Solving Antibiotic Resistance

There has been much recent talk about how to target the rising tide of antibiotic resistance across the world, one of the biggest threats to global health today. While there is no doubting the size of the problem facing scientists, healthcare professionals and the pharmaceutical industry, there are innovative ways we can target antibiotic resistance in the short term.

With only a few antibiotics in development and a long drug development process (often 10-15 years), there is concern that what is being done to combat antibiotic resistance may be 'too little, too late'.

While any antimicrobial resistance is concerning, the increasing incidence of antibiotic-resistant Gram-negative bacteria has become a particular problem as strains resistant to multiple antibiotics are becoming common and no new drugs to treat these infections (eg, carbapenem-resistant Enterobacteriaceae) will be available in the near future. These Gram-negative bacteria are considered the most critical priority in the list of the 12 families of bacteria that pose the greatest threat to human health that was just released by the World Health Organization.

An innovative strategy that is gaining momentum is the synergistic use of antibiotics with FDA-approved non-antibiotics. Using this novel approach, an FDA-approved non-antibiotic drug is combined with a specific antibiotic that enables it to breach the outer membrane barrier and so restore the activity of an antibiotic. Several researchers had described how combining antibiotics with other non-antibiotic drugs or compounds can boost their effectiveness against Gram-negative 'superbugs'.

For example, loperamide, an anti-diarrheal medication sold in most pharmacies, enhances the effectiveness of eight different antibiotics (all in the tetracycline class). In particular, when added to the tetracycline antibiotic minocycline, along with the Parkinson's disease drug benserazide, it significantly increased antibiotic activity against multi-drug resistant Pseudomonas aeruginosa, a causative agent in hospital-acquired infections such as ventilator-associated pneumonia.

Polymyxins are a type of antibiotics that target Gram-negative bacterial infections and have traditionally been used as a last resort to treat serious infections such as those caused by Gram-negative 'superbugs' Klebsiella pneumoniae, P. aeruginosa and Acinetobacter baumannii. Resistance to polymyxins is not common, but in late 2015 the first transferable resistance gene to colistin (polymyxin E) was discovered (plasmid-borne mcr-1 gene). This caused significant concerns, as once resistance to polymyxins is established, often no other treatments are available.

Some interesting findings have ensued, with a number of different combinations having a beneficial effect. Some notable examples that increased antibiotic activity when combined with polymyxin B include: ivacaftor and lumacaftor, two new drugs used to treat cystic fibrosis; and closantel, a drug used to treat parasitic worm infections.

Another interesting combination that has shown promise against methicillin-resistant Staphylococcus aureus (MRSA), according to Schneider and co-authors, is combining the antibiotics ampicillin or oxacillin with berberine. Berberine is extracted from the roots, stems and bark of plants such as barberry.

n 2005, the Drugs for Neglected Diseases initiative identified fexinadole as a potential treatment for sleeping sickness and it is now undergoing a Phase III trial. This drug had been developed as an antimicrobial in the 1970s, but only reached pre-clinical development.

In addition to the above, researchers are looking for new, untested sources of antimicrobial activity to try and develop new drugs. A recent success in this area was, teixobactin, a new antibiotic developed by NovoBiotic Pharmaceuticals, discovered by using an 'iChip' to culture and isolate soil bacteria in situ.

"Non-antibiotic strategies are just as important, such as developing vaccines or probiotic therapies to prevent infections, as they can help to reduce the overuse of antibiotics. They will never completely replace antibiotics, but can help to preserve our existing antibiotics so they still work when needed."

Inspired by recent article: Antibiotics and non-antibiotics combination

by 

Dr. Akshaya Srikanth Bhagavathula

Pharm.D India

Injectable Antiretroviral Therapy: The Future

HIV therapy has dramatically improved over the past few decades due to advances in new drug discoveries and reformulations allowing for simple oral regimens. These advancements have helped to combat resistance and reduce pill burden for patients. Once-daily antiretroviral regimens are quickly becoming new standards for new patients; however, adherence is still a concern. But what if patients no longer had to take a pill every day? This could be possible with the new, long-acting injectable antiretrovirals cabotegravir and Edurant.

