Novel combination therapy overcomes difficult-to-treat form of antibiotic resistance

February 06, 2017

Washington, DC - Feb. 6, 2017 - Combination therapy with two antibiotic compounds overcame pathogenic Enterobacteriaceae harboring a pernicious form of antibiotic resistance, in a bone-infected patient, where other drugs had failed. The research describing this successful treatment regimen is published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

Corresponding author, Robert A. Bonomo, MD, Professor of Medicine, Pharmacology, Molecular Biology and Microbiology Chief, Medical Service, Louis Stokes Cleveland Department of Veteran Affairs Medical Center, was originally moved to investigate the possibility that these two compounds could treat infections due to this form of resistance, after reading in an online discussion group about a 72 year old female patient with an untreatable bone infection. The resistance is caused by metallo ß-lactamases, resistance causing compounds that have been spreading rapidly around the globe.

The problem this combination therapy overcame is that many so-called class C and class A ß-lactamases present in Gram negative bacteria confer resistance to ß-lactams, a very important class of antibiotics. (ß-lactamases cut ß-lactam antibiotics, destroying their activity.) But ceftazidime/avibactam, one of the compounds, inactivates these ß-lactamases, freeing aztreonam, the other, to prevent the pernicious resistance proteins, called metallo-ß-lactamases, from clipping the antibiotics.

Bonomo's laboratory tested the two compounds in vitro against ß-lactam resistant Enterobacteriaceae, and then against a bacterial infection in animal models. In both cases, the combination therapy killed, and prevented further growth of the Enterobacteriaceae cells. Thus, the combination appeared potent enough to try in the patient, who was being treated by one of Bonomo's coauthors.

The woman had fallen while on vacation in eastern Europe, fracturing her hip. She had had hip replacement surgery there, returning home after two weeks, with the surgical site red and painful from the infection. The clinicians removed the arthroplasty, and tested intraoperative cultures. These grew the pathogen, Enterobacter cloacae, which carried the blaNDM-1 metallo-ß-lactam resistance gene.

After all else had failed, the clinicians gave the patient the ceftazidime/avibactam. and aztreonam, combination, which ultimately cleared the resistant infection. Six months after completion of antibiotics, the patient underwent successful final reimplantation of a total hip arthroplasty.

At around the same time, Bonomo explored this same combination in a patient at Nationwide Children's Hospital and The Ohio State University, in a child with a transplanted kidney, who had had prolonged bacteremia caused by another metallo-ß-lactam producing strain , Stenotrophomonas maltophilia, and who was thus successfully treated. (That report was also published in Antimicrobial Agents and Chemotherapy.)

In both cases, the use of the drug combination was a "desperate, last ditch measure," said Bonomo. Currently, these investigators are working on experimental models, in order to make a more accurate estimation of the best doses for patients. It is hoped that this research will lead to a clinical trial while the medical community awaits the release of other promising agents.

Metallo-ß-lactamase resistance genes are found in a wide variety of pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and E.coli, and constitute a growing global public health problem. They are particularly dangerous because they confer resistance to all beta-lactam antibiotics, severely limiting treatment options.
-end-
The American Society for Microbiology is the largest single life science society, composed of over 48,000 scientists and health professionals. ASM's mission is to promote and advance the microbial sciences.

ASM advances the microbial sciences through conferences, publications, certifications and educational opportunities. It enhances laboratory capacity around the globe through training and resources. It provides a network for scientists in academia, industry and clinical settings. Additionally, ASM promotes a deeper understanding of the microbial sciences to diverse audiences.

American Society for Microbiology

Related Antibiotics Articles from Brightsurf:

Insights in the search for new antibiotics
A collaborative research team from the University of Oklahoma, the Memorial Sloan Kettering Cancer Center and Merck & Co. published an opinion article in the journal, Nature Chemical Biology, that addresses the gap in the discovery of new antibiotics.

New tricks for old antibiotics
The study published in the journal Immunity reveals that tetracyclines (broad spectre antibiotics), by partially inhibiting cell mitochondria activity, induce a compensatory response on the organism that decreases tissue damage caused during infection.

Benefits, risks seen with antibiotics-first for appendicitis
Antibiotics are a good choice for some patients with appendicitis but not all, according to study results published today in the New England Journal of Medicine.

How antibiotics interact
Understanding bottleneck effects in the translation of bacterial proteins can lead to a more effective combination of antibiotics / study in 'Nature Communications'

Are antivitamins the new antibiotics?
Antibiotics are among the most important discoveries of modern medicine and have saved millions of lives since the discovery of penicillin almost 100 years ago.

Hygiene reduces the need for antibiotics by up to 30%
A new paper published in the American Journal of Infection Control (AJIC), finds improved everyday hygiene practices, such as hand-washing, reduces the risk of common infections by up to 50%, reducing the need for antibiotics, by up to 30%.

Antibiotics: City dwellers and children take the most
City dwellers take more antibiotics than people in rural areas; children and the elderly use them more often than middle-aged people; the use of antibiotics decreases as education increases, but only in rich countries: These are three of the more striking trends identified by researchers of the NRW Forschungskolleg ''One Health and Urban Transformation'' at the University of Bonn.

Metals could be the link to new antibiotics
Compounds containing metals could hold the key to the next generation of antibiotics to combat the growing threat of global antibiotic resistance.

Antibiotics from the sea
The team led by Prof. Christian Jogler of Friedrich Schiller University, Jena, has succeeded in cultivating several dozen marine bacteria in the laboratory -- bacteria that had previously been paid little attention.

Antibiotics not necessary for most toothaches, according to new ADA guideline
The American Dental Association (ADA) announced today a new guideline indicating that in most cases, antibiotics are not recommended for toothaches.

Read More: Antibiotics News and Antibiotics Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.