scholarly journals Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Sonia Luque ◽  
Carol Escaño ◽  
Luisa Sorli ◽  
Jian Li ◽  
Nuria Campillo ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Intravenous Administration ◽  
Bacterial Infections ◽  
High Performance ◽  
Multidrug Resistant ◽  
Limited Information ◽  
Urinary Recovery ◽  
Gram Negative ◽  
Content Type ◽  
Colistimethate Sodium

ABSTRACT Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (C min ss) and at the end of the CMS infusion (C max ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; C min ss and C max ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

scholarly journals Correlation of β-Lactamase Production and Colistin Resistance among Enterobacteriaceae Isolates from a Global Surveillance Program

2015 ◽  
Vol 60 (3) ◽  
pp. 1385-1392 ◽  
Author(s):  
Patricia A. Bradford ◽  
Krystyna M. Kazmierczak ◽  
Douglas J. Biedenbach ◽  
Mark G. Wise ◽  
Meredith Hackel ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Surveillance Program ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Content Type ◽  
Geographic Dispersion ◽  
Carbapenem Resistant ◽  
Species Groups ◽  
Low Prevalence

The increasing use of carbapenems for treating multidrug-resistant (MDR) Gram-negative bacterial infections has contributed to the global dissemination of carbapenem-resistantEnterobacteriaceae(CRE). Serine and metallo-β-lactamases (MBLs) that hydrolyze carbapenems have become prevalent and endemic in some countries, necessitating the use of older classes of agents, such as colistin. A total of 19,719 isolates ofEnterobacteriaceae(excludingProteeaeandSerratiaspp., which have innate resistance to colistin) were collected from infected patients during 2012 and 2013 in a global surveillance program and tested for antimicrobial susceptibility using CLSI methods. Isolates of CRE were characterized for carbapenemases and extended-spectrum β-lactamases (ESBLs) by PCR and sequencing. Using EUCAST breakpoints, the rate of colistin susceptibility was 98.4% overall, but it was reduced to 88.0% among 482 carbapenemase-positive isolates. Colistin susceptibility was higher among MBL-positive isolates (92.6%) than those positive for a KPC (87.9%) or OXA-48 (84.2%). Of the agents tested, only tigecycline (MIC90, 2 to 4 μg/ml) and aztreonam-avibactam (MIC90, 0.5 to 1 μg/ml) consistently tested with low MIC values against colistin-resistant, ESBL-positive, and carbapenemase-positive isolates. Among the 309 (1.6%) colistin-resistant isolates from 10 species collected in 38 countries, 58 carried a carbapenemase that included KPCs (38 isolates), MBLs (6 isolates), and OXA-48 (12 isolates). These isolates were distributed globally (16 countries), and 95% wereKlebsiella pneumoniae. Thirty-nine (67.2%) isolates carried additional ESBL variants of CTX-M, SHV, and VEB. This sample ofEnterobacteriaceaedemonstrated a low prevalence of colistin resistance overall. However, the wide geographic dispersion of colistin resistance within diverse genus and species groups and the higher incidence observed among carbapenemase-producing MDR pathogens are concerning.

scholarly journals A Whole-Cell Screen Identifies Small Bioactives That Synergize with Polymyxin and Exhibit Antimicrobial Activities against Multidrug-Resistant Bacteria

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Shawn M. Zimmerman ◽  
Audrey-Ann J. Lafontaine ◽  
Carmen M. Herrera ◽  
Amanda B. Mclean ◽  
M. Stephen Trent
Keyword(s):  
Bacterial Infections ◽  
Large Scale ◽  
The United States ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Synergistic Activity ◽  
Multidrug Resistant Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Eskape Pathogens

ABSTRACT The threat of diminished antibiotic discovery has global health care in crisis. In the United States, it is estimated each year that over 2 million bacterial infections are resistant to first-line antibiotic treatments and cost in excess of 20 billion dollars. Many of these cases result from infection with the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), which are multidrug-resistant bacteria that often cause community- and hospital-acquired infections in both healthy and immunocompromised patients. Physicians have turned to last-resort antibiotics like polymyxins to tackle these pathogens, and as a consequence, polymyxin resistance has emerged and is spreading. Barring the discovery of new antibiotics, another route to successfully mitigate polymyxin resistance is to identify compounds that can complement the existing arsenal of antibiotics. We recently designed and performed a large-scale robotic screen to identify 43 bioactive compounds that act synergistically with polymyxin B to inhibit the growth of polymyxin-resistant Escherichia coli. Of these 43 compounds, 5 lead compounds were identified and characterized using various Gram-negative bacterial organisms to better assess their synergistic activity with polymyxin. Several of these compounds reduce polymyxin to an MIC of <2 μg/ml against polymyxin-resistant and polymyxin-heteroresistant Gram-negative pathogens. Likewise, four of these compounds exhibit antimicrobial activity against Gram-positive bacteria, one of which rapidly eradicated methicillin-resistant Staphylococcus aureus. We present multiple first-generation (i.e., not yet optimized) compounds that warrant further investigation and optimization, since they can act both synergistically with polymyxin and also as lone antimicrobials for combating ESKAPE pathogens.

scholarly journals Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
David Corbett ◽  
Andrew Wise ◽  
Tara Langley ◽  
Kirsty Skinner ◽  
Emily Trimby ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Fusidic Acid ◽  
Bacterial Infections ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Permeability Barrier ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Conventional Antibiotics

