I think the most challenging problem is the emergence and spread of resistances in Gram negatives, such as Escherichia coli (cephalosporins, quinolones), Klebsiella pneumoniae (cephalosporins, quinolones, carbapenems) and non fermenters, such as A. baumannii (carbapenems). These are endemic in hospitals of most countries or in some areas of developed countries (e.g. Greece and Italy, in Europe). A more serious problem is their spread in LTCF or nursing homes, where surveillance is lacking at all and epidemiological data are unavailable. This could be a large reservoir of resistances, where they spill-out easily from towards the hospitals along with their old and co-morbid hosts.

In Palermo, Italy, where I am working since many years about this issue, we have seen the spread of such MDR or XDR organisms first in high risk wards, then in all wards and, recently, in some NICUs also, that is a very worrying development.

Antibiotic stewardship is indispensable, but I think there is a widespread under-appreciation of this problem by many healthcare workers. I agree also with D. Graham about the gross under-appreciation of "hygiene" and logistic/management issues, especially by the medical directions of the healthcare structures. A further problem arises from the need to approach the problem at a (at least) regional level.

I think "drifting towards a pre-antibiotic era" is an exaggeration. However, we clearly are losing efficacy in many clinically important antibiotics, and there is an urgent need to re-assess how and where we use our most critical antibiotics and also more expansively view why resistance is actually increasing.

There is a gross under-appreciation of the role of poor sanitation and waterborne resistance transmission by the medical community, and until the role of the broader environment to AR is more recognized by the medical world, things will get worse regardless of what is done in clinics. Humans are 75-80% water and, given over 80% of the world does not have remotely clean water, what we do relative to medical use (and veterinary) will have little effect on increased AR in poorer parts of the world. These are the nucleating places for the worst types of resistance and solving problems in such locations should be our highest priority, including control of use and environmental quality.

In my opinion, resistance to most or all antibiotics is only a matter of time. My assessment is that the antibiotics, as they are now, we can use another 20-25 years (if so long). There is no development of new antibiotics. If it start now, the results can be expected only in 15-20 years, according to current practice. On the other hand, production of vaccines is an alternative. But it takes time also. I think this will be the only way.

Gary Taubes, Jose Martinez, et al. in a special issue of Science (18 July 2008) have argued that we may be losing the battle and highlighted many contributing factors in a series of articles (environmental, clinical, management and development). Well worth a quick read.

Indeed, I think that the era of antibiotics is about to end. But they are not the only way to fight bacterial infections.

One of the most promising alternatives in recent years is the phage therapy. It's based on the utilization of bacteriophages (bacterial viruses) to kill harmful bacteria and it has many advantages when compared to antibiotics. The most noticeable are the following: 1) bacteria can't create a resistance to phages in a long-term manner as phages undergo mutations as well and some of these mutations will help to overcome the resistance => neverending race; 2) phages are highly specific, particular phage strain infects only one or a few bacterial strains => saves the intestinal flora; 3) production of phage-based drugs is much much much less expensive than production of antibiotics => cheaper and more effective drugs; 4) production of such drugs is also much faster than production of antibiotics => no comment

In the present day, there are some preparatives for the treatment of infections caused by Staphylococcus spp., Pseudomonas spp., Streptococcus spp. etc. However, the problem is that people don't know about this possibility and if they do, they may be scared to use virus-based drugs :-)

So, to conclude my post, my oppinion is that it might seem we are drifting towards pre-antibiotic era. But there is a big difference - now we have knowledge and methods how to deal with dangerous bacterial infections in several other ways apart from using antibotics. Therefore we should not rely on these chemicals too much and try to improve the most promising alternatives.

I think the most challenging problem is the emergence and spread of resistances in Gram negatives, such as Escherichia coli (cephalosporins, quinolones), Klebsiella pneumoniae (cephalosporins, quinolones, carbapenems) and non fermenters, such as A. baumannii (carbapenems). These are endemic in hospitals of most countries or in some areas of developed countries (e.g. Greece and Italy, in Europe). A more serious problem is their spread in LTCF or nursing homes, where surveillance is lacking at all and epidemiological data are unavailable. This could be a large reservoir of resistances, where they spill-out easily from towards the hospitals along with their old and co-morbid hosts.

In Palermo, Italy, where I am working since many years about this issue, we have seen the spread of such MDR or XDR organisms first in high risk wards, then in all wards and, recently, in some NICUs also, that is a very worrying development.

Antibiotic stewardship is indispensable, but I think there is a widespread under-appreciation of this problem by many healthcare workers. I agree also with D. Graham about the gross under-appreciation of "hygiene" and logistic/management issues, especially by the medical directions of the healthcare structures. A further problem arises from the need to approach the problem at a (at least) regional level.

Not at all, working in a tertiary level hospital and in a primary level clinic, I have the opportunity to deal with mdr and xdr gram negatives (probably 2 % of all the germs I deal with) and the usually sensible and mild resistant gram positives, negatives and levadures.

