Pandrug-resistant Gram-negative bacteria: a systematic review of current epidemiology, prognosis and treatment options

2019 ◽  
Author(s):  
Stamatis Karakonstantis ◽  
Evangelos I Kritsotakis ◽  
Achilleas Gikas
Keyword(s):  
Case Reports ◽  
Controlled Trial ◽  
Treatment Options ◽  
Relevant Literature ◽  
Gram Negative Bacteria ◽  
Term Care ◽  
Gram Negative ◽  
Treatment Regimens ◽  
Synergistic Combinations

Abstract Background The literature on the epidemiology, mortality and treatment of pandrug-resistant (PDR) Gram-negative bacteria (GNB) is scarce, scattered and controversial. Objectives To consolidate the relevant literature and identify treatment options for PDR GNB infections. Methods A systematic search in MEDLINE, Scopus and clinical trial registries was conducted. Studies reporting PDR clinical isolates were eligible for review if susceptibility testing for all major antimicrobials had been performed. Characteristics and findings of retrieved studies were qualitatively synthesized. Results Of 81 studies reviewed, 47 (58%) were published in the last 5 years. The reports reflected a worldwide dissemination of PDR GNB in 25 countries in 5 continents. Of 526 PDR isolates reported, Pseudomonas aeruginosa (n=175), Acinetobacter baumannii (n=172) and Klebsiella pneumoniae (n=125) were most common. PDR GNB were typically isolated in ICUs, but several studies demonstrated wider outbreak potential, including dissemination to long-term care facilities and international spread. All-cause mortality was high (range 20%–71%), but appeared to be substantially reduced in studies reporting treatment regimens active in vitro. No controlled trial has been performed to date, but several case reports and series noted successful use of various regimens, predominantly synergistic combinations, and in selected patients increased exposure regimens and newer antibiotics. Conclusions PDR GNB are increasingly being reported worldwide and are associated with high mortality. Several treatment regimens have been successfully used, of which synergistic combinations appear to be most promising and often the only available option. More pharmacokinetic/pharmacodynamic and outcome studies are needed to guide the use of synergistic combinations.

scholarly journals Case Commentary: the Need for Cefiderocol Is Clear, but Are the Supporting Clinical Data?

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Ryan K. Shields
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Salvage Therapy ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Potential Utility ◽  
Gram Negative

ABSTRACT Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated patients. Taken together, clinicians must balance a clear need for cefiderocol in clinical practice with the uncertainties that have stemmed from the available data.

scholarly journals An Update on Eight “New” Antibiotics against Multidrug-Resistant Gram-Negative Bacteria

2021 ◽  
Vol 10 (5) ◽  
pp. 1068
Author(s):  
Erlangga Yusuf ◽  
Hannelore I. Bax ◽  
Nelianne J. Verkaik ◽  
Mireille van Westreenen
Keyword(s):  
Drug Administration ◽  
Food And Drug Administration ◽  
Treatment Options ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Beta Lactamases ◽  
New Antibiotics ◽  
Tract Infections ◽  
The U.S

Infections in the ICU are often caused by Gram-negative bacteria. When these microorganisms are resistant to third-generation cephalosporines (due to extended-spectrum (ESBL) or AmpC beta-lactamases) or to carbapenems (for example carbapenem producing Enterobacteriales (CPE)), the treatment options become limited. In the last six years, fortunately, there have been new antibiotics approved by the U.S. Food and Drug Administration (FDA) with predominant activities against Gram-negative bacteria. We aimed to review these antibiotics: plazomicin, eravacycline, temocillin, cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam. Temocillin is an antibiotic that was only approved in Belgium and the UK several decades ago. We reviewed the in vitro activities of these new antibiotics, especially against ESBL and CPE microorganisms, potential side effects, and clinical studies in complicated urinary tract infections (cUTI), intra-abdominal infections (cIAI), and hospital-acquired pneumonia/ventilator-associatedpneumonia (HAP/VAP). All of these new antibiotics are active against ESBL, and almost all of them are active against CPE caused by KPC beta-lactamase, but only some of them are active against CPE due to MBL or OXA beta-lactamases. At present, all of these new antibiotics are approved by the U.S. Food and Drug Administration for cUTI (except eravacycline) and most of them for cIAI (eravacycline, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam) and for HAP or VAP (cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam).

scholarly journals Treatment Options for K. pneumoniae, P. aeruginosa and A. baumannii Co-resistant to Carbapenems, Aminoglycosides, Colistin and Tigecycline. An Approach Based on the Mechanisms of Resistance to Carbapenems

2020 ◽  
Author(s):  
Stamatis Karakonstantis ◽  
Evangelos Kritsotakis ◽  
Achilleas Gikas
Keyword(s):  
Case Reports ◽  
Treatment Options ◽  
Case Series ◽  
Diagnostic Methods ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Mechanisms Of Resistance ◽  
Carbapenem Resistant ◽  
Synergistic Combinations

The management of carbapenem-resistant infections is often based on colistin, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, colistin and tigecycline (CACT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CACT-resistant GNB are scarce and based exclusively on few case reports and small case series but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review we consolidate the available literature to inform clinicians dealing with CACT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CACT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CACT-resistant K. pneumonia. Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g. colistin- or fosfomycin-based synergistic combinations) may represent a last resort option but their use against CACT-resistant GNB requires further study.

