Jun
27
2020

A New Antibiotic, Teixobactin Can Overcome Antibiotic-Resistant Superbugs

By | antibiotics, Infectious Disease, Mortality

A new antibiotic, teixobactin can overcome antibiotic-resistant superbugs. The discovery of teixobactin took place in 2015. It is a peptide with 11 amino acid units. Teixobactin is derived from a gram-negative bacterium, Eleftheria terrae. It is the first of a new class of antibiotics that can kill superbugs. Two examples, for instance are methicillin-resistant Staphylococcus aureus and resistant Mycobacterium tuberculosis. Researchers have been battling with difficult solubility of teixobactin and problems synthesizing this peptide in the laboratory. Teixobactin binds to the membranes of the bacteria it fights. This is a new mechanism for this new class of antibiotics, different from conventional antibiotics.

Mechanisms of fighting bacteria resistant to conventional antibiotics

But it is exactly this quality that is necessary to fight the antibiotic-resistant bacteria. The researchers showed that teixobactin binds weakly to a component of the bacterial cell wall, called “Lipid II”. But they found a second mechanism, namely blocking precursors of cell membrane synthesis in the bacteria they fight. Because of these unique mechanisms it is possible for them to fight a multitude of bacteria resistant to conventional antibiotics. Teixobactin has a unique molecular structure, which makes it difficult for resistant bacteria to develop resistance to it.

Antibiotic resistance

Resistance to antibiotics is a worldwide problem. There are several factors that worked together to make antibiotic resistance such a big issue. For instance, in the past many doctors prescribed antibiotics for any viral cold, even knowing that antibiotics only work against bacteria. Aside from this, the agricultural practice of using antibiotics as a growth stimulator is also an important factor for antibiotic resistance to develop. It is the bacteria that become resistant, not the human body. Several clinical entities involving resistant bacteria exist that show the magnitude of the problem.

Flesh-eating disease

Necrotizing fasciitis (or flesh-eating disease) can develop when you swim in contaminated waters and the bacterium, Vibrio vulnificus enters through skin sores or wounds. The CDC warns that you should stay out of salt water or brackish water, if you have a skin wound. The flesh-eating bacteria, Vibrio vulnificus can become very aggressive, once it has entered the body. Right now, 1 out of 5 people who get infected will die and many people require ICU treatment. Others need limb amputations. All of this can happen within only 1 or 2 days of becoming ill. The hope is that with the development of teixobactin as an injectable medication or as an oral pill there will no longer be deaths, amputations and scarring due to this bacterium, as the antibiotic will very quickly eradicate Vibrio vulnificus. I have previously written about what hospitals can do to fight superbugs.

The most common antibiotic-resistant bacteria

Here is a brief review of the most common antibiotic-resistant bacteria.

Mycobacterium tuberculosis

Since the 1950’s and 1960’s tuberculosis was treatable with a combination of two antibiotics over a period of six months to two years. But in the last 10 years more and more resistant strains of tuberculosis have developed. This is called multi-drug-resistant TB. In 2013 statistics showed that 3.7% of newly diagnosed tuberculosis cases were multi-drug-resistant TB. Many of these cases can be traced back to prisons and homeless shelters.

Methicillin-resistant Staphylococcus aureus (MRSA)

MRSA has become a common resistant bacterium that can present with difficult to treat boils in the skin, but also as a fulminant infection as necrotizing fasciitis (or “flesh-eating disease”). About 1/3 of the cases of flesh-eating disease are caused by MRSA.

Clostridium difficile (C. difficile)

This gut bacterium is naturally resistant to many antibiotics. The rest of the gut bacteria usually suppress the growth of C. difficile. But many patients can get overgrowth of C. difficile in their gut following treatment with antibiotics. Recolonization with probiotics can help to reintroduce a balanced bowel flora. In the US about 500,000 individuals come down every year with diarrhea due to C. difficile. This leads to approximately 15,000 deaths yearly.

Vancomycin-resistant Enterococci (VRE)

Physicians find enterococci in the gut and the female genital tract of patients. They can become resistant when the patient is treated with vancomycin for another infection. The VRE can then become a problem of its own with difficult to treat infections in the genital tract of females, the gut or in wounds from surgery. It has become a problem in immunocompromised patients.

The gonorrhea causing bacteria

In the last 70 to 80 years Neisseria gonorrhoea, the cause of gonorrhea, has been treated with only one antibiotic, but gradually the bacterium developed antibiotic-resistance. Lately, with more and more resistant strains of Neisseria gonorrhoea, the CDC has recommended to treat gonorrhea with two overlapping antibiotics.

Carbapenem-resistant Enterobacteriaceae (CRE)

There are two problem bugs among this category of enterobacteria, Klebsiella species and Escherichia coli (E. coli). These bacteria reside in hospitals where they can accumulate and are present in patients with immune system compromise. Medical devices like catheters and ventilators transmit these bacteria. Once a patient is sick with CRE, there is a danger of blood poisoning (septicemia), which has a high death rate.

How do regular antibiotics kill bacteria and how can they become resistant?