It's clear that we probably never have to deal with amputation due to gas gangrene (I mean, it still happens, but for other reasons than the microbial resistance) or the death of children and elders because of pneumonia (again, I'm not saying that doesn't happen now, I'm talking of the helpless scenery that doctors should have prior to 1900), but, the reality is that we are not doing a good job in the use of the antimicrobials, we are breeding such a strains of patogens with extensive resistance patterns that pose new challenges to the medical science, nevertheless, I do believe that, if in our area of influence, every one of us stride for a good, real stewardship antimicrobial program, as well as contact/isolation policies, leaded by IDs and Epidemiologists; we can manage pretty well the surge and emergence of resistance.

This has been an ongoing concern from the late 1990's. The biggest problems are NOT because of antibiotic use in humans. The biggest problem is the unregulated use of antibiotics in agriculture. Until this practice is banned, we are going to see different species of bacterium acquiring resistance. One more thing that is interesting is that different bacterium have been observed sharing their acquired resistance with different species of bacterium.

Unfortunately, agriculture is not the main cause of the most serious forms of resistance, such as NDM-1. Agricultural use is highly influential is some settings (and we have published on them), but agriculture is not the main cause everywhere.

In the case of NDM-1, which is causes consequential multi-resistance, transmission among humans almost certainly results from over self-prescription of critical antibiotics by humans coupled with inadequate human waste treatment and poor water quality. I am no apologist for agricultural antibiotic use, but it is simply incorrect to state that agriculture is the dominant cause. Agriculture is one important cause, but in places like India or Pakistan where multi-resistance is rapidly growing, it is not an important factor.

Well, with some strains of Pseudomonas, Acinetobacter, etc. we ARE in the non-antibiotic era. But not for most infections. The original question was "how prepared are we" and the answer is "not very". We are still using 1940s-1960s technology to treat most of our infections. We need to think outside of vaccination and antibiotics for common bacterial infections. For now, antimicrobial stewardship is the only tool we have besides infection control and vaccination to deal with the threat. And we know very little about antimicrobial stewardship!

From the responses to the original question, while it is clear that multiple factors have led to emergence of AR and presently we do not have new antibacterials agents to deal with this serious situation staring at us. While education and awareness about hygiene, sanitation, proper use and disposal of antibiotics etc. to medical community and to the general public, might contain further emergence of AR to an extent, the pressing need of the hour is to look for new antimicrobial agents against the threatening gram negatives and also to develop such molecules which prove difficult for the pathogen to aquire resistance, which ofcourse would depend on our understanding of the fundamental mechanisms responsible for developing resistance in the pathogen.

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(09)70105-7/abstract

I would invite all to read (if you have not read it before) the above paper. To add a further concerning piece to this very very complex landscape, it seems that reversal to antibiotic susceptibility, after removal of the selective pressure by a given antibiotic, is neither guaranteed nor quick.

That's right, development of alternative novel strategies and therapies, besides new antimicrobials for prevention and cure of infections, do demand due attention of all the stake holders:policy makers, funders, peer reviewers and scientists. Infact, a multi-pronged approach in treating difficult pathogens is likely to be more effective and sustainanble.

Just I want to add to this discussion, that according with new studies, seems that AR in natural environment is not affected for anthropogenic forces such as wastewater irrigation in agriculture. Thus, the results in this area show not significant changes in microbial community structure and microbial activity in soils under irrigation with recycled wastewater (including antibiotic compounds). However, also seems that AR can be transfer for soil microorganism to human pathogenic bacteria. If the last sentence is correct we can expect for new cases of AR emergence, including AR against new antibiotics; although maybe more important is the relation between the apparition of a new antibiotic with the emergence of AR for this antibiotic.

The AR issue is actually a very complex and multifacet problem and as such has to be faced by everybody involved in this: the MDs, DVMs, researchers, policy makers, including the public- do not forget the patients who demand an antibiotic presecription for common cold.... However, the AR problem continues to exist despite the various health and hygiene strategies that have been applied from time to time, from country to country and from continent to continent during the last 20 years. Whether we are going to be faced with a "no antibiotics era" or a "novel antibiotics era" depends on many factors, but microbes themselves are playing the key role and whatever we shall do, we should bare in mind that, they will also do whatever they can do to survive. It is a simple problem of survival (ours or theirs), Darwin might have the right answer.

I agree at all with Mohamed. At this time it is really urgent to dedicate money, time and persons to manage the problem of multiantibiotic resistance in the animal husbandry, healthcare facilities (with a special focus to non-hospital settings, such as LTCFs) and community settings.

Antibiotic resistance is a rather generic definition only meaning that a well-defined organisms is no susceptible in vitro to the action of a well defined antibacterial molecule according with criteria established by authoritative organizations such as CLSI or EUCAST. Of course, the test has to be carried out by the standardized procedures. Multiresistant is, according with the most agreed definition, an isolate which is resistant to three or more classes of antibiotics.

However, for some organisms in the present epidemiological situation, the resistance to one antibiotic is a very reliable proxy of multiresistance: Two examples: a) rifampicin-resistant MTB is resistant at least also to isoniazide and is defined as MDR TB; carbapenem resistant Gram negatives, such as A. baumannii or K. pneumoniae, are very often resistant also to all beta-lactams, aminoglycosides and fluoroquinolones. So they are multiresistant according to the definition of MDR.

