Antibiotic combination effective against drug-resistant Pseudomonas

By Dr. Ananya Mandal, MDJul 8 2019

Two well known and used antibiotics when combined have been found to be more effective against a deadly bacteria Pseudomonas aeruginosa, a common cause of hospital-based infections. This new research was conducted by a team from Case Western Reserve University School of Medicine and Louis Stokes Cleveland VA Medical Center and is published in the latest issue of the Journal of Infectious Diseases. The study is titled, “Ceftazidime-Avibactam in Combination with Fosfomycin: A Novel Therapeutic Strategy against Multidrug-Resistant Pseudomonas aeruginosa”.

3D illustration of a Pseudomonas aeruginosa bacteria. Image Credit: Supergalactic / Shutterstock

The team of researchers used ceftazidime-avibactam – a combination that is being used against serious bacterial infection and fosfomycin that is used in treatment of urinary tract infections. This combination was tried on mice models with Pseudomonas infections and the results showed that the combination was more effective in killing the bacteria compared to either antibiotic alone.

Lead author of the study Krisztina M. Papp-Wallace, assistant professor of medicine at the School of Medicine and a research scientist at the Cleveland VA Medical Center explained, “By successfully combining these two drugs against this widespread form of bacteria, we hope to lay a foundation for eventually eradicating the infection. These findings have significant implications for further studies directed at clinical applications and could bring benefits to numerous patients worldwide.”

The researchers explained that some patients with compromised immunity such as those with cancers or trauma and burn victims, those on ventilators and those with cystic fibrosis are more susceptible to getting Pseudomonas infections from the healthcare set ups. This infection spreads via unwashed hands of healthcare providers and equipment that is contaminated, the team writes. Pseudomonas in addition is a difficult bacteria to kill because of the rising antibiotic resistance. This means that these resistant “superbugs” are raising the risk of mortality and morbidity and also the healthcare costs and hospital stays. The team wrote that around 10 percent of all hospital acquired infections are caused due to Pseudomonas and it is the commonest gram negative bacteria that cause Ventilator-associated-pneuomonia (VAP).

The team of researchers used this combination of antibiotics to destroy the enzymes present in the cell walls of the bacteria. It is especially effective against the CL232 strain of P. Aeruginosa. The team found that when they used the ceftazidime-avibactam-fosfomycin combination, the progression of the bacteria multiplication was significantly halted.

The team of researchers wrote that the ceftazidime-avibactam-fosfomycin primarily targeted a cell wall based enzyme of the Pseudomonas called “penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA”. It is this enzyme that leads to the development of multi-drug resistance (MDR) in pseudomonas they wrote. To check the efficacy of the combination, the team used “checkerboard susceptibility analysis”. The minimum inhibitory concentrations (MICs) and fractional inhibitory concentration (FIC) index was performed to assess the efficacy of the antibiotics alone and in combination. They noted that this combination was synergistic with each other when it came to bacterial killing.

For their study the researchers first analyzed the genetic mutations in the strains of Pseudomonas to check the method of its development of resistance to antibiotics. They found that there were mutations that caused it to be resistant to beta lactam antibiotics like penicillins and cephalosporin group of drugs. In addition there was also overexpression of certain genes such as “blaPDC, the mexAB-oprM efflux pump, and murA” in the resistant pseudomonas strains. They noted that if fosphomycin was given alone, the resistance development was higher in the bacteria. On the other hand when fosphomycin was combined with ceftazidime-avibactam, the development of mutations leading to resistance was lesser in frequency, the team wrote. The combination led to reduced “P. Aeruginosa colony-forming units (CFUs)”, the researchers added.

Senior author Robert A. Bonomo, professor of medicine, pharmacology, molecular biology and microbiology at the School of Medicine and chief of the medical service at the Cleveland VA Medical Center said in a statement, “Dr. Papp-Wallace's insight about combining the two antibiotics proved to be right on target. This is superb bench-to-bedside science and has positive implications for future patients worldwide.”

The study received support from the CETR and National Institute of Allergy and Infectious Diseases, National Institutes of Health and U.S. Department of Health and Human Services among others.