Normally, when antibiotics are not resistant, they interfere with the cell membrane production of the bacteria. Specifically, conventional antibiotics prevent bacteria from synthesizing a molecule, called peptidoglycan. Without peptidoglycan bacteria are not stable enough to survive in humans. But there are other mechanisms as explained in this link how antibiotics manage to kill bacteria.

Now I like to address the question how bacteria can become resistant to conventional antibiotics. This happens with overuse of antibiotics, i.e. prescribing antibiotics when a person suffers from a viral illness where antibiotics do not work. Other overuse comes from agriculture where cattle in feed lots get antibiotics as growth promoters. The FDA is strongly criticizing this practice, because residuals of antibiotics in beef can alter the bowel flora in man. The antibiotics kill all the sensitive bacteria. But the resistant bacteria, that have undergone mutations and adapted to the antibiotics, will survive.

Why teixobactin and analogues can avoid resistance

Since the detection of teixobactin many analogues have been synthesized. A new antibiotic, teixobactin can overcome antibiotic-resistant superbugs. The teixobactin analogues need more fine tuning, but they will be a breakthrough in the treatment of resistant bacteria. As this peptide attacks two targets on bacteria, it is not easy for bacteria to develop resistance against these new antibiotics.

A New Antibiotic, Teixobactin Can Overcome Antibiotic-Resistant Superbugs

A New Antibiotic, Teixobactin Can Overcome Antibiotic-Resistant Superbugs

Conclusion

Resistant bacteria have become a serious health concern in the last decade. Physicians overprescribing antibiotics and farmers feeding antibiotics to cattle in feedlots as growth promoters were the driving forces. In 2015 came the breakthrough and discovery of teixobactin. This is a peptide with 11 amino acid units. Teixobactin is a derivative of a gram-negative bacterium, Eleftheria terrae. A new antibiotic, teixobactin can overcome antibiotic-resistant superbugs. In the meantime, researchers have been able to improve solubility by developing teixobactin analogues. More research is necessary. But all of the researchers who work in this field claim that this will very soon be extremely useful for patients with super bugs. This super-antibiotic will be a weapon fighting super bugs. Before the release of this medication clinical trials will be the next step.

Aug
05
2017

Death From Heartburn Drugs

By | Cardiovascular disease, fractures, Gastrointestinal Disease, heart attack, Mortality, ulcers

A study was recently published showing that death from heartburn drugs can come early, when compared to controls. The study was published in June 2017 in the online British Medical Journal Open. The researchers were located at the Washington University School of Medicine, Saint Louis, Missouri, USA.

They compared 349, 312 US veterans on proton pump inhibitors (PPI) to an equal amount of veterans on conventional H2 blockers. Over a follow-up period of 5.71 years there was an increased risk of death of 25% when patients took PPI drugs. No matter to what the researchers compared the PPI group to, there were always more deaths in the PPI group versus other control groups.

Causes of death

According to the senior author, Dr. Ziyad Al-Aly many deaths were due to kidney disease, dementia, fractures, pneumonia, Clostridium difficile infections and cardiovascular disease. Out of 500 patients who took the PPI drug there was one death within one year. But over the years the deaths increased. Dr. Al-Aly thinks that the PPI drug is interfering in some way with the genetic expression of some genes and suppressing others. These genetic differences may explain the early deaths.

As this was a retrospective study, it can only show an association of PPI drugs with earlier deaths, but this does not prove causation. It would require a prospective random study to prove causation.

Other studies regarding the risk of PPI drugs

An Icelandic study from May 2017 showed that there was a 30% increased risk of fractures in males and females following PPI drugs when observed over 10 years. Opiates had a risk of almost 50%, sedatives a 40% risk of increased fractures. Control groups of NSAIDs, statins and beta-blockers showed no increased fracture risk, nor did histamine H2-antagonists.

Side effects of PPI’s

An article from March 2017 is a critical review of the safety of PPI drugs. It notices that with long-term use there are adverse effects like fractures of the long bones, enteric infections and hypomagnesemia. PPI’s can increase the risk for heart attacks and can cause kidney disease and dementia. One of the problems is that gastroesophageal reflux usually dictates the long term use of anti acid drugs like PPI’s, but the longer patients are taking these drugs, the higher the death rate and side-effect rate. The physician should only use PPI drugs initially and after a few weeks switch to the less potent histamine H2-antagonists (like ranitidine).

Listeriosis as side effect of PPI’s

A Danish study from April 2017 noted an increased risk for listeriosis in patients who were on PPI drugs. Over 5 years there was a 2.81-fold higher risk of developing listeriosis in patients on PPI’s compared to a control group. If patients were on corticosteroids and a PPI the risk was even higher, namely 4.61-fold increase to develop listeriosis. In contrast, using histamine H2-antagonists had a risk of only 1.82-fold of developing listeriosis.