It is need to pay attention to the panel of antibiotics to test. Gram negatives and Gram positives, because of their differential structure and their metabolic mechanisms, are no susceptible to the same molecules. So, it is not really sound form both the microbiological and clinical-therapeutic points of view, to test penicillin on Gram negatives or polymixins on Gram positives. Moreover, some species, such as Proteus/Providencia/Morganella oer Enterobacter, have some intrinsic resistances.

I think you can refer to the EUCAST (or CLSI) site about the choice of antibiotics and the interpretation of the susceptibility test results.

YEs, the issue of the multiple infections is very complex as well as that of attributing an etiological role to one microrganism. What I think it is 1) these conditions are not very common; 2) they are more common when underlying conditions are present (e.g. elderly, immunosuppressed individuals or, alternatively, predisposing local conditions). So, in these cases, it is this condition to be as the first step identified and controlled. It is unreasonable to fight a bacterial community with a broad spectrum antibiotic or a cocktail.

yes, you are right.. But linked also to some "conditioned reflex" to the isolation of a microrganism or, to some extent, the year-long aptitude to the use of antibiotics, with the presumption of their omnipotence and without attention to the ecological effect of their administration.

Indeed it is one the serious problem of this modern world. This problem is much more serious in our third wolrd countries bcoz there is irrational use of anibiotics .

Mis use of antibiotics espicially in deveopping countries

I quite agree with Laura, all possibilities need to be considered and nothing should be excluded. We must take our lessons form the problem that has assumed such an alarming proportion to devise appropriate means and strategy towards dsdiscovery, development and application of new drugs and molecules. The enormity of AR problem was also recently highlighted by Englands Chief Medical Officer Professor Dame Salley Davies by callling it as "ticking time bomb". It surely requires some serious global effort to succeed in resolving the situation

Yes I agree, We also face the same problem, Salmonella in our country is resistant to the first line drugs and even 3rd generation cephalosporins in poor underdeveloped countries we face number of problems specially cost of the drugs

Looking at the whole scenario of antibiotic resistance among pathogens from a different perspective, do we really need to panic so much about it! Isn't that our immune system must also be watching this game carefully and must be preparing itself adequately to take on the challenge!

I would like to invite all the followers of this debate to support the initiatives of "Antibiotic action" at http://antibiotic-action.com/. We need not only know more, but act soon. Emergence of MDR organisms is unavoidable, but their spread has to be controlled. Unfortunately, as acutely Sandora et al wrote on NEJM (http://www.nejm.org/doi/full/10.1056/NEJMp1212370) we know what to do, but this is not easy to be done "even in the most prestigious institutions". Combinations of smarter, more user-friendly and more cost-effective strategies are to be developed and tested. They should also be customized on the local epidemiology. I think also that is very important to translate quickly the mountain of literature about MDR organisms in evidence-based guidelines which should be easily accessible to policymakers (who cannot be quite familiar with the scientific literature and have to make decisions in short times). Finally, as Laura Piddock said, availability of new antibiotics is a part of the solution.

We are still afraid of infections and yet hope to fight them with antibiotics. To seek emerging resistance I think we have to look to the patients to whom prophylaxis is done (hemato/ onco, like my field). We also have to seek necropsy results to asess pathogenicity of strains like fungi and some microbes like CoNS, which can be MDR. I am studying these strains and I look for international cooperation to assess pathogenicity and MDR in my strains coming from blood culture in hemato/onco patients.

Isn't that our immune system must also be watching this game carefully and must be preparing itself adequately to take on the challenge!..... Did we think about self defense (immunity) of our body. You can see people living dirt with good health.......

I recently visited an ICU in a tertiary care hospital where all patients who are put on ventilator are given Piperacillin -tazobactam and voriconazole. their rationale for this use was that psuedomonas and candida are most common infectious agents in their ICU and prophylactic use prevents these infections. That there use will lead to development of resistant bugs was conveniently being ignored under the pretext that culture positivity in our lab is not very high and we do not have access to good quality microbiology laboratory , so we can not wait for the positive culture . The definitions of HAIs are to cumbersome to apply and again need good laboratories and sufficient manpower to put into practice, thus leading to inadvertent use of antibiotics. The need is to develop easily applicable clinical definitions of HAIs and good laboratory support so that a rational antibiotic policy for inpatients becomes acceptable to physicians .

Hi Caterina, I tried to sign in the "Antibiotic Action" web-page. But it does not seem to permit signing in. Any suggestions please.

I think the best is you contact Mrs. Felisha Johnson

[email protected]

Thanks for the suggestion.

We can start preparing our immune systems by producing vaccines against the highly resistant strains i.e. producing vaccines using distinct immunogens extracted from strains resistant to 3rd or 4th generation cephalosporins / carbapenems.

