scholarly journals A Proof-of-Concept Study of the Efficacy of Systemically Administered Polymyxins in Mouse Burn Wound Infection Caused by Multidrug-Resistant Gram-Negative Pathogens

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Yu-Wei Lin ◽  
Ke Chen ◽  
Jiping Wang ◽  
Tony Velkov ◽  
Qi Tony Zhou ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Wound Infections ◽  
Proof Of Concept ◽  
Burn Wound ◽  
Gram Negative ◽  
Content Type ◽  
Therapeutic Benefits

ABSTRACTThe efficacy of subcutaneously administered polymyxins against burn wound infections caused byPseudomonas aeruginosa,Acinetobacter baumannii, andKlebsiella pneumoniaewas examined in a murine infection model. Subcutaneously administered colistin and polymyxin B (30 mg/kg thrice daily) achieved a ≥2-log10reduction in the bacterial load forP. aeruginosaandA. baumanniiinfections, whereas wound infections byK. pneumoniaewere less responsive (<1-log10reduction). This study highlights the potential therapeutic benefits of parenteral polymyxins for treating burn wound infections.

The Bacteriological Profile of Burn Wound Infections at a Tertiary Burns Center in Nepal

2019 ◽  
Vol 40 (6) ◽  
pp. 838-845 ◽  
Author(s):  
Ojas Jyoti Singh Pujji ◽  
Kiran Kishor Nakarmi ◽  
Basudha Shrestha ◽  
Shankar Man Rai ◽  
Steven Leonard Alexander Jeffery
Keyword(s):  
Traffic Accidents ◽  
Burn Injury ◽  
Road Traffic ◽  
Average Distance ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Wound Infections ◽  
Burn Wound ◽  
Gram Negative

AbstractIn Nepal, burn is the third most common injury after falls and road traffic accidents. Infection is the leading cause of mortality in burn injury. A profile exploring predominant flora and antimicrobial sensitivity is important to facilitate treatment ahead of microbiology results and to aid prevention of multidrug-resistant organisms. The aim of this study was to document epidemiological and bacteriological data of burn wound infections at a tertiary level burns center in Nepal. Samples were collected from January 2017 to May 2017, over a period of 5 months. Patient notes were referred to and information regarding baseline characteristics and burn wound infection data was collected. A total of 76 patients were included in the study during the 5-month period, which resulted in 113 samples being included for review. Females were injured most with burns 70% (n = 53) compared with males 30% (n = 23). Only 6 (8%) of 77 patients lived locally in Kathmandu. The average distance traveled by patients was 233 km (median 208, range 0–765, SD 181). Average TBSA% of burn was 22% (median 20, range 3–50, SD 12). Gram-negative organisms predominated, with Acinetobacter spp. in 42 cases (55%), Pseudomonas aeruginosa in 26 cases (34%), and Enterobacter spp. in 16 cases (21%). Colistin, polymyxin B, and tigecycline were found to be most sensitive covering 108, 98, and 94 organisms. Gram-negative bacteria colonized the majority of burn wounds. Colistin, polymyxin B, and tigecycline were the most sensitive to gram-negative bacteria. Gram-positive Staphylococcus aureus was sensitive most to vancomycin and tigecycline.

scholarly journals Outer Membrane Interaction Kinetics of New Polymyxin B Analogs in Gram-Negative Bacilli

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Noushin Akhoundsadegh ◽  
Corrie R. Belanger ◽  
Robert E. W. Hancock
Keyword(s):  
Outer Membrane ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Intact Cells ◽  
Membrane Interaction ◽  
Gram Negative ◽  
Content Type ◽  
Interaction Kinetics ◽  
Hill Numbers ◽  
Multiple Strains

