New combinations and repurposed antibiotics active against the pandrug-resistant Nevada CRE, NDM-1 strain early release today in AAC
Our latest manuscript: "Synergistic combinations and repurposed antibiotics active against the pandrug-resistant Klebsiella pneumoniae Nevada strain." Antimicrobial Agents and Chemotherapy early release identifies:
Highly synergistic activity of several antimicrobial combinations.
Low apramycin and spectinomycin MIC values.
CDC previously reported that none of 26 antimicrobials they tested were active against the Nevada strain. That made the strain until now pandrug-resistant.
Links to several news articles about this pandrug-resistant strain::
The Atlantic. NPR, NBC, PBS. Forbes
A primer on use of inkjet printing and time-kill studies for combination antimicrobial susceptibility testing
Adopted by the CDC .in their Antimicrobial Resistance Laboratory Network based on our prior publications in Journal of Clinical Microbiology, Journal of Antimicrobial Chemotherapy, and Antimicrobial Agents and Chemotherapy for testing of aztreonam/ceftazidime-avibactam combination activity using inkjet printing. We provide a step by step video demonstration of assay setup in the Journal of Visualized Experimentation. Link to article landing page (PDF protocol access and video), "Antimicrobial Synergy Testing by the Inkjet Printer-assisted Automated Checkerboard Array and the Manual Time-kill Method" by Thea Brennan-Krohn and James E. Kirby.
JoVE manuscript accepted on use of Inkjet Printing to perform antimicrobial susceptibility testing for single and drug combinations and follow up time-kill study methodology
Postdoctoral fellow, Thea Brennan-Krohn, recently had a manuscript accepted in the Journal of Visualized Experimentation, aka JoVE. The title of the manuscript and link to the abstract are "Antimicrobial Synergy Testing by the Inkjet Printer-Assisted Automated Checkerboard Array and the Manual Time-Kill Method." We have been fielding a lot of questions over the past two years about implementation of inkjet printing antimicrobial susceptibility testing technology and thought it would be useful to share a video of the technique as well as classic time-kill analysis to analyze antimicrobial synergy. We are excited to learn that the CDC has decided to implement the technology in the near future in their Antimicrobial Resistance Laboratory Network (ARLN), initially to test, the combination of ceftazidime-avibactam and aztreonam for activity against multidrug-resistant Gram-negatives.
Excel and Powerpoint have been banned for figure preparation. Converted my lab over to GraphPad Prism. A very well designed graphing and statistics program. Love several features including the ability to apply standard dimension formats for charts, and wand tool to covert charts to exact format used previously. Application of statistics to data is facile, also a wand tool to apply the same statistics to multiple tables. Grateful to Assay and Drug Development Technology for their requirement (recommendation?) to use this or similar programs in figure preparation. Powerpoint never worked well for figure preparation and conversion to vector-graphics format, for use with illustrator was a nightmare. Now we just start out using a freeware vector graphics program or Adobe Illustrator directly. Greatly speeds up manuscript preparation.
P.S. I have no financial relationship with GraphPad Prism, but it is a good product so therefore my endorsement!
BIDMC news release on Thea's antimicrobial synergy paper:
"Bacteria—especially Gram-negative strains—are becoming increasingly resistant to current antibiotic drugs, and the development of new classes of antibiotics has slowed. Faced with these challenges, investigators are studying the potential of combination therapy, in which two or more drugs are used together to increase or restore the efficacy of both drugs against a resistant bacterial pathogen. Now new research indicates that such synergy may work even when bacteria become resistant to colistin, which is considered a treatment agent of last resort.
The findings are especially promising because recent evidence indicates the potential for rapid worldwide spread of colistin resistance. “For an infected patient, if the multidrug-resistant Gram-negative bacterial pathogen is resistant to colistin, then there is a big problem,” said senior author James Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC.
In their Antimicrobial Agents and Chemotherapy study, Kirby and his colleagues Thea Brennan-Krohn, MD and Alejandro Pironti, PhD screened 19 different antibiotics for synergy with colistin. The team discovered several combinations where synergy was present and infections with resistant pathogens could potentially be treated with the combination therapy.
Of particular interest, colistin demonstrated high rates of synergy with linezolid, fusidic acid, and clindamycin, which are protein synthesis inhibitor antibiotics that individually have no activity against Gram-negative bacteria. “It was remarkable to see two drugs, each of which is inactive on its own against these bacteria, inhibiting them in combination,” notes Brennan-Krohn. “These findings suggest that colistin retains sub-lethal activity against colistin-resistant bacteria, which may enable drugs like linezolid to reach their targets.”
“Faced with highly resistant pathogens, clinicians often currently treat with multiple antibiotics without knowing the benefit the combinations may provide,” said Kirby. “This study now provides some scientific underpinning for these choices and direction for future investigation.” He added that combination therapy may also allow clinicians to use lower effective doses of colistin and other drugs, which would help avoid toxicities associated with the medications as well as slow the development of antibiotic resistance.
This work was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the Department of Health and Human Services."
Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae.
Published online today in Antimicrobial Agents and Chemotherapy! Thea Brennan-Krohn, Alejandro Pironti, and James E. Kirby. Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae. Antimicrob. Agents Chemother. Accepted manuscript posted online 30 July 2018 , doi:10.1128/AAC.00873-18.
Congratulations to Kat Truelson on her publication in DMID on apramycin activity against contemporary multidrug-resistant strains of Staphylococcus aureus
Kat had a very productive undergraduate experience in the laboratory while attending Boston University as an undergraduate. Her first author manuscript titled: "Evaluation of Apramycin Activity Against Methicillin-Resistant, Methicillin-Sensitive, and Vancomycin-Intermediate Staphylococcus aureus Clinical Isolates" was just accepted into Diagnostic Microbiology and Infectious Diseases, more commonly referred to as DMID. Congratulations! She found that apramycin was equally active against MSSA, MRSA, and VISA strains, and demonstrated rapid time-kill kinetics. This manuscript expands apramycin's known activity spectrum to include contemporaneous human clinical strains of multidrug-resistant carbapenem=resistant Enterobacteriaceae = CRE; Acinetobacter baumannii, and Pseudomonas aeruginosa, and now Staphylococcus aureus.
We are very excited for Kat as she is moving this summer to the University of Chicago to work on a much beloved organism, Legionella pneumophila, in Howard Shuman's laboratory.
"The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on Minimal Inhibitory Concentration Determination."
The manuscript describes use of D300-based inkjet printing technology to investigate the inoculum effect with a resolution not previously possible. The inoculum effect is the general observation that the minimal inhibitor concentration (in other words level of resistance) of an organism to an antibiotic increases when a higher density of organisms is tested. This is effect is especially prominent for beta-lactam antiibiotics. It is of potential clinical concern during some types of infections when the organism burden is high. Here we explored whether subtle differences in inoculum within the range allowed by current standards can effect the susceptibility testing results that clinical laboratories obtain and provide to clinicians. Our findings for organisms with certain types of multidrug-resistance and very important classes of antibiotics was that these small allowable differences in inoculum could change the MIC determinations and the determination of whether organisms were susceptible or resistant to the antibiotics tested.
Congratulations to lab members, Anthony Kang, and colleagues for our manuscript newly accepted in Antimicrobial Agents and Chemotherapy titled: "Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model"
The manuscripts describes potent in vitro and in vivo activity of the apramycin, an aminocyclitol aminoglycoside, against multidrug-resistant and extensively-drug resistant Acinetobacter baumannii.
In prior manuscripts, we demonstrated broad activity against several types of multidrug-resistant pathogens including carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii and Pseudomonas aeruginosa
Kirby Lab Blog