ABSTRACTNovel approaches for the treatment of multidrug-resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed thein vitroefficacies of combinations of SPR741 with conventional antibiotics againstEscherichia coli,Klebsiella pneumoniae, andAcinetobacter baumannii. Of 35 antibiotics tested, the MICs of 8 of them were reduced 32- to 8,000-fold againstE. coliandK. pneumoniaein the presence of SPR741. The eight antibiotics, azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and telithromycin, had diverse targets and mechanisms of action. AgainstA. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin, and rifampin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multidrug-resistant or clinical isolates ofE. coliandK. pneumoniaeand 17 additionalA. baumanniiisolates in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump inE. coli, effectively circumventing the contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.

scholarly journals WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Michael Huband ◽  
Ronald N. Jones ◽  
Robert K. Flamm
Keyword(s):  
Antimicrobial Activity ◽  
Bacterial Infections ◽  
The United States ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Asia Pacific ◽  
Gram Negative ◽  
Content Type ◽  
Broth Microdilution Method

ABSTRACT WCK 5222 consists of cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (n = 5,946), Pseudomonas aeruginosa (n = 1,291), and Acinetobacter spp. (n = 639) from the United States (n = 2,919), Europe (n = 3,004), the Asia-Pacific (n = 1,370), and Latin America (n = 583). The isolates were tested by a reference broth microdilution method for susceptibility against cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC50/90, ≤0.03/0.12 μg/ml [1:1] and 0.06/0.25 μg/ml [2:1]; 99.9% of isolates were inhibited at ≤4 [1:1] and ≤8 μg/ml [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC50/90, ≤0.03 to 0.06/≤0.03 to 0.5 μg/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC50/90, 1/4 μg/ml; 99.3% of isolates were inhibited at ≤8 μg/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/ml (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC50/90 values of 1/4 μg/ml, and 99.5% of isolates were inhibited at ≤8 μg/ml (1:1). The MIC values for cefepime-zidebactam at the 1:1 ratio were generally 2-fold lower than those for cefepime-zidebactam at the 2:1 ratio (MIC50/90, 2/8 μg/ml) and zidebactam alone (MIC50/90, 4/8 μg/ml). Against Acinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC50/90, 16/32 μg/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support the clinical development of WCK 5222 for the treatment of Gram-negative bacterial infections, including those caused by multidrug-resistant isolates.

scholarly journals Real-World Experience with Ceftolozane-Tazobactam for Multidrug-Resistant Gram-Negative Bacterial Infections

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Sarah C. J. Jorgensen ◽  
Trang D. Trinh ◽  
Evan J. Zasowski ◽  
Abdalhamid M. Lagnf ◽  
Samuel P. Simon ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Apache Ii Score ◽  
High Dose ◽  
Clinical Failure ◽  
Primary Efficacy ◽  
Prescribing Practices ◽  
Gram Negative ◽  
Content Type

ABSTRACT Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

scholarly journals The Anthelmintic Drug Niclosamide Synergizes with Colistin and Reverses Colistin Resistance in Gram-Negative Bacilli

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Ronald Domalaon ◽  
P. Malaka De Silva ◽  
Ayush Kumar ◽  
George G. Zhanel ◽  
Frank Schweizer
Keyword(s):  
Bacterial Infections ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Colistin Resistance ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type ◽  
Anthelmintic Drug ◽  
Lipopeptide Antibiotic ◽  
Approved Drugs

ABSTRACTThere is an urgent need for new therapies to overcome antimicrobial resistance especially in Gram-negative bacilli (GNB). Repurposing old U.S. Food and Drug Administration-approved drugs as complementary agents to existing antibiotics in a synergistic combination presents an attractive strategy. Here, we demonstrate that the anthelmintic drug niclosamide selectively synergized with the lipopeptide antibiotic colistin against colistin-susceptible but more importantly against colistin-resistant GNB, including clinical isolates that harbor themcr-1gene. Breakpoints for colistin susceptibility in resistant Gram-negative bacilli were reached in the presence of 1 μg/ml (3 μM) niclosamide. Reversal of colistin resistance was also observed in combinations of niclosamide and polymyxin B. Enhanced bacterial killing was evident for the combination, in comparison to colistin monotherapy, against resistantPseudomonas aeruginosa,Acinetobacter baumannii,Klebsiella pneumoniae,Escherichia coli, andEnterobacter cloacae. Accumulating evidence in the literature, along with our results, strongly suggests the potential for the combination of niclosamide and colistin to treat colistin-resistant Gram-negative bacillary infections. Our finding is significant since colistin is an antibiotic of last resort for multidrug-resistant Gram-negative bacterial infections that are nonresponsive to conventional treatments. With the recent global dissemination of plasmid-encoded colistin resistance, the addition of niclosamide to colistin therapy may hold the key to overcome colistin resistance.

scholarly journals 4CPS-048 Evaluation of colistimethate sodium (cms) prescriptions for the management of multidrug-resistant gram-negative bacterial infections

2018 ◽  
Author(s):  
S Sadyrbaeva ◽  
R García-Fumero ◽  
M Sánchez-Argaiz ◽  
S Guijarro-Herrera ◽  
A Jiménez-Morales ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Colistimethate Sodium

scholarly journals Cyclic Boronates Inhibit All Classes of β-Lactamases

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Samuel T. Cahill ◽  
Ricky Cain ◽  
David Y. Wang ◽  
Christopher T. Lohans ◽  
David W. Wareham ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Bacterial Infections ◽  
Binding Mode ◽  
Gram Negative ◽  
Content Type ◽  
Class A ◽  
Class D ◽  
Dual Action ◽  
The Common ◽  
Continued Use

ABSTRACT β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of “dual-action” inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.

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