The Role of Adjunctive Therapies in Septic Shock by Gram Negative MDR/XDR Infections.
Ontology highlight
ABSTRACT:
SUBMITTER: Busani S
PROVIDER: S-EPMC5523464 | biostudies-other | 2017
REPOSITORIES: biostudies-other
Similar Datasets
Project description: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.
| S-EPMC6477053 | biostudies-literature
Project description:The emergence of infections by carbapenem resistant Enterobacteriaceae (CRE) pathogens has created an urgent public health threat, as carbapenems are among the drugs of last resort for infections caused by a growing fraction of multi-drug resistant (MDR) bacteria. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. Here, we report on the efficacy of a novel macrocyclic peptide, minimized theta-defensin (MTD)-12813 in CRE sepsis. MTD12813 is a theta-defensin inspired cyclic peptide that is highly effective against CRE pathogens K. pneumoniae and E. coli in vivo. In mouse septicemia models, single dose administration of MTD12813 significantly enhanced survival by promoting rapid host-mediated bacterial clearance and by modulating pathologic cytokine responses, restoring immune homeostasis, and preventing lethal septic shock. The peptide lacks direct antibacterial activity in the presence of mouse serum or in peritoneal fluid, further evidence for its indirect antibacterial mode of action. MTD12813 is highly stable in biological matrices, resistant to bacterial proteases, and nontoxic to mice at dose levels 100 times the therapeutic dose level, properties which support further development of the peptide as a first in class anti-infective therapeutic.
| S-EPMC8648872 | biostudies-literature
Project description:ObjectivesInhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics.MethodsMICs were determined for 369 clinical isolates (234 Enterobacteriaceae and 135 non-fermentative Gram-negative bacilli). Time-kill assays with LPC-058 were performed on four MDR/XDR strains, including Escherichia coli producing CTX-M-15 ESBL and Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii producing KPC-2, VIM-1 and OXA-23 carbapenemases, respectively.ResultsLPC-058 was the most potent antibiotic and displayed the broadest spectrum of antimicrobial activity, with MIC90 values for Enterobacteriaceae, P. aeruginosa, Burkholderia cepacia and A. baumannii of 0.12, 0.5, 1 and 1 mg/L, respectively. LPC-058 was bactericidal at 1× or 2× MIC against CTX-M-15, KPC-2 and VIM-1 carbapenemase-producing strains and bacteriostatic at ≤4× MIC against OXA-23 carbapenemase-producing A. baumannii. Combinations of LPC-058 with β-lactams, amikacin and ciprofloxacin were synergistic against these strains, albeit in a species-dependent manner. LPC-058's high efficacy was attributed to the presence of the difluoromethyl-allo-threonyl head group and a linear biphenyl-diacetylene tail group.ConclusionsThese in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies.
| S-EPMC5031916 | biostudies-literature
Project description:We report the first case of necrotizing fasciitis due to the uncommon Gram-negative pathogen Sphingobacterium multivorum in an immunocompromised patient, who presented with septic shock. This case adds necrotizing fasciitis to the spectrum of S. multivorum-related infections and highlights the emergence of Gram-negative bacteria in severe soft tissue infections.
| S-EPMC3256725 | biostudies-literature
Project description:BackgroundIntestinal colonization by MDR/XDR gram-negative bacteria leads to an increased risk of subsequent bloodstream infections (BSI) in patients receiving chemotherapy as a treatment for hematologic malignancies.ObjectivesThe objective of this study was to evaluate the efficacy of oral colistin in eradicating the intestinal carriage of MDR/XDR Gram-negative bacteria in patients with hematological malignancies.MethodsIn a tertiary hematology center, adult patients with intestinal colonization by MDR/XDR Gram-negative bacteria were included in a randomized controlled trial (RCT) during a period from November 2016 to October 2017. Patients were treated with oral colistin for 14 days or observed with the primary outcome set as decolonization on day 21 post-treatment. Secondary outcomes included treatment safety and changes in MICs of isolated microorganisms. ClinicalTrials.gov Identifier: NCT02966457.ResultsShort-time positive effect (61.3% vs 32.3%; OR 3.32; 95% CI 1.17-9.44; p=0.0241) was demonstrated on the day 14 of colistin treatment, without any statistical difference on day 21 post-treatment. The incidence of BSI in decolonization group was lower in the first 30 days after the intervention (3.2% vs. 12.9%), but overall in the 90-day observation period, it did not show any advantages comparing to control group (log-rank test; p=0.4721). No serious adverse effects or increase in resistance to colistin was observed.ConclusionsThis study suggests that in hematological patients the strategy of selective intestinal decolonization by colistin may be beneficial to decrease the rate of MDR/XDR Gram-negative intestinal colonization and the risk of BSI in the short-term period, having no long-term sustainable effects.
| S-EPMC5937973 | biostudies-literature
Project description:One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress, and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when coadministered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings in vivo using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development, and stewardship of novel combination therapies.IMPORTANCE There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in vitro against a diverse range of recalcitrant Gram-negative clinical isolates and in vivo in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.
