Dr V Ramasubramanian

V. Ramasubramanium

 

 

 

 Dr V Ramasubramanian

 

The serendipitous observation by Alexander Fleming on the morning of September 3, 1928, a halo of inhibition of bacterial growth around a contaminant blue-green mould, paved the way for the discovery of a miracle - Penicillium notatum, from which penicillin was produced. This was the first step in the journey towards the antibiotic revolution. Antibiotics helped transform the practice of medicine in the fight against bacterial infections. The heady euphoria created by the discovery of various antibiotics in the 1950s prompted Dr William Stewart, the Surgeon General of the United States to remark, “The time has come to close the book on Infectious Diseases. We have basically wiped out infections in the United States”. But we failed to realize the resilience of the microbes; their survival skills characterized by their ability to develop resistance in the face of antibiotic pressure started the fight back.

The resistance phenomenon can be characterized as follows:

  • Given sufficient time and drug use, resistance will emerge
  • Resistance is progressive, evolving from low levels to high levels
  • Organisms resistant to one drug are likely to develop resistance to others
  • Once resistance appears, it declines slowly if at all
  • Use of antibiotics in one person affects others

Even though our learning curve has been steep, we failed to understand the implications for the future. Antibiotic resistance can be spontaneous, but is usually induced by evolutionary selection pressure on exposure to an antibiotic.

The mechanisms of antibiotic resistance:

  • Modification of antibiotic receptor
  • Loss of porin channels
  • Development of efflux pumps
  • Production of enzymes to destroy antibiotics

Genes that confer resistance can be transferred between bacteria by conjugation, transduction or transformation. This enables a rapid spread of resistance genes between colonies of the same bacteria and at times to similar bacterial populations.


Escalating Resistance Wars

  • Staphylococcus aureus – Methicillin-Resistant Staphylococcus aureus (MRSA)
  • Enterococcus – Vancomycin-Resistant Enterococci (VRE)
  • Gram negatives -Extended spectrum beta lactamase (ESBL) producers and           AmpC producers
  • Gram negatives – Carbapenemases (KPC, Oxa, NDMs)
  • Tuberculosis – MDR, XDR, TDR…
  • Malaria - Artemesinin resistant falciparum
  • Candida non-albicans – Azole resistant

Though the evolution of resistance has been a recognized fact, the availability of newer antibiotics managed to keep apprehensions at bay. But in recent times, the rapidity of development of novel mechanisms of resistance coupled with the lack of research in New Chemical Entities (NCE) have precipitated a crisis in the field of Infectious Diseases. Pharmaceutical companies are unwilling to invest in the development of newer antibiotics as returns are poor. We are slowly, but surely, running out of options to treat infections. Though the problem was initially restricted to infections acquired in hospitals, generally caused by multi-drug resistant organisms, we are now facing the threat of resistant community infections. This resistance phenomenon is not limited to the bacteria, but escalating to involve parasitic infections like malaria and fungal infections like Candida. We are facing the grim scenario of the post-antibiotic era of untreatable infections.

To arrive at a solution to tackle this apparently insurmountable fiasco, we need to identify the process of creation and spread of resistance. Resistant bacteria have been identified in nature even several thousands of years before antibiotics were developed. Though mutation in bacteria, which may result in the formation of resistant bacteria, occurs at random, the selection pressure of antibiotics accelerates this process. This killing paradox of the miracle drugs results in the phenomenon of ‘the more we use them, the more we lose them’. This phenomenon escalates if sub-optimal doses or truncated course of antibiotics are used. Moreover, the indiscriminate use of antibiotics as growth promoters in the agriculture industry and animal husbandry has led to widespread antibiotic resistance.

Inadequate sanitation and hygiene and lack of clean drinking water have encouraged community spread of multi-drug resistant bacteria, which colonize the gut of healthy persons and can result in endogenous infections. The rise of rapid and frequent international travel has fuelled the spread of resistance.

It has always been perceived that community acquired infections are caused by drug sensitive bugs and that infections acquired in hospitals are caused by pathogens that are generally resistant to several antibiotics. This is because of the fact that bugs which are in the hospital environment have been exposed to various antibiotics and hence possess resistance to several of them. The earlier distinction between community acquired pathogens and hospital acquired pathogens is now getting blurred as the resistance bugs are now sharing their resistance genes with sensitive ones, equipping them with the ability to survive better. This has happened due to poor sanitation and hygiene, which has enabled resistant bugs to enter into the water sources of the community thereby causing colonization of the bacteria in the gut of healthy individuals in the community. These can subsequently cause infections in the community. These developments have made the management of serious infections from the community all the more difficult as clinicians have to use high0end antibiotics even for community acquired infections.

