Aug
04
2018

Phage Therapy Against Superbugs

Introduction

Phage therapy against superbugs is the latest concept in treating infections. Antibiotic resistance has developed into a huge clinical problem. Every year in the US about 2 million people have infections from antibiotic resistant bacteria, and 23,000 people die as result of it. Certainly, there is a desperate need to find alternative treatment options to treat antibiotic resistant infections. One such option is to use phages, a specific form of viruses to treat antibiotic resistant bacteria. Here is a scientific overview regarding the use of phages for the treatment of antibiotic resistant infections.

History of phages

The observation of phages attacking bacteria goes back more than 100 years. The French Canadian microbiologist, Félix Hubert d’Herelle (1873–1949) described in 1917 what bacteriophages are. He also coined the term of “phage therapy” for the treatment of bacteria with phages. Dr. d’Herelle recognized phages to be virus-like organisms that attacked bacteria and could kill them. When Fleming detected antibiotics, phage research came to a halt. Drug companies invented more and more antibiotics, as it was easier to kill bacteria this way. But now with emerging resistances of bacteria to antibiotics, there is a sudden revival of the 100-year old research on phages. The problem is that there has not been much clinical experience with phage therapy against super bugs until lately. In 1923 Dr. d’Herelle co-founded the Eliava Institute in what is now Tbilisi, Georgia. This institute has the world’s most comprehensive database on phage therapy in man.

Two clinical examples of phage therapy against super bugs

Chronic prostatitis due to superbug

Pranav Johri, a Canadian of Indian descent was suffering of a chronic prostate infection. Physicians had used five different antibiotics, but all to no avail. His doctor told him that he had a chronic prostatitis problem for which there was no cure. But Pranav saw another specialist who determined that Pranav had a prostatitis due to a superbug, which was resistant against all the common antibiotics. Pranav traveled to the Eliava Institute in Tbilisi, Georgia. He paid 6000.00 CAD and had three treatments. After the first treatment his temperature became normal for the first time in months, and his chronic pain subsided. He and his wife were so excited that they felt like celebrating. They did sightseeing, went out to restaurants and enjoyed their travels, all things he was unable to do for months. Pranav had finally received a cure with phage therapy to his chronic prostate infection.

Enteric infection due to superbug

Tom Patterson who had visited Egypt in 2015 together with his wife fell ill on the last night of his holiday. Eventually he went into a hospital in his hometown, San Diego. The doctors told him that he would likely die. He had acquired a multi-antibiotic resistant infection. He was slipping in and out of consciousness. His wife, Steffanie Strathdee, an infectious disease epidemiologist, remembered having heard about phage therapy during a virology class during her training in Toronto. Tom received two separate phage cocktails that two separate research teams in the US had prepared for his condition. He received the first dosage into his abdomen.

Intravenous phage therapy

The second administration was intravenously. There are only a handful of patients who had received treatment with phage therapy in the US; he is probably the first one who received phage therapy intravenously. A few days later he woke up. He had to relearn basic life skills like swallowing and speaking. But he made a full recovery from a serious disease with multi-antibiotic resistant bacteria. The University of California San Diego School of Medicine had helped Tom to recover from his illness. They announced at the end of June 2018 that they would be opening the Center for Innovative Phage Applications and Therapeutics in San Diego.

Modern phage technology

Basically phages are viruses that specialize in killing bacteria. They exist in nature wherever bacteria grow and help that they do not over-proliferate.  But they can be useful in fighting difficult to treat bacterial infections as well, like pseudomonas ear infections, Clostridium difficile gut infections or Methicillin-resistant Staphylococcus aureus infections in skin wounds. In the former Soviet Union and in the Eliava Institute in Tbilisi, Georgia, extensive phage research has accumulated valuable data over decades. In the West physician relied on the power of antibiotics, and phages were left on the back-burner of the research lab.

Genetic engineering of phages and toxins produced by phages

Combining phage research and genetic engineering research we are entering a new era of manufacturing biological compounds that can kill bacteria similar to antibiotics. Here is a review article of this new exciting field. I only include this link to show that researchers are now getting a handle on phages. They can be genetically modified to specifically attack one kind of bacterium. The DNA of the phage can be isolated and injected into bacteria. I do not expect you to understand all of what is discussed in this link.

Phage Therapy Against Superbugs

Phage Therapy Against Superbugs

Conclusion

As a result phages are more and more in use to treat difficult chronic infections where bacteria have become resistant to multiple antibiotics. It requires a team of experts who are familiar with phage cocktails. The cocktail is a careful combination of various phages that will fight the antibiotic resistant infection.The composition of it has to be according to the bacteria present in the patient’s bacterial flora. As shown with two clinical examples very sick patients can recover relatively quickly from their chronic infections. After this breakthrough more and more centers for phage therapy will open and this should help reduce the death rate from antibiotic-resistant infections.