| S-EPMC7492738 | biostudies-literature
Project description:Background:A multitude of definitions determining multidrug resistance (MDR) of Gram-negative organisms exist worldwide. The definitions differ depending on their purpose and on the issueing country or organization. The MDR definitions of the European Centre for Disease Prevention and Control (ECDC) were primarily chosen to harmonize epidemiological surveillance. The German Commission of Hospital Hygiene and Infection Prevention (KRINKO) issued a national guideline which is mainly used to guide infection prevention and control (IPC) measures. The Swiss University Hospital Zurich (UHZ) - in absentia of national guidelines - developed its own definition for IPC purposes. In this study we aimed to determine the effects of different definitions of multidrug-resistance on rates of Gram-negative multidrug-resistant organisms (GN-MDRO). Methods:MDR definitions of the ECDC, the German KRINKO and the Swiss University Hospital Zurich were applied on a dataset comprising isolates of Escherichia coli, Klebsiella pneumoniae, Enterobacter sp., Pseudomonas aeruginosa, and Acinetobacter baumannii complex. Rates of GN-MDRO were compared and the percentage of patients with a GN-MDRO was calculated. Results:In total 11'407 isolates from a 35?month period were included. For Enterobacterales and P. aeruginosa, highest MDR-rates resulted from applying the 'ECDC-MDR' definition. 'ECDC-MDR' rates were up to four times higher compared to 'KRINKO-3/4MRGN' rates, and up to six times higher compared to UHZ rates. Lowest rates were observed when applying the 'KRINKO-4MRGN' definitions. Comparing the 'KRINKO-3/4MRGN' with the UHZ definitions did not show uniform trends, but yielded higher rates for E. coli and lower rates for P. aeruginosa. On the patient level, the percentages of GN-MDRO carriers were 2.1, 5.5, 6.6, and 18.2% when applying the 'KRINKO-4MRGN', 'UHZ-MDR', 'KRINKO-3/4MRGN', and the 'ECDC-MDR' definition, respectively. Conclusions:Different MDR-definitions lead to considerable variation in rates of GN-MDRO. Differences arise from the number of antibiotic categories required to be resistant, the categories and drugs considered relevant, and the antibiotic panel tested. MDR definitions should be chosen carefully depending on their purpose and local resistance rates, as definitions guiding isolation precautions have direct effects on costs and patient care.
| S-EPMC6883537 | biostudies-literature
Project description:Septic shock-associated mortality in intensive care units (ICUs) remains high, with reported rates ranging 30-50%. In particular, Gram-negative bacilli (GNB), which induce significant inflammation and consequent multiple organ failure, are the etiological bacterial agent in 40% of severe sepsis cases. Hemoperfusion using polymyxin B-immobilized fiber (PMX), which adsorbs endotoxin, is expected to reduce the inflammatory sepsis cascade due to GNB. However, the clinical efficacy of this treatment has not yet been demonstrated. Here, we aimed to verify the efficacy of endotoxin adsorption therapy using PMX through a retrospective analysis of 413 patients who received broad spectrum antimicrobial treatment for GNB-related septic shock between January 2009 and December 2012 in 11 ICUs of Japanese tertiary hospitals. After aligning the patients' treatment time phases, we classified patients in two groups depending on whether PMX hemoperfusion (PMXHP) therapy was administered or not within 24 hours after ICU admission (PMXHP group: n = 134, conventional group: n = 279). The primary study endpoint was the mortality rate at 28 days after ICU admission. The mean age was 72.4 (standard deviation: 12.6) years, and the mean Sequential Organ Failure Assessment score at ICU admission was 9.9 (3.4). The infection sites included intra-abdominal (38.0%), pulmonary (18.9%), and urinary tract (32.2%), and two thirds of all patients had GNB-related bacteremia. Notably, the mortality at 28 days after ICU admission did not differ between the groups (PMXHP: 29.1% vs. conventional: 29.0%, P = 0.98), and PMXHP therapy was not found to improve this outcome in a Cox regression analysis (hazard ratio = 1.16; 95% confidence interval, 0.81-1.64, P = 0.407). We conclude that PMX-based endotoxin adsorption within 24 hours from ICU admission was not associated with mortality among patients with septic shock due to GNB.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012748).
| S-EPMC5373513 | biostudies-literature
Project description:This study compared the activity of cefepime + zidebactam (FEP-ZID) and selected currently available antibacterial agents against a panel of multidrug-resistant (MDR) clinical isolates chosen to provide an extreme challenge for antibacterial activity. FEP⁻ZID had a very broad and potent in vitro spectrum of activity, and was highly active against many MDR isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. Notably, it inhibited isolates producing carbapenemases of Ambler classes A, B, and D, and P. aeruginosa isolates with multiple resistance mechanisms including combinations of upregulated efflux, diminished or non-functional OprD porins, and AmpC overproduction. Its clinical role will be determined initially by the breakpoints assigned to it, comparison studies with other investigational β-lactamase inhibitor combinations, and ultimately by the developing body of therapeutic outcome data.
| S-EPMC6466586 | biostudies-literature
Project description: Not available
| S-EPMC7790338 | biostudies-literature