Nontuberulous mycobacteria cause chronic lung infection. Mycobacterium abscessus infections are particularly challenging with only a 50% cure rate. Antimicrobial therapy may be necessary for months to over a year to slow down the progression of these infections. Side effects from therapy are often life limiting and include deafness and kidney damage. Better solutions are urgently needed.
Antimicrobials are given in combinations of three or more drugs for treatment. However, they are chosen based on susceptibility of a bacterial isolate to each drug tested individually without consideration of how the multiple agents may interact to augment or diminish their individual effects.
Using advanced technology, the Kirby laboratory is testing the effects of 2, 3, or more drugs together to identify combinations that will lead to improved outcome for patients. Currently, most antibiotic activity laboratory analysis is done by adding each antibiotic at a fixed concentration to organisms suspended in liquid medium and testing effects on organism growth or viability. However, in humans, drug levels rise quickly after an antibiotic is dosed and then fall progressively over several hours with a speed defined by a parameter called a half life. Therefore, when treating an infection, antibiotic exposure is pulsatile. The rise and fall of antibiotics are known as its pharmacokinetics or PK. Our current lab methods therefore are static and do not address pulsatile PK, and therefore are less predictive of how well a drug will work as a human therapy.
To address this limitation, we have set up a system called the Hollow Fiber Infection Model or HFIM. Here organisms are trapped on one side of what is essentially a hemodialysis casettte. Inside, a membrane with a huge surface area allows antibiotics and nutrients to diffuse easily into the bacterial compartment, while the bacterial are held captive for us to evaluate their viability. On the other side of the membrane, we flow medium in which we exactly match the PK for each drug that is already well established in humans. Therefore, pathogens are exposed to antibiotics as they would be in a human infection during treatment. This model is highly predictive of human treatment efficacy. Through use of automated syringe pumps we can model the effects of 3 or 4 drugs given dosed as they would be in humans. Using these and other systems, our goal is to develop life saving therapy for patients, and to develop safer, simpler, and more effective combination treatments for the devastating infections caused by M. abscessus and other NTM.
Some recent publications by our group in the NTM field:
Huang Y, Truelson KA, Stewart IA, O'Doherty GA, Kirby JE. Enhanced Activity of Apramycin and Apramycin-Based Combinations Against Mycobacteroides abscessus. bioRxiv [Preprint]. 2025 Apr 9:2025.04.09.648020. doi: 10.1101/2025.04.09.648020. PMID: 40391321; PMCID: PMC12087987.
Huang Y, Chiaraviglio L, Bode-Sojobi I, Kirby JE. Triple antimicrobial combinations with potent synergistic activity against M. abscessus. Antimicrob Agents Chemother. 2025 Apr 2;69(4):e0182824. doi: 10.1128/aac.01828-24. Epub 2025 Mar 14. PMID: 40084880; PMCID: PMC11963555.
Please consider donating to our efforts so that we can devote additional resources to this area of great medical need.
Donations can be made to via credit card through Beth Israel Deaconess Medical Center.
Under "Gift Information, " please check "Select Gift Designation" , scroll to the bottom of the list, then select "Other" and specify "Research Laboratory of James Kirby, Dept. of Pathology".
Thank you for your support!!!
Antimicrobials are given in combinations of three or more drugs for treatment. However, they are chosen based on susceptibility of a bacterial isolate to each drug tested individually without consideration of how the multiple agents may interact to augment or diminish their individual effects.
Using advanced technology, the Kirby laboratory is testing the effects of 2, 3, or more drugs together to identify combinations that will lead to improved outcome for patients. Currently, most antibiotic activity laboratory analysis is done by adding each antibiotic at a fixed concentration to organisms suspended in liquid medium and testing effects on organism growth or viability. However, in humans, drug levels rise quickly after an antibiotic is dosed and then fall progressively over several hours with a speed defined by a parameter called a half life. Therefore, when treating an infection, antibiotic exposure is pulsatile. The rise and fall of antibiotics are known as its pharmacokinetics or PK. Our current lab methods therefore are static and do not address pulsatile PK, and therefore are less predictive of how well a drug will work as a human therapy.
To address this limitation, we have set up a system called the Hollow Fiber Infection Model or HFIM. Here organisms are trapped on one side of what is essentially a hemodialysis casettte. Inside, a membrane with a huge surface area allows antibiotics and nutrients to diffuse easily into the bacterial compartment, while the bacterial are held captive for us to evaluate their viability. On the other side of the membrane, we flow medium in which we exactly match the PK for each drug that is already well established in humans. Therefore, pathogens are exposed to antibiotics as they would be in a human infection during treatment. This model is highly predictive of human treatment efficacy. Through use of automated syringe pumps we can model the effects of 3 or 4 drugs given dosed as they would be in humans. Using these and other systems, our goal is to develop life saving therapy for patients, and to develop safer, simpler, and more effective combination treatments for the devastating infections caused by M. abscessus and other NTM.
Some recent publications by our group in the NTM field:
Huang Y, Truelson KA, Stewart IA, O'Doherty GA, Kirby JE. Enhanced Activity of Apramycin and Apramycin-Based Combinations Against Mycobacteroides abscessus. bioRxiv [Preprint]. 2025 Apr 9:2025.04.09.648020. doi: 10.1101/2025.04.09.648020. PMID: 40391321; PMCID: PMC12087987.
Huang Y, Chiaraviglio L, Bode-Sojobi I, Kirby JE. Triple antimicrobial combinations with potent synergistic activity against M. abscessus. Antimicrob Agents Chemother. 2025 Apr 2;69(4):e0182824. doi: 10.1128/aac.01828-24. Epub 2025 Mar 14. PMID: 40084880; PMCID: PMC11963555.
Please consider donating to our efforts so that we can devote additional resources to this area of great medical need.
Donations can be made to via credit card through Beth Israel Deaconess Medical Center.
Under "Gift Information, " please check "Select Gift Designation" , scroll to the bottom of the list, then select "Other" and specify "Research Laboratory of James Kirby, Dept. of Pathology".
Thank you for your support!!!