The components of the injectable regimen consist of a non-nucleoside reverse transcriptase inhibitor (NNRTI), Edurant (rilpivirine, Janssen Therapeutics), and a new integrase strand transfer inhibitor (INSTI), cabotegravir (ViiV Healthcare). Rilpivirine is a second-generation NNRTI approved in 2011 for the indication of treatment-naive patients with HIV-1 RNA less than 100,000 copies/mL. Its increased potency, longer half-life (oral: 50 hours; intramuscular: 20-40 days) and reduced adverse effect profile in comparison with a first-generation NNRTI such as Sustiva (efavirenz, Bristol-Myers Squibb) made it ideal to combine with the new INSTI.

The discovery of integrase inhibitors in the late 2000s was pivotal for drug regimens as these agents were associated with few adverse reactions and were very effective for treatment-naive patients. Despite being new agents, Isentress (raltegravir, Merck) and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Gilead Sciences), already have documented resistance in treatment-naive and previously treated patients, thus prompting the development of the second-generation Tivicay (dolutegravir, ViiV Healthcare), an INSTI that is more sustained against resistance and has an improved administration profile. Cabotegravir, a potent analog of dolutegravir, possesses a long half-life (oral: 40 hours; intramuscular: 30-90 days), allowing for once-daily dosing with no need for a booster.

Impact of an injectable regimen

Current results appear promising for this new injectable therapy option. It is unique to have a two-drug regimen for maintenance therapy of HIV, but thus far development of resistance does not appear significant. The utility of an injection could pose several challenges for the patient. Adherence may continue to be an issue given that the initial induction phase is similar to many other current once-daily oral regimens. Patients still need to prove adherence to the oral regimen before starting an injectable maintenance therapy. Additionally, adherence to an injectable may pose its own setbacks. While satisfaction was reported to be high, it may be unfavorable to request that patients visit the clinic every 1 to 2 months when it could be reduced to once- or twice-yearly visits. If patients are able to administer the injections at home, this regimen could be a game-changer for those who are nonadherent. However, a gluteal injection may be too complicated for self-administration. The company expressed the possibility of investigating administration of the thigh, which sounds very reasonable as a new standard regimen. Lastly, the cost of these injectables will be another debate as current oral regimens are well-covered by insurance companies. The price of these new formulations is not currently available, but to incentivize use, they will likely need to be comparable to oral regimens.

More results from the phase 2b study and a future phase 3 study will determine if this is a feasible therapy regimen from an efficacy and safety standpoint. The once-daily, triple-therapy oral regimens show good tolerability and low resistance rates, making this regimen fit within the current standards. The major appeal to an injectable regimen would be the potential for improved adherence. This could dramatically change a patient’s quality of life as they are able to return to a pill-less (or at the least, a lower pill burden) life.

Source: LATTE Trial

by

Dr.Akshaya S Bhagavathula, Pharm.D

Egg Consumption doubles Cardiometabolic Risk

The gut flora or microbiota is undoubtedly crucial to the digestive process. However, there is growing interest in the role of the gut microbiota as an environmental factor influencing propensity for cardiometabolic disease. Studies have implicated the gut microbiota in susceptibility to obesity and insulin resistance; germ-free mice fed a high-fat, high-carbohydrate Western-style diet were protected against diet-induced obesity, glucose intolerance and insulin resistance.

More recently, research has linked dietary lipid intake, the gut microbiota and increased risk for atherosclerosis.(2,3) Cholesterol-rich foods, such as egg yolks, contain phosphatidylcholine which is hydrolysed by phospholipase enzymes to release choline. The gut microbiota then convert choline to trimethylamine (TMA), whichundergoes oxidation in the liver to trimethylamine N-oxide (TMAO), released into the plasma.

In mice susceptible to atherosclerosis fed a diet supplemented with phosphatidyl choline, there was an increase in plasma levels of TMAO concomitant with increased atherosclerotic plaque development. Mechanistically, increased dietary choline was associated with suppression of multiple macrophage scavenger receptors which protect against atherosclerosis.3 These data therefore implicate excess dietary choline as an emerging modifiable risk factor for cardiovascular disease, mediated by the gut microbiota.