This is not to dismiss the crucial lifesaving qualities of antibiotics--we will have that with us forever no doubt. But we ARE near the "end" of the antibiotic era with nowhere to go until we look up and see that strengthening immunology is where we should be going with our research and practice. Today, the routine and indiscriminate use of antibiotics, remembering we are at the end of tether because no real antibiotics have brought to the scene in such a very long time, are causing as much or more damage than good, to wit:

-A recent study showing damage to heart vasculature as in the case of Z-Pak

-Severe digestive issues (Tetracyclines)

-Pathogen mutation into untreatable forms of fungi, psuedomonas-both gramm negative and positive (Ciprofolaxin)

-Acute otoxicity and neurotoxicity causing deafness, neuropathies (amino glycosides)

-Mutated bacteria from overuse of slow-acting Amox

Only hopped-up, fast acting yet gentle Augmentin in short courses stands out as a champion among laggards. So, yes, we definitely need to be looking at delivery systems for immune boosters like Zinc Picolinate, Vitamin C, short-chained Pectin, Curcumin BCM95, and other gentle but powerful approaches. Just the Black Plagues occurred primarily from weakened immunology on a macro level (from almost universal heavy metal poisoning) rather than viruses, fleas, or rats (the proof of which rests in the immunity of the lead-less jewish villages in the region, which we might use as "controls"). We back up on pervasively high lead levels today and weakened immunology, which begs that science becomes honest and put its focus and resources in strengthening immunology instead of pocketbooks.

Strengthening immunology so that mitochondria--the doctor in every body--can do its job should be where our main resources go. That will require these markers: Cellular pH 7.45, A1C

It is not so meaningful to list adverse effects of antibiotics. Administration of antibiotics such as of any other drug is to be done by balancing favourable vs. adverse effects. That is why it is so important to manage appropriately antibiotics and to warrant a range of therapeutic options. Antibiotics have allowed us for many decades to protect our quality of health and care and to develop sophisticated life-saving treatments, such as organ transplants or cancer chemotherapy. Smarter and eclectic approaches are urgently needed, but we have to multiply our efforts to lengthen survival of the available antibiotics and promote the development of new ones.

Sydney Bush: Are you marketing the tablets?

We have been studying antibiotic resistance in India and China, especially related to drinking water quality and general sanitation.

Two dominant factors appear to define antibiotic resistance at the community scale (in hospitals and elsewhere) for bacterial strains that can be transmitted through water. The first is over self-prescription on antibiotics for treating minor medical problems (e.g., quinolones in urban India). This is clearly a stewardship issue; however, the solution to this problem is social and should center on convincing individuals that it is not necessary to use such important drugs for minor ailments. This is not a hospital or prescriptive use problem

However, the scale of the impact of over-self-prescription is amplified by chronically poor urban sanitation. If one group of people overuse antibiotics and others in their society drink waters directly impacted by wastes, you get an increasing spiral in antibiotic resistance. Overuse fuels AR, but poor water quality fuels overuse.

Stewardship alone will not solve the problem because much of most serious forms of AR are exported by personal air transport from areas with water poor quality. Therefore, both stewardship and improved water quality must be combined to reduce AR at the largest scales.

Sanjeev, thank you for your comments. As stated above, the crucial importance of antibiotics (in the treatment) for acute infection will be with us essentially as long as man exists. I note your studies on mycosis, extremely valuable. We have so little defense in public health today for the fast-rising emergence of mycosis that our oral antifungals, antiprotozoans, antibiotics, sulfa drugs, etc. are admittedly very dangerous approximations of any therapeutic value and highly ineffective. I once asked one of my pharmaceutical students (who was a scientist for a pharmaceutical) why they were not approaching these issues as strongly in terms of research dollars as the far more questionable and less needed or effetive areas of amyloid plaque modeled drugs (for dementias) and the SSRIs antidepressants. Their answer was that there was far less money in it or market. I was stunned. We have pervasive and fast growing mutated forms of bacterial/fungi etc. pathogens and there is not enough market for it?

Now to the larger question as the one for this blog, that of the pre-antibiotic era; my reply is that we are in danger of going there because the adapation, mutation, overuse (as D. Graham ably mentioned above--and overuse is from both professional and consumer instigation), and toxicity issues (I am profoundly deaf today because of unwise prescribing of oral aminoglycosides by my doctors many decades ago who virtually destroyed my cochlear hearing while a young child). There are limits, as we all know, to the allopathic approach of killing the pathogen while ignoring immunogical sensivities. In the US, more than anywhere I've traveled in my research and lecture work, is in my opinion by far guilty of overuse of antibiotics and have driven common OME in children, for instance, which arose from increased childhood allergy than infection, into immunological crisis where it need not be. Using proliferate Cipro for just about everything that smacks of nuemococcus or areus has further created entrenched pathogenic crises in the ENT field (most of this NOT by the ENTs but by general practice and of course self-medicating).

