thrombectomy may be considered for acute ischemic stroke due to large vessel occlusion (ICA terminus, M1, basilar artery) in patients aged 1–18 years (Level C evidence; Class IIb recommendation). The existing evidence base is likely affected by selection and publication bias. A prospective multinational registry is recommended as the next investigative step.

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