These findings may be relevant in the light with recent research which showed an association between egg yolk consumption and carotid plaque burden. Individuals consuming 3 or more eggs per week had a significantly higher plaque burden that those with reduced consumption. This suggests that egg yolk consumption should be reduced or avoided in high-risk individuals with established cardiovascular disease. Consumption of a large egg (which equates to about 200 mg of dietary cholesterol) not only increases the susceptibility of low-density lipoproteins (LDL) to oxidation, but also increases postprandial lipaemia, and potentiates the adverse effects of dietary saturated fat. Additionally, egg consumption effectively halves postprandial clearance of atherogenic chylomicron remnants, which implies a need to re-consider egg yolk consumption in individuals with cardiometabolic disease, including those with diabetes. Indeed, in observational studies, regular egg consumption was associated with increased risk of new-onset diabetes, cardiovascular disease and all-cause mortality. These epidemiological data, together with the FOCUS paper, provide a strong rationale for a prospective randomized trial comparing the effects of consumption of eggs or egg white-based substitutes on hard clinical outcomes.  Currently, international guidelines are inconsistent in considering the dietary cholesterol. Currently, international guidelines are inconsistent in their consideration of dietary cholesterol. There are also misconceptions that because of the efficacy of statins in lowering plasma total cholesterol and LDL cholesterol, consideration of dietary cholesterol is less relevant in statin-treated patients. Yet even with intensive statin therapy, there remains about 70% residual cardiovascular risk.

by

Dr.Akshaya Srikanth, Pharm.D

Pharm.D in India: What is known and What is unknown ?

Doctor of Pharmacy (Pharm.D) in India has created a huge hike on young pharmacists, expecting the future is much better than the other branches of pharmacy. Pharm.D's syllabus is we framed with lot of debates and observations from the developed world to provide a competent clinical pharmacist for the better health care in India. See the syllabus the other health care professionals were excited to see the practicality of this course in their work place. But, theoretically Pharm.D has made a huge impact on the developed nations and developing nations to adopt the India Pharm.D syllabus a standard one to practice in their own countries. To the same, the Indian Pharm.D has many pitfalls in practicality, which is hard to answer the route cause. For instance, a competent clinical pharmacist needed more practical training which need much focus on patient care by training them in the wards and engaging them in all the activities that can make them to learn how to implement the clinical pharmacy and collaborative work with other health professionals. Due to lack of competitive faculties the scope of bed-side teaching was negligible. Its fact, when Pharm.D students enter into the wards, they see the nursing staff training their nurses, Doctors training their medicos but Pharm.D students were relaying on the medical doctors to provide some support as the faculties never likely to participate in the bed-side teaching and working with the health professionals in the wards.

Increasing number of colleges increased the demand of Pharm.D admission, but there is none to answer the practicality of their roles and jobs. Disparities in training and unsuccessful competencies with poor health care acceptance kept the Pharm.D's into dilemma. Furthermore, it also made a lot of confusion among the student minds and unable to fulfill their dreams. For instance, course such as  Pharmacoepidemiology and clinical research were elaborative in syllabus, but faculties unable to engage them in any activities such visiting clinical research sites, engaging them in some pharmacovigilance activities. Furthermore, the organizations well focusing on conferences for showoff and unnecessary hikes over the Pharm.D without know the practical barriers faced by the students. For instance, there are many pharmacy organizations inviting the international delegates to participate in the national and international conferences, but unable to engage the Indian Pharm.D's to get trained in overseas.

Now the number of Pharm.D's increasing and coming out with any vision. This is because of lack of planning and support from the Pharmacy board. This situation is especially burning in southern states where the number of colleges are more than that of other parts of India. All colleges promising to give admission but unable to secure them in jobs. The student associations such as "IPSF", and "IPA-SF" etc., are focusing on conferences and international fame rather to supporting the local Pharm.D students. The silence answers from the pharmacy leaders increasing the tensions in the student mind. There is much more needed to work at ground level, focusing on providing standard practical training rather basic theoretical knowledge, providing a scope and hope on the Pharm.D's for securing the jobs is crucial.

In conclusion, Pharm.D's are currently in great frustration and needed support from all phases for the future of clinical pharmacy in India. Further, clinical pharmacy is a practice of patient care through pharmaceutical care. If the theoretical knowledge can fulfill the dream then we are in world of delusion.
by
Dr.Akshaya Srikanth, Pharm.D
Pharm.D India