These and more are challenges that we all (hopefully) recognize. Without a near-crash program into better delivery, better ways of matching antigens with antibodies, better ways of strengthenin immunology, softening the immunological devastation that comes from most of the more recent antiobiotic/anti-everything delivery systems, we will have more and more public health crises. Sydney raised the question of immunology through more natural approaches. I visited with one of Dr. Pauling's assistants some years ago where she shared the transformation of his work when he connected the immunological responses of Vitamin C, and later turned his attention to what constituted Vitamin C, realizing that some of his earlier hypotheses were wrong or limited when he discovered the universe of immunology, dna, etc. If he was alive today he would be creating the delivery systems and providing the intellectual and scientific foundation to how we approach disease control...because of recent discorveries in the role and capability of mitochondria, preservation of telomeres, and healing. We get off the health management kick and more toward a healing kick. Not as much money in it, admittedly, but the health of the world's population would advance and many problems resolved. Thank you for the discussion.

Caterina, in my feeling we are not articulating enough in medical education the research that uncovers the true trade-offs when using anitbiotic therapies. I teach MDs as well as PhDs and find that until we share the current research (like that re Z-Pak and blood vessel thickeing) many errors are made in prescribing and in adjudging tradeoffs. I am totally deaf today because of the ignorance of an entire field medicine to the ototoxic effects of long course aminoglycosides precribed for my repeated strep infections as a child, when ordinary pencillin in that day worked fine. That overshoot in judgment has rendered many more than me deaf, damaged kidneys, neuropathies, etc. that did not have to happen. So getting research to practice in short order is of absolute crucial importance. Likewise, our research shows that the current approach to pain (shooting the messenger as we do in the US) management is leading to other more serious disease. So again, under many venues of disease, medical practice departs from the knowledge base at the research level. The amyloid plaque theory which dominates pharmacologic treatment of dementia is another that is about as far off base as anything when we take the larger (objective) picture into account. But I do thank you for your input and respectfully appreciate the opportunity to respond. Thank you.

Thank you, Max. I agree about overuse/misuse of antibiotics and the poor awareness of many physicians about the absolute need of using (or no using) antimicrobials appropriately. In your case, for example, there was not the antimicrobial therapy the problem, but the right antibiotic. Strep infections, such as many other bacterial infections, are surely more hazardous for our health than the right antibiotic.

Sydney Bush: Thank you for your detailed reply. In regards to ascorbic acid; I use it to make cheese. Once upon a time I ran out of citric acid and found that high quality product substitution did not affect the taste. Consequently I kept buying it locally. Making cheese is just a hobby, and I do not consume vast quantities. I compensate for this with a blend of fresh chili peppers, guavas, dark leafy greens and other foods I grow in my yard.

I also make my own penicillin. Believe it or not, that funky looking blue mold on that deli salami you bought is none other than the best! Most people peel that off their salami in disgust and toss it in the trash. Take that rind and keep it. Take a paring knife to it and scrape the mold off the peel and place it in a plastic container. Leave a piece of the meat in there with it to keep it alive. Puncture a small hole in the bottle so air can get in because penicillin is an aerobic bacteria, which means it needs air. That way, even after it eats up the meat and lies dormant, you will be able to revive the spores anytime you want by placing a small portion of it in with some more cured meal or damp bread or old cantaloupe, which is one of this particular mold's favorite foods.

Always remember, even dead penicillin is good stuff. Never throw it out. It could save your life or the life of someone you love. Antibiotics are going to become as valuable as gold and as rare as chicken lips, so you'll have the market cornered.

Just noticed your outstanding and voluminous work, Caterina! Phenomenal. We are faced with overuse on a lot of things in the United States as a result of defensive medicine (horrendous cost of professional liability insurance, endless unnecessary tests, overprescribing of meds due to consumer demand, etc.), challenges you may not have in Europe. This has posed issues over here that at some time the future with which we are going to come to grips. Congratulations again on your outstanding work!

Thank you, Max. Unfortunately, defensive medicine is producing its adverse effects here also. I agree with you about the unfavourable consequences of this approach in terms of unnecessary antibacterial drug treatments. Maybe restrictive policies on antibiotic use can limit to some extent the risk, but they are not so easy to apply. As someone in this blog has highlighted, there is not an adequate and updated education about this issue in the medical schools and the physicians who are now working in all healthcare settings and community are generally poorly aware of the peculiar properties of antibiotics as "social" drugs. Thank you again.

Hello, One of the remedy for this problem could be use of sterile medicinal maggots. Medicinal maggots were used widely for soldiers to treat non healing wounds. After emergence of antibiotics, use of maggots as therapy declined, but last two decades involved in scientific study of medicinal maggots. A clinical study in 2007 established their use as one of the best therapy to combat wounds and heal diabetic foot.

Sydney Bush: Just because one person thinks conspiracy theories are interesting doesn't make your data more valuable, especially if the voter has a low score as well. As a matter of fact, if the person has a negative record it could have a negative effect on your total score.

The antibiotic use must be strictly regulated. Proper rules must be put in place to ensure that the antibiotics are sold by the pharmacies only upon doctor's prescription to stop self medication. Self medication is common in many places and could be a significant contributor to the AR problem.

Also, the medical school curriculum must contain adequate and up-to-date content on the science and application of antibiotics. In my opinion, unless untill it is absolutely necessary (in the light of severiety of infection, condition of the patient etc.), antibiotics should not be used as a first hand choice. As most of us are aware, the best pharmacy is our own body, which produces n-number of novel substances and therapeutics which cure and heal our ailments on regular basis. Therefore, the "pharmacy" of human body should be given an opportunity to respond to an infection or an health condition first before any external intervention, which should be undertaken only when it becomes absolutely unavoidable.