Poor prescribing habits for PPI’s

A Dec. 2016 study from Dublin, Ireland with patients older than 65 examined their PPI drug use. The comparison of data occurred between 1997 and for 2012. The researchers noted that the maximal PPI dose for long-term use was 0.8% of individuals in 1997 and 23.6% in 2012. The risk of prescribing high dose PPI drugs in 2012 was 6.3-fold in comparison to the risk in 1997. Examination of the health records showed that the indication for prescribing PPI drugs had no correlation with significant gastrointestinal bleeding risk factors. The study concluded that there was definitely room for improving prescribing habits.

Triple therapy

This January 2016 paper describes the standard treatment of H. pylori and gastric and duodenal ulcer treatment, which involves the triple therapy consisting of a PPI and two antibiotics. It pointed out that this treatment protocol “improves healing and prevents complications and recurrences”.

PPI’s causing risk for fractures

A paper from Leipzig, Germany dated July 2016 reviews the usage of PPIs. It mentions that there has been a significant increase of prescriptions in the past 25 years. Patients on PPI’ are at a greater risk for fractures. There is also a risk of low B12 levels from malabsorption of B12. The physician should check this from time to time, and if necessary give B12 injections.

Clostridium difficile infections

A Canadian study from May 2015 found that Clostridium difficile infections (CDI) were linked to chronic antibiotic use or to prolonged use of high doses of PPI drugs. There was a 1.5-fold risk of recurrent CDI in patients older than 75 years who were taking PPI drugs continuously. There was a 1.3-fold recurrence of CDI after antibiotic re-exposure.

Alternative remedies for heartburn

  • Dr. Weil recommends the use of deglycyrrhizinated licorice (DGL) for heartburn or early ulcers.
  • Here is a clinical study with 56 patients with duodenal and gastric ulcers that was published in 1968. Both radiographic evidence as well as clinical findings showed that the ulcers healed and that stomach spasms subsided with DGL treatment. Nobody knew at that time that DGL had antibacterial effects and that often chronic heartburn, stomach and duodenal ulcers can be due to H. pylori infections that are simultaneously present.
  • A December 2016 study showed that probiotics could be a valuable adjunct in triple therapy for H. pylori infection. The study also points out that H. pylori is present in about 50% of the world’s population.

Antibacterial effects of DGL

  • A paper of December of 2012 shows that an important tooth decay bacterium responds to DGL.
  • In a 1989 study 20 patients with aphthous mouth ulcers were followed. DGL mouthwash led to a 50 to 75% improvement in 15 patients within one day of treatment and by the 3rd day there was complete resolution.
  • Here is a suggestion of a four-step approach against H. pylori.
  • DGL has been shown to be useful in gut regeneration in patients with Clostridium difficile infection.

Discussion

I started with a review of a recent paper that pointed out the side effects of PPI drugs. PPI’s are common medications for acid reflux disease, stomach and duodenal ulcers, either alone or as part of the triple therapy. Chronic infection of H. pylori is often the cause of these problems. I reviewed the literature surrounding deglycyrrhizinated licorice (DGL), a natural antacid remedy. It turns out that DGL can be quite useful either as a parallel treatment or instead of the triple therapy.

The problem over the past 25 years is that physicians have been treating acid problems with higher and higher doses of PPI’s. They are also using ASA prophylaxis against heart attacks and strokes more often. This has caused gastric erosions that are bleeding, which in turn caused physicians to prescribe more PPI’s. The side effects of PPI’s belongs to the iatrogenic (doctor- induced) diseases. This is an artificial disease that occurs from the side effects of overprescribed medicine. PPI’s are a very useful short-term anti-acid medication. However, do not use this medication for more than 4 to 8 weeks. But as patients receive years and years of this medication, serious problems like heart attacks, fractures, kidney disease, dementia, and pneumonia as well as Clostridium difficile infections become the consequence. Overall there was an increase of the death rate of 25%.

It sounds quite reasonable that doctors should return to a more conservative approach as the FDA has suggested. This includes alternative natural methods including DGL and probiotics.

Death From Heartburn Drugs

Death From Heartburn Drugs

Conclusion

A recent study from the online British Medical Journal Open has pointed out a high death rate among long-term proton pump inhibitor (PPI) drug users. The se drugs are used to suppress acid formation in the stomach. They are helpful, if there are significant gastrointestinal bleeding risk factors present. But prolonged use of PPIs causes severe side effects as described, including a chronic persistent Clostridium difficile infection (CDI) of the gut that can become resistant to antibiotic therapy. In cases of recurrent CDI one important step is to discontinue PPIs. The physician should consider switching to one of the conventional histamine H2-antagonist drugs (like ranitidine). Overusing PPIs in an older population is not responsible, as this leads to disease that is caused by a physician! There is no need for this to happen.

Avoiding toxic drug levels of PPI’s

The prescribing physician has to exercise caution and restraint and the patients, and their loved ones need to be aware of multidrug interactions. PPIs belong to the drugs that are eliminated in the liver through the cytochrome P450 enzyme system (CYP2C19). But this enzyme system interfering with the drug elimination process may also eliminate other drugs taken by the patient. The end results can be toxic drug levels of PPIs. It can potentiate the side effects and become responsible for the 25% increased risk of death when the patient takes PPI drugs chronically. Even though PPIs are the newer medication, newer does not always mean better.