Antimicrobial activity of POL7306 tested against clinical isolates of Gram-negative bacteria collected worldwide

2020 ◽  
Vol 75 (6) ◽  
pp. 1518-1524 ◽  
Author(s):  
Helio S Sader ◽  
Paul R Rhomberg ◽  
Leonard R Duncan ◽  
Hans H Locher ◽  
Glenn E Dale ◽  
...  
Keyword(s):  
Protein Targeting ◽  
Treatment Options ◽  
Asia Pacific ◽  
Surveillance Program ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
The Usa

Abstract Background POL7306 belongs to a new class of peptidomimetic outer-membrane-protein-targeting antibiotics with a novel mechanism of action. POL7306 is in development for the treatment of infections caused by antimicrobial-resistant Gram-negative bacteria and has demonstrated low cytotoxicity and nephrotoxicity. Methods A total of 891 isolates were collected by the SENTRY Antimicrobial Surveillance Program from 134 medical centres in Europe (n = 424; 41 centres in 18 nations), the USA (n = 411 isolates from 67 centres), the Asia-Pacific region (n = 24; 15 centres in 6 nations) and Latin America (n = 32; 11 centres in 9 nations) and included 558 Enterobacterales, 310 non-fermenters and 23 fastidious organisms. Susceptibility testing was performed using the reference broth microdilution method and the medium was supplemented with 0.002% polysorbate-80 for testing POL7306. Resistant subsets were characterized by WGS. Results POL7306 demonstrated potent in vitro activity against Enterobacterales [including carbapenem-resistant (MIC50/90, 0.06/0.25 mg/L), ESBL-producing (MIC50/90, 0.06/0.12 mg/L), KPC-producing (MIC50/90, 0.12/0.25 mg/L), MBL-producing (MIC50/90, 0.06/0.25 mg/L), colistin-non-susceptible, mcr-negative (MIC50/90, 0.5/2 mg/L) and mcr-positive (MIC50/90, 0.12/0.25 mg/L) Enterobacterales], Pseudomonas aeruginosa (MIC50/90, 0.25/0.25 mg/L), Acinetobacter baumannii (MIC50/90, 0.06/0.12 mg/L) and Stenotrophomonas maltophilia (MIC50/90, 0.06/0.25 mg/L). Conclusions POL7306 demonstrated potent activity against a large collection of Gram-negative organisms collected worldwide that included colistin-resistant, XDR and ESBL- and carbapenemase-producing isolates for which there are currently limited treatment options.

scholarly journals Description of an effective treatment regimen for ventilator-associated pneumonia due to pandrug-resistant Providencia: a case report

Pneumologia ◽  
2020 ◽  
Vol 69 (1) ◽  
pp. 53-56
Author(s):  
Elham Pourheidar ◽  
Rezvan Hassanpour ◽  
Mehrdad Haghighi ◽  
Seyedpouzhia Shojaei ◽  
Mehran Kouchak ◽  
...  
Keyword(s):  
Clinical Signs ◽  
High Dose ◽  
Gram Negative Bacteria ◽  
Ventilator Associated Pneumonia ◽  
Gram Negative ◽  
Treatment Regimens ◽  
Antibacterial Regimen ◽  
Negative Sputum ◽  
Effective Treatment Regimen

AbstractBecause of an increased prevalence of infections with resistant Gram-negative bacteria, finding optimal treatment regimens for these cases is one of the major healthcare concerns. Providencia is a Gram-negative bacteria belonging to the Enterobacteriaceae family. This article aims to describe an effective antibacterial regimen used for treating ventilator-associated pneumonia (VAP) with species of Providencia that are resistant to all antimicrobial classes. We present the case of a 74-year-old woman suffering from VAP caused by pandrug-resistant Providencia. The patient received high-dose intravenous meropenem (1 g every 12 h, infused over 4 h), intravenous amikacin (1,500 mg every 48 h) and nebulised amikacin (250 mg every 6 h). The dosages were calculated based on weight and renal function (GFR = 13.69 ml/min/1.73). After 23 days of treatment, following improvement in clinical signs (including fever), a drop in leucocytes counts, a higher than 80% reduction in procalcitonin levels (0.12), together with confirmed microbial eradication (negative sputum cultures), the antibacterial regimen was discontinued. In conclusion, when dealing with an infection with a pan-resistant microorganism, using combinations of antibiotics in high doses can be an option. These treatment regimens have the potential of overcoming in vitro resistance, leading to clinical improvement and microbial eradication.

scholarly journals Polymyxins–Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 506 ◽  
Author(s):  
Chongshan Dai ◽  
Yang Wang ◽  
Gaurav Sharma ◽  
Jianzhong Shen ◽  
Tony Velkov ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Inhibitory Effect ◽  
Limiting Factors ◽  
Therapeutic Window ◽  
Limiting Factor ◽  
Gram Negative Bacteria ◽  
Gram Negative