I agree with Ashok. The exception to the body's ability to produce the immunologic corrections to environmental assaults is when the assualt is in the form of an implanted prosthesis. Wherever there is a prosthesis of any kind in the body, immunology is interrupted, septic or dead debris gathers, and inflammation may occur. That is the reason that those with prosthetic joints are routinely expected to take a short course of antibiotics before dental work is performed. Lost in the discussion, however, is that same short of antibiotics (I suggest Augmentin rather than slow-acting Amox in such cases) needs to be prescribed periodically in prophylactic fashion to avoid inflammatory reactions in the body (cortical depression, rhuematoid, generalized pain or stiffness) at least once a quarter, depending on one's immunology. In doing so in fast-acting short course fashion the patient is less apt to develop antibiotic resistant strains of bacteria, and inflammatory illness (the most common cause of chronic disease) is minimized. The two week courses we see now from many physicians in prosthetic cases, using slow-acting antibiotics (Amox, Keflex, Z-Pac) are counter-productive and ultimately lead to antibiotic resistance and increased disease states.

I think the emphasis should be on how to reduce antibiotic resistance. This can be done by the proper use of antibiotics on the part of patients. Education on the issue also needs to be intensified while allowance will be made for the gene mutations which lead to resistance.

Microbially-synthesized or plant-synthesized natural antimicrobial peptides are the solution to the scourge of antibiotic resistance in this generation. These natural peptides have specific activity against selected pathogens and the pathogens cant acquire resistance against them since they are normal metabolites. A lot of novel antimicrobial peptides are being discovered now with activity against pathogens such as Streptococcus salivarus which causes halitosis and Helicobacter species.

No-one seems to have mentioned the tremendous amount of work going on around the world to develop new antibiotics and modify existing antibiotics to overcome resistance. Resistance is undeniably a huge problem and yes, we must improve our handling of antibiotic administration and exposure, but there are some very exciting developments in the antibiotic pipeline - you just have to attend an ICAAC meeting to be impressed by the number and diversity of approaches being actively investigated with very encouraging results (a Pubmed search for "novel antibiotic" brings up 7300 papers in the last 5 years!). Personally, I have faith that the ingenuity and endeavors of the antimicrobial pharmaceutical industry and academic research groups working in this area will keep the doomsday scenarios at bay.

Thanks Jeff for introducing a new aspect to this ongoing debate. Indeed the efforts around the globe to develop new antibiotics is surely important and critical to addressing the AR resisitance problem.

Sanjeev, I think you will be surprised; there are several new antibiotics in Phase III trials close to being released. Also, since the hazards of antibiotic resistance have been widely debated in medical circles and the lay press for decades, you can hardly say anyone was caught napping! Unfortunately, getting a new drug to market is extraordinarily expensive and difficult, and not always successful in the long term (e.g. telithromycin). The ability of microorganisms to become resistant to new classes of antimicrobials means we are always going to be on the back foot - but scientific ingenuity and medical research can accomplish much!

I am always for innovative approaches in antimicrobials. Most of the ones we have seen in our clinic in recent years have been seriously toxic and cause far too many undesireable effects (particularly in the new sulfas and cipros). But I do appreciate Jeff's input in the current efforts under such difficult circumstances. Balancing benefit to cost present insurmountable challenges it seems. A more positive direction for today, in my feeling, is making sure we recognize that it is primarily weakened immunology that allows pathogens to overwhelm the human body--strong immunology provides profoundly greater immunity that weakened immunity. In other words, how to do we address the threats to human immunological defense mechanisms so that the need for antibiotics is not so crucial? In our own family, we have severely restricted exposure to antibiotics during our children's lifetimes, opting instead to boost their immunity with zinc picolinate (this, to them, is an antibiotic), vitamin C, and organic B-complex--chelating for heavy metals (not IV). They and their children have never had a flu shot and are rarely sick with anything, in spite of the fact that those around them seem to succumb in droves to every fluvirus that comes down the pike. They do not microwave their food, and they avoid GMOs at every opportunity. This is a subject for serious discussion that could take a lot of pressure and expense off the antibiotic side of the equation.

I strongly disagree about thinking our immune system will save our lives from the attack of MDR organisms without effective antibiotics. All of us will become elderly (we hope...) and our immune system will be naturally ineffective. Moreover, the likelihood we will start a trip into the healthcare system network (hospitals, LTCFs, home care) will increase more and more. What about surgery or artroplastic or...without effective antibiotics? At the opposite end, what about preterm infants in NICU without effective antibiotics? Yes, there is a lot of complementary approaches, such as lactoferrin, probiotics, vitamins, but today to combat a clinical infection we need antibiotics and, if our organism is an MDR, our battle is often lost before starting. We have to fight antibiotic resistance by a judicious use of the antibiotics we still have and prevent/control emergence and transmission of MDR.

Did you read an issue of the Economist (yes, the Economist, not an epidemiology or microbiology journal) about antibiotic resistance which said: "Ignorant humans, smart microbes"? Well, we have to invert this sentence.