The Way Forward

We need to ensure basic hygiene and sanitation in our society to prevent the transmission of resistant bacteria. Blocking the colonization of these resistant bacteria in our gut will, to a significant extent, enable their eradication. Legislation is warranted to ensure appropriate use of antibiotics and ensure sensible utilization. Indiscriminate use of antibiotics in animal husbandry and the agricultural sectors and over-the-counter sale of antibiotics should be discouraged. Practical legislations with effective policing are mandated for these measures to succeed. There should also be a system in place guiding medical practitioners on use of antibiotics. This program of antibiotic stewardship should include surveillance of community and hospital infections and their etiological agents, whereby sensitivity profiles and resistance patterns of these bacteria are available for interpretation to help guide selection of antibiotics. The antibiotic usage in hospitals should also be monitored to enable doctors to correlate antibiotic use with resistance trends. This will also help guide antibiotic use regionally. There should be a mandate on hospital accreditation by a process that should include collection of data on bacterial prevalence and their sensitivities.

The Government should evaluate through bio-equivalence studies the safety and potency of generic drugs. Criminal action should be imposed on spurious drug manufacturers and the ruling should be enforced to deter such practice.

Education on Infection Control should be included as an important part of the medical curriculum. All health care workers should be periodically updated through Continuous Medical Education (CME) on the importance of Infection Control. All hospitals should have a robust Infection Control Program to enable better control on hospital-acquired infections. Antimicrobial Stewardship should be an integral part of Infection Control.

The public should be educated on the current scenario of antibiotic resistance so that individual responsibility is instilled in limiting antibiotic abuse. An increased awareness will encourage more responsible prescription and utilization. More Indian studies are also required on the prevalence of antibiotic resistance and antibiotic utilization. This will also help guide introduction of regional guidelines and recommendations on antibiotic usage.

While all the above measures will help tackle the crisis in the long-term, a better approach in the diagnosis of infections, including newer diagnostic tests, are needed to stem the rising tide of empiric broad spectrum antibiotic use in emergency and intensive care. Pharmacokinetic and pharmacodynamic optimization should be implemented through improved recommendations on correct dosing and administration.

Finally, research on new chemical entities is urgently needed to ensure availability of antibiotics with novel modes of action that will overcome the current resistance mechanisms.

As French painter Picabia said “Our heads are round so that our thinking can change directions.” Unless we think real hard about the dismal situation that we have led ourselves into, mankind runs the risk of becoming endangered.

 

Dr V Ramasubramanian is a specialist in Infectious Diseases, adolescent and adult vaccinations and travel medicine. He is currently a Senior Consultant in Infectious Diseases, HIV & Tropical Medicine at Apollo Hospital, Chennai and a Professor of Infectious Diseases at the Sri Ramachandra Medical Centre and the MGR Medical University, Chennai. He is also an Adjunct Associate Professor of Infectious Diseases at the University of Queensland, Australia. In 2008 he founded Immune Boosters, a unique clinic dedicated to adolescent and adult vaccinations and Travel Health (www.immuneboosters.com). The clinic, the first of its kind in India, propagates the concept of preventive health and travel medicine.

 

I would find it hard to answer eihter way. I think multidrug

I would find it hard to answer eihter way. I think multidrug resistance is a serious and potential threat, and there have been recommendations for some time that reports, such as that published by Walsh et al. in Lancet Infectious Diseases, be published and acted upon.Molecular epidemiological studies are a crucial underpinning to work on predicting antimicrobial resistance (PAR), especially when these elements are associated with, or are in the same ecological niche, as promiscuous mobile genetic elements, and arising in nosocomial environments.However, whilst the a/biotic pipeline could certainly have been considerably better stocked, the efforts of numerous small biotechs and academic researcher looking at alternatives to the rather poultry introduction of new a/biotic classes, seems to be chronically undervalued. There are valiant efforts to target bacterial virulence, the mechanisms of horizontal transfer, and to inhibit the means by which bacteria resistant antibiotics in all cases rendering more time for new drug discovery, but crucially more time in clinical therapy. Is it likely that we will be dealing with infections in the UK that are completely resistant to antibiotics within 10 years? Or is this simply a case of media hysteria? Yes, if the funding is not made available and we rely on the efforts of a (majority) disinterest of large pharmaceuticals to invest in new drug class leads, we will be dealing with increased prevalence of multidrug resistance as we already are in isolated pockets with some strains of Gram (+)ve bacterial pathogens.Media hype should be reflective, and not doomsaying. They should be pointing out the threats, but identifying the huge efforts being taken to provide alternative solutions brought about by the lack of real investment. We know so much more about bacteriology, molecular epidemioloigy and drug discovery now than we did in the heyday of a.biotic discovery. A/biotics were used for years without a full understanding of their mechanisms, nor the mechanisms of resistance. Many instances of a/biotic resistance spread could (and should) have ben predicted and prevented.Ironically, some of the systems biology, high-throughput infrastructures that have been stealing so much of the research funding pot (that could have gone into a/biotic and resistance research), could actually now be of some considerably use in speeding up the whole process of recognising new resistance determinants, tracking their spread and identifying resistance trends that can be exploited to clinical benefit.

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