Apr
07
2018

Antibiotic Resistant Bacteria Killed By Teixobactin

Antibiotic resistant bacteria killed by teixobactin would be a dream for infection specialists. In the last few decades drug resistance among antibiotics has become a major problem in chronic care homes and hospitals. Fortunately in January 2018 a publication announced that a research team from Lincoln, Great Britain was successful in synthesizing a new antibiotic, called teixobactin.

Origin of teixobactin

First of all, teixobactin is a peptide, and it comes from a soil bacterium that was difficult to culture. But a new culture method made it possible to isolate teixobactin. Subsequently the biochemists were able to create the identical antibiotic synthetically.

This moment likely is as important as the original discovery of penicillin. Experiments in the Petri dish and in mice show that teixobactin is a broad spectrum antibiotic, has no toxicity and treats all of the problem bugs that are associated with drug resistance. To the clinician it is a dream come true. For decades they hoped for an effective treatment for drug resistant bacteria. And now this seems to materialize. In the US there are 2 million drug resistant infections every year. More than 23,000 patients die from them every year.

Six problem bugs that are drug resistant

There are currently 6 problem bugs that have developed resistance. 1 in 4 nursing home patients may have one of these resistant bugs: carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae, vancomycin-resistant Enterococcus (VRE), multidrug-resistant Pseudomonas aeruginosa and multidrug-resistant Acinetobacter.

3 years ago a research team showed that teixobactin killed MRSA and VRE.  The underlying publication by Ishwar Singh and colleagues described how cyclic peptides their research team has successfully synthesized teixobactin analogues. He said that these findings may “lead to the first new class of antibiotic drug in 30 years”.

Mouse experiments using teixobactin analogues

The next level of evidence came from mouse experiments. Ten analogues of teixobactin were tested on mice that had infections due to drug resistant bacteria.

One team working at the Singapore Eye Research Institute could show that mice that had Staphylococcus aureus keratitis (infection of the cornea with bacteria) achieved a cure of this infection with synthetic teixobactin. An additional observation was that the amount of swelling (edema) and inflammation that is part of the infection was quickly resolving with teixobactin. This additional anti-inflammatory effect of teixobactin is an asset that will be a necessity, when it comes to treating infections in patients.

At this point there have been no clinical trials. This is the next step before physicians can prescribe teixobactin for their patients. Dr. Singh said, “We are probably around six to ten years away from a drug that doctors can prescribe to patients”.

New antibiotic treats

antibiotic resistant tuberculosis

In addition to teixobactin there is another story that gives hope for cases of resistant tuberculosis. In an Iranian publication from August 2017 it is described how compounds from the Persian shallot have full antibiotic activity against known drug resistant E.coli strains.

The same antibiotic derived from Persian shallot is also effective against resistant tuberculosis. Dr. Sanjib Bhakta and Professor Gibbons from Great Britain said that their ability to synthesize the effective antibiotics is a great breakthrough. Prof. Gibbons said: “Natural products from plants and microbes have enormous potential as a source of new antibiotics. Nature is an amazingly creative chemist, and it is likely that plants such as the Persian shallot produce these chemicals as a defence against microbes in their environment. Dr. Bhakta and I will be dedicating our research to discovering new antibiotics and understanding how they function.”

Persian shallot-derived antibiotics

Dr. Bhakta tested the Persian shallot-derived antibiotics against various drug-resistant bacteria. There were inhibitory effects on Escherichia coli, Klebsiella pneumoniae, multidrug resistant Staphylococcus aureus and Proteus mirabilis. But the most impressive inhibition (inhibiting growth by 99.9%) was against the tuberculosis bacterium, Mycobacterium tuberculosis. Consequently this is a significant finding as drug-resistant tuberculosis strains have been on the rise killing a lot of people.

Antibiotic Resistant Bacteria Killed By Teixobactin

Antibiotic Resistant Bacteria Killed By Teixobactin

Conclusion

Research has opened a door to a new era that will be ready for prime time in 6 to 8 years. Research has identified two groups of new antibiotics, synthetic teixobactins and Persian onion-derived antibiotics. They are both effective in preliminary in vitro and in vivo mouse experiments against drug-resistant bacteria. The most important effects are against Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and antibiotic resistant tuberculosis (Mycobacterium tuberculosis). At this stage there is an urgent need to conduct clinical trials to get FDA approval for these new antibiotics. With this approval the new antibiotics are ready for use in clinical medicine against drug-resistant infections. In the antibiotic field no such finding of that significance has occurred in the last 30 years. In the US more than 23,000 patients die from them every year. It is high time that there is a cure for these infections.