Caterina, I am not proposing that immunology replace the need for better antibiotic therapies at all. I apologize if that is the impression. The propensity toward strong medicines is so robust in scientific efforts compared to the effort in immunology that can strengthen the population's resistance to disease that I suppose that is why I speak more in that direction. In the US we are faced with epidemics of diabetes mellitus 2, CVD, and cancer--in my view because we are a population that is falling in cellular pH and stressed immunology. In your research, for instance, in anti-inflammatory (vs proinflammatory) cytokine activity to cancer cell growth--what a marvelous world inside the human body that it can deliver such powerful and sure defenses to such a threatening abnormality. To my thinking we need both tracks equally--human immunology and its relationship to changes in food supply, nutrition, heavy metals, dehyrdration, and resistance to disease, as well as the deepening quest for stronger and more effective antimicrobials. My family is a good example of the former--an effort that we see so little of in the general population. I hope you see the need for balance in our approach to human disease. That is the side my work in which my work is primarily is involved with outstanding results. Meanwhile, the effort on the other side of the equation must go on, as well. I only caution concern for safety and immunological efficacy.

PS- at 65 I am probably in that "elderly" category you spoke of and my personal quest is ever a strong immune system to resist all that I see happening to my fellow humans (smile).

Max, I agree about balancing our views. About PS, age as a risk factor is not a demographic variable...

Of course, my work is in chronic disease and prevention, and many of those on this question seem to be in acute medicine, hence, the diversion of perspectives. We need both to benefit the most people, obviously, and please know that I appreciate yours and their work.

I think Max has put forward the view very well about having a balanced approach to therapy, stronger medicines vis-a-vis proper health management like boosting immune system etc. Modern medicine has primarily focused on understanding the diseases, their etiology, transmission etc and how to check the symptoms of the disease from expressing. In other words, it has been a science of disease and NOT a science of health. If we follow the science of health, we will understand it better how to keep the body disease free and healthy. The ancient systems of medicine, which we now call as Alternative medicine, were more focused on learning and understanding the concepts of health, ways and means to neutralize those factors which adversely impact health and make people sick. But in current times a comprehensive and holistic approach appears to be the need, where the adverse effects and outcomes of improper application and use of drugs can be minimized and the normal state of health is restored through application of evidence-based alternative therapies.

Thank you, Ashtok. Astute observations, and ones I hope the various interests will recognize. Thank you again.

Caterina, you are right as in the event of an MDR attack, we can not just entirely depend on the immunity of the patient to fight it back. It has to be attacked with an effective antibiotic and more so in elderly and immuno-compromised people. However, one of the main points of this ongoing discussion is how to reduce the emergence of antibiotic resistance in common pathogens? This debate has highlighted many reasons for the emergence of AR. May be we can address these issues collectively and may probably submitting a recommendation to WHO in this regard, which might help.

I would like to suggest you a very interesting perspective on NEJM January 2013. It shows a series of new interventions to address the antibiotic resistance crisis. It is possible the persons who participate to this discussion know it, but anyway I am attaching the file. What do you think about?

Max, thanks for your opinion and comments. It has been put together very well.

Caterina, this is a wonderful article. Many thanks for sending the file. It has talked about everything and much more that has emerged during this debate.The table is very very informative and useful. The last line stating that "new approaches, based on a reconceptualization of the nature of resistance, disease and prevention, are needed" is remarkably true and deserves full attention of the scientific community. Thanks again.

This a great discussion. Thanks for the article Caterina. I think there is still a lot that we have to learn from nature about engaging in microbial warfare. I think that we should try to develop non-natural antimicrobials - as opposed to naturally-evolved (and co-evolved with resistance genes) antibiotic drugs - that have better specificity for the exact pathogenic strain we wish to hit with a given treatment. For instance, bacteriocins are able to bind membrane receptors with exquisite specificity and kill target cells accordingly without hurting the rest of the bacterial community in a sample. Also, the hydrophobic/amphipathic yet promiscuous nature of some MDR efflux pumps speaks to the fact that our crude approach to drug import (passive diffusion of hydrophobic/lipophilic drugs accross the various permeability barriers of bacterial cells) needs rethinking. I personally think if we could hijack more specific (yet still essential) import pathways to efficiently bring in hydrophilic drugs we'd stand a better chance of avoiding efflux resistance mechanisms. Finally, ribosomal non-natural amino-acid/peptide synthesis together with in-vitro display (ribosome, mRNA display)-based selection and screening of leads could also allow us to play catch up with Nature and evolve in a test tube and using a virtually unlimited supply of building blocks in a few days what it's taken nature eons to evolve using the 20 (or 22) naturally-occuring amino acids.