ABSTRACT Infections caused by drug-resistant Gram-negative bacilli are a severe global health threat, limiting effective drug choices for treatment. In this study, polymyxin analogs designed to have reduced nephrotoxicity, direct activity, and potentiating activity were assessed for inhibition and outer membrane interaction kinetics against wild-type (WT) and polymyxin or multidrug-resistant (MDR) Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. In MIC assays, two polymyxin B (PMB) analogs (SPR1205 and SPR206) and a polymyxin E analog (SPR946), with shortened peptide side chains and branched aminobutyryl N termini, exhibited promising activity compared with PMB and previously tested control polymyxin analogs SPR741 and polymyxin B nonapeptide (PMBN). Using dansyl-polymyxin (DPX) binding to assess the affinity of interaction with lipopolysaccharide (LPS), purified or in the context of intact cells, SPR206 exhibited similar affinities to PMB but higher affinities than the other SPR analogs. Outer membrane permeabilization measured by the 1-N-phenyl-napthylamine (NPN) assay did not differ significantly between the polymyxin analogs. Moreover, Hill numbers were greater than 1 for most of the compounds tested on E. coli and P. aeruginosa strains which indicates that the disruption of the outer membrane by one molecule of compound cooperatively enhances the subsequent interactions of other molecules against WT and MDR strains. The high activity demonstrated by SPR206 as well as its ability to displace LPS and permeabilize the outer membrane of multiple strains of Gram-negative bacilli while showing cooperative potential with other membrane disrupting compounds supports further research with this polymyxin analog.

scholarly journals Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Anthony D. Kang ◽  
Kenneth P. Smith ◽  
Anders H. Berg ◽  
Katherine A. Truelson ◽  
George M. Eliopoulos ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Maximum Concentration ◽  
Area Under The Curve ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Model Treatment

ABSTRACT Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against Acinetobacter baumannii . In a neutropenic murine thigh infection model, treatment-associated A. baumannii CFU reductions of >4 log 10 per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum ( C max )/MIC was ≈10 or higher. Based on these findings, we suggest that apramycin deserves further preclinical exploration as a repurposed therapeutic for multidrug-resistant Gram-negative pathogens, including A. baumannii .

scholarly journals Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii

2016 ◽  
Vol 60 (5) ◽  
pp. 2671-2679 ◽  
Author(s):  
Mya Thandar ◽  
Rolf Lood ◽  
Benjamin Y. Winer ◽  
Douglas R. Deutsch ◽  
Chad W. Euler ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bacterial Pathogen ◽  
Antibacterial Activities ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Human Red Blood Cells ◽  
Phage Lysin

ABSTRACTAcinetobacter baumanniiis a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistantA. baumanniiclones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to killA. baumannii(>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307SQ-8C(>5-log kill). Both P307 and P307SQ-8Cshowed highin vitroactivity againstA. baumanniiin biofilms. Moreover, P307SQ-8Cexhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model ofA. baumanniiskin infection, P307SQ-8Creduced the bacterial burden by ∼2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

scholarly journals Therapeutic Effect and Mechanisms of the Novel Monosulfactam 0073

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Ying Sun ◽  
Xueyuan Liao ◽  
Zhigang Huang ◽  
Yaliu Xie ◽  
Yanbin Liu ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Serial Passage ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Infection Model ◽  
The Novel ◽  
Gram Negative ◽  
Content Type

ABSTRACT This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria in vitro and in vivo and to characterize the mechanisms underlying 0073 activity. The in vitro activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define in vivo efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against β-lactamases was evaluated by the half-maximal inhibitory concentration (IC50), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates producing metallo-β-lactamases (MBLs) and serine β-lactamases. In preliminary experiments, compound 0073 exhibited safety both in vitro and in vivo. In the murine thigh infection model and the pneumonia models in which infection was induced by P. aeruginosa and Klebsiella pneumoniae, 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine β-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against β-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both in vitro and in vivo. The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine β-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by β-lactamase-producing multidrug-resistant bacteria.

scholarly journals Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
David P. Nicolau
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Diverse Population ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction

ABSTRACT Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

scholarly journals Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-ResistantKlebsiella pneumoniae

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Yu-Wei Lin ◽  
Nusaibah Abdul Rahim ◽  
Jinxin Zhao ◽  
Mei-Ling Han ◽  
Heidi H. Yu ◽  
...  
Keyword(s):  
Limit Of Detection ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Combination Group ◽  
Infection Model ◽  
New Delhi ◽  
Content Type ◽  
Antimicrobial Synergy ◽  
Time Kill

ABSTRACTPolymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM)-producingKlebsiella pneumoniae. However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility. This study aimed to investigate the pharmacodynamics of polymyxin B in combination with the antiretroviral drug zidovudine againstK. pneumoniae. Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. Anin vitroone-compartment pharmacokinetic/pharmacodynamic (PK/PD) model (IVM) was used to simulate humanized dosage regimens of polymyxin B (4 mg/liter as continuous infusion) and zidovudine (as bolus dose thrice daily to achieve maximum concentration of drug in broth [Cmax] of 6 mg/liter) againstK. pneumoniaeBM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model againstK. pneumoniae02. In the static time-kill studies, polymyxin B monotherapy produced rapid and extensive killing against all three isolates followed by extensive regrowth, whereas zidovudine produced modest killing followed by significant regrowth at 24 h. Polymyxin B in combination with zidovudine significantly enhanced the antimicrobial activity (≥4 log10CFU/ml) and minimized bacterial regrowth. In the IVM, the combination was synergistic and the total bacterial loads were below the limit of detection for up to 72 h. In the murine thigh infection model, the bacterial burden at 24 h in the combination group was ≥3 log10CFU/thigh lower than each monotherapy againstK. pneumoniae02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.

scholarly journals Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1080
Author(s):  
Joana Stokniene ◽  
Lydia C. Powell ◽  
Olav A. Aarstad ◽  
Finn L. Aachmann ◽  
Philip D. Rye ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Bacterial Infections ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Laser Scanning Microscopy ◽  
Gram Negative ◽  
Therapeutic Benefits ◽  
Recent Emergence ◽  
Alginate Oligosaccharide

The recent emergence of resistance to colistin, an antibiotic of last resort with dose-limiting toxicity, has highlighted the need for alternative approaches to combat infection. This study aimed to generate and characterise alginate oligosaccharide (“OligoG”)–polymyxin (polymyxin B and E (colistin)) conjugates to improve the effectiveness of these antibiotics. OligoG–polymyxin conjugates (amide- or ester-linked), with molecular weights of 5200–12,800 g/mol and antibiotic loading of 6.1–12.9% w/w, were reproducibly synthesised. In vitro inflammatory cytokine production (tumour necrosis factor alpha (TNFα) ELISA) and cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) of colistin (2.2–9.3-fold) and polymyxin B (2.9–27.2-fold) were significantly decreased by OligoG conjugation. Antimicrobial susceptibility tests (minimum inhibitory concentration (MIC), growth curves) demonstrated similar antimicrobial efficacy of ester- and amide-linked conjugates to that of the parent antibiotic but with more sustained inhibition of bacterial growth. OligoG–polymyxin conjugates exhibited improved selectivity for Gram-negative bacteria in comparison to mammalian cells (approximately 2–4-fold). Both OligoG–colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro “time-to-kill” (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. Bi-functional OligoG–polymyxin conjugates have potential therapeutic benefits in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections, directly reducing toxicity whilst retaining antimicrobial and antibiofilm activities.

scholarly journals In VivoActivities of Simulated Human Doses of Cefepime and Cefepime-AAI101 against Multidrug-Resistant Gram-Negative Enterobacteriaceae

2015 ◽  
Vol 59 (5) ◽  
pp. 2688-2694 ◽  
Author(s):  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Multidrug Resistant ◽  
Time Profile ◽  
Free Drug ◽  
Bacterial Density ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Drug Concentrations