The emergence of antimicrobial resistance in Gram-negative bacteria poses a huge health challenge. The therapeutic use of polymyxins (i.e., colistin and polymyxin B) is commonplace due to high efficacy and limiting treatment options for multidrug-resistant Gram-negative bacterial infections. Nephrotoxicity and neurotoxicity are the major dose-limiting factors that limit the therapeutic window of polymyxins; nephrotoxicity is a complication in up to ~60% of patients. The emergence of polymyxin-resistant strains or polymyxin heteroresistance is also a limiting factor. These caveats have catalyzed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and resistant organisms and/or minimize the unwanted side effects. Curcumin—an FDA-approved natural product—exerts many pharmacological activities. Recent studies showed that polymyxins–curcumin combinations showed a synergistically inhibitory effect on the growth of bacteria (e.g., Gram-positive and Gram-negative bacteria) in vitro. Moreover, curcumin co-administration ameliorated colistin-induced nephrotoxicity and neurotoxicity by inhibiting oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. In this review, we summarize the current knowledge-base of polymyxins–curcumin combination therapy and discuss the underlying mechanisms. For the clinical translation of this combination to become a reality, further research is required to develop novel polymyxins–curcumin formulations with optimized pharmacokinetics and dosage regimens.

scholarly journals Activity of ceftolozane/tazobactam against commonly encountered antimicrobial resistant Gram-negative bacteria in Lebanon

2020 ◽  
Vol 14 (06) ◽  
pp. 559-564
Author(s):  
George F Araj ◽  
Dana M Berjawi ◽  
Umayya Musharrafieh ◽  
Nancy K El Beayni
Keyword(s):  
Bacterial Resistance ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Beta Lactamases ◽  
E Coli ◽  
Extended Spectrum Beta Lactamases ◽  
In Vitro Data

Introduction: In view of the continuous rise in Gram-negative bacterial resistance and limited treatment options, Ceftolozane/tazobactam (C/T) is a newly introduced antimicrobial agent in Lebanon for its demonstrated activity against resistant Gram-negative bacteria. However, in vitro data is not available about its activity against commonly isolated bacteria in this country. Methodology: The analysis included clinical isolates, multidrug–resistant (MDR) and extended-spectrum Beta-lactamases (ESBLs), representing 124 Escherichia coli, 75 Klebsiella pneumoniae and 100 Pseudomonas aeruginosa, identified using the MALDI-TOF. The minimum inhibitory concentration (MIC) for C/T was determined by the Etest (Liofilchem, Roseto degli Abruzzi, Italy). In addition, the disk diffusion (DD) test was used to determine the activity of C/T and of the antimicrobials routinely used to test for such pathogens. Results: The C/T activity against the ESBL producers E. coli and K. pneumoniae isolates were similar (MIC90 value of 1 and 1.5 µg/mL, respectively; susceptibility of 100% and 96%, respectively). However, the activity of C/T against the E. coli and K. pneumoniae MDR isolates was much lower (MIC90 value of 256 and 96 µg/mL, respectively; susceptibility of 54% for each). The C/T MIC90 value for the non-MDR P. aeruginosa isolates was 3 µg/mL and ≥ 256 µg/mL for the MDR P. aeruginosa isolates (susceptibility of 96% vs 42% respectively). Overall, the C/T activities show comparable or higher susceptibility to the routinely used antimicrobials. Conclusion: The high in vitro activity of C/T points out its value as a possible alternative to the antimicrobials currently used for treatment of infections caused by such pathogens and would help in minimizing toxicity and bacterial resistance.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19

2020 ◽  
Vol 21 (6) ◽  
pp. 427-435 ◽  
Author(s):  
Cheng Cui ◽  
Siqi Tu ◽  
Valerie Sia Jie En ◽  
Xiaobei Li ◽  
Xueting Yao ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Clinical Efficacy ◽  
Relevant Literature ◽  
The United States ◽  
Efficacy And Safety ◽  
Open Label ◽  
Infected People ◽  
Treatment Regimens ◽  
Therapeutic Drugs

Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

2020 ◽  
Vol 20 (3) ◽  
pp. 192-208 ◽  
Author(s):  
Talita Odriane Custodio Leite ◽  
Juliana Silva Novais ◽  
Beatriz Lima Cosenza de Carvalho ◽  
Vitor Francisco Ferreira ◽  
Leonardo Alves Miceli ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Mass Spectrometry Analysis ◽  
World Health ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dione Derivative ◽  
In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

scholarly journals Coumarin Exhibits Broad-Spectrum Antibiofilm and Antiquorum Sensing Activity against Gram-Negative Bacteria: In Vitro and In Silico Investigation

ACS Omega ◽  
2021 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohammad Shavez Khan ◽  
Iqbal Ahmad ◽  
Fohad Mabood Husain ◽  
Rais Ahmad Khan ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
In Silico ◽  
Gram Negative Bacteria ◽  
Gram Negative
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