ABSTRACTThe combination of cefepime with AAI101, a novel extended-spectrum β-lactamase inhibitor, possesses potentin vitroactivity against many resistant Gram-negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime-nonsusceptible strains of the familyEnterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and thein vivoefficacy of simulated human doses of cefepime and cefepime-AAI101 in a neutropenic murine thigh infection model. At 2 h after inoculation, mice were dosed with regimens that provided a profile mimicking the free drug concentration-time profile observed in humans given cefepime at 2 g every 8 h (q8h; as a 30-min infusion) or cefepime-AAI101 at 2 g/0.5 g q8h (as a 30-min infusion). Efficacy was determined by calculation of the change in thigh bacterial density (log10number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 ± 0.1 log10CFU (mean ± standard error) was observed in control animals. Efficacy for cefepime monotherapy was observed against only 3 isolates, whereas increases in bacterial density similar to that in the control animals were noted for the remaining 17 strains (all with cefepime MICs of ≥64 mg/liter). The humanized cefepime-AAI101 dosing regimen resulted in bacterial reductions of ≥0.5 log10CFU for 12 of the 20 strains. Evaluation of efficacy as a function of the fraction of the dosing interval during which free drug concentrations were above the MIC determined with different fixed concentrations of AAI101 suggested that a fixed concentration of 8 mg/liter AAI101 is most predictive ofin vivoactivity for the studied regimen.

scholarly journals High Level of Multidrug-Resistant Gram-Negative Pathogens Causing Burn Wound Infections in Hospitalized Children in Dar es Salaam, Tanzania

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Fatima Kabanangi ◽  
Agricola Joachim ◽  
Emmanuel James Nkuwi ◽  
Joel Manyahi ◽  
Sabrina Moyo ◽  
...  
Keyword(s):  
Antimicrobial Susceptibility ◽  
Pediatric Patients ◽  
Multidrug Resistant ◽  
Dar Es Salaam ◽  
Wound Infections ◽  
Burn Wound ◽  
Gram Negative ◽  
E Coli ◽  
Acinetobacter Spp ◽  
Klebsiella Spp

Background. Bacterial infection remains the most common cause of morbidity and mortality in pediatric patients with burn wounds. The increase in infection and multidrug-resistant (MDR) pathogens necessitates a periodic review of antimicrobial susceptibility patterns in the burn units. The study aimed to determine the magnitude of multidrug-resistant Gram-negative (MDRGN) bacteria in children with burn wound infections and describe the resistance patterns in the tertiary and regional hospitals in Dar es Salaam, Tanzania. Materials and Methods. The study was a hospital-based cross-sectional study design conducted between May 2017 and February 2018. Bacterial isolates from 103 wound swabs of pediatric patients with burn wounds were identified using conventional methods and API 20E. The antimicrobial susceptibility pattern was determined by the Kirby–Bauer disc diffusion method. Data were analyzed using Statistical Package for Social Science (SPSS) version 23.0. Results. A total of 136 pathogenic Gram-negative organisms were isolated from burn wound infections in pediatric patients. The most isolated Gram-negative bacterium was Pseudomonas aeruginosa (39.0%), followed by Acinetobacter spp. (28.7%) and Klebsiella spp. (16.2%). MDRGN strains made up 80.1% of all Gram-negative isolates. All (100%) Klebsiella spp. and E. coli were MDR, while 69.2% and 79.2% of Acinetobacter spp. and P. aeruginosa, respectively, displayed MDR strains. We observed high levels of resistance to commonly prescribed antibiotics. Among P. aeruginosa isolates, highest resistance (81.8%) was seen toward meropenem and piperacillin, 79.5% of Acinetobacter spp. showed resistance to aztreonam, while 93–100% of Klebsiella spp and E. coli displayed resistance to amoxyclavulanic acid, ceftriaxone, and ceftazidime. The proportion of extended-spectrum beta-lactamase producers among Enterobacteriaceae was 78.6%. There was a significant higher rate of infection with MDRGN organisms in pediatric patients with a higher percentage of total burn surface area (TBSA) than patients with lower TBSA ( p  = 0.016). Conclusions. P. aeruginosa, Acinetobacter spp., and Klebsiella spp. are the common Gram-negative pathogens causing burn wound infections in hospitalized pediatric patients in our setting. A high proportion of these organisms were multidrug resistant. The findings appeal for regular antimicrobial resistance surveillance in burn wound infection to inform empirical therapy.

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