Yes, I agree, Sydney, we have endless examples of pharmaceutical cover-ups--from cancer treatments that were promptly banned because they worked (who was that Italian Oncologist in the 1930s who demonstrated that simple injections of sodium bicarbonate into tumors would shrink them in a short time and when presented to a Harvard Medical School audience was promptly banned from having a US Visa? or the Physician husband and wife in the early 1970s (Portland, Oregon, I believe) that were promptly shut down by the newly formed FDA because their highly successful Laetrille treatment for certain skin cancers was a threat to US pharmaceuticals--now, available just about everywhere in the world but not in the "enlightened" United States, the list goes on and on and on). Ever it be that innocuous, low risk approaches to serious disease are banned outright and garner total disinterest from the investors of medical solutions while medications that render tens of thousands of emergency room visits and attributable deaths are protected by the same agencies that were ommissioned to be interested in the safety and efficacy of medications. The truth of such matters is on record everywhere and extant. One would hope that those who are researchers are interested only in the truth not in bias and vested interests. But your are right and we need to bring these to light to bring us out of the dark ages of medicine and health before we are all doomed down the road buttressed by false models and biased research.

Yes, it was Simoncini. I remember reading a transcript of a speech on that experience when I was working on my Cellular pH Model some years ago--we determined the pH level required for the environment at which cancer cells would grow (6.8--but in some individuals, as high as 7.0)--but in all cases cancer would only grow in acidosis state bodies--so one has to ask, "Then why isn't cancer research making a beeline to the pH hypothesis?" As a friend of mine who was manager of an oncology research unit said a few years back when I was discussing this with him, "If we went there, our funding would dry up in a heartbeat." Now, this all seems off topic to the question at hand, but in spite of the enormous amount of sophisticated research going on (the Manhatten Project of (fill in the blank: antibiotics, cancer, diabetes, etc.) we have to ask where are the brave souls who march to the drummer of objectivity? If a billion (US) dollars is spent to research a drug that will present more long-term harm to the population than benefit and a measley $50,000 spent on non-drug approach which poses little if any risks and enormous benefit, should there be an automatic difference in the validity of the data or findings? The former drugs are tied up in uncountable lawsuits from harmed individuals and groups; the latter goes years at a time without a single lawsuit.

On the Simoncini topic, a perusal of the Internet finds two kinds of treatment of this topic:

http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/herbsvitaminsandminerals/sodium-bicarbonate

http://www.bibliotecapleyades.net/salud/salud_defeatcancer17.htm

The first is the American Cancer Society's treatment, which is devoid of any information but what they could glean from the Internet--no hard research to refute his claims, not a single study. The latter a more detailed treatment of the topic, and painting the larger picture to which you alluded above (oxygen deprivation). If indeed acid state (low pH) and oxygen deprivation are implicated in cancer and in infections in general, reason begs the question: Why isn't the hard research going there?

I think that all the participants to this multidisciplinary debate could prepare a brief draft of their contribution. Maybe we could elaborate a document to be published on this site or a true paper to be submitted to a journal. There are many different options. What's your opinion?

Caterina, I agree with you. An elaborate document should be prepared and published. It would certainly serve the purpose well.

Good question!

I do not think that we are drifting towards pre-antibiotic era in view of fast developing antibiotic resistance in pathogens against the current antibiotics, but I think we will be focussing more on research to find the ways to avoid antibiotic resistance, and to overcome resistance.

Surely, ways to avoid emergence and spread of antibiotic resistance in new pathogens and to overcome the MDR issue must be the focus research, which may produce results i future, but the real time scenario is not so good and poses a serious challenge.

Further, its heartening to see that there is great deal of enthusiasm about conducting unbiased research and not ignoring such findings which look simple but offer great opportunities to cheaper, more dependable and less injurious (to patients) therapies and treatments. There is no doubt that vested financial and business interests have driven drug development efforts that often ignore patient care issues and adverse consequences over long term use/misuse of such drugs.

I think Caterina's idea to put our thoughts down on paper might be helpful and useful.

I thought its about time to summarize the opinion of the esteemed scientists and professionals from around the world on the issue of antibiotic resistance under discussion for quite some time on this site.

1. The antibiotic genes and the resistance genes have co-evolved and co-exhisted among the microbes during their struggle for exhistance since billions of years. Accordingly, emergence of resistance in a population of microbes is a quite natural response when they are continuously asaulted with antibiotics aimed at killing them.

2. The ill-conceived human intervention in dealing with infectious diseases of humans, animals, and plants with rampant application of antibiotics have only accelerated the emergence of resistance among the pathogens. This has assumed alarming situation in respect of certain pathogens as highlighted by Caterina and others earlier.

3. We may not be drifting towards pre-antibiotic era (D. Graham / Jeff Keelan) due to our current understanding of the subject, but we are certainly not well prepared to deal with this issue effectively right now (Andrew Morris / Satya Sarkar).

4. The way out from this is: (i). Non-human use of antibiotics should stop, (i) Proper hygein and sanitation practices to be put in place to prevent spread through water and food, (iii) extensive education and training to healthcare workers, medical graduates and doctors to strict adherance to the pracuces of antimicroial stewardship, (iv) programs to creat awareness in public to ckeck antibiotic misuse, (v) Antibiotic should not be avoided as first line of treatment as far as possible, (vi) Non-injurous non-toxic approaches as practiced by some systems of medicines (of course only those which have strong evidence of effectiveness and usefulness) should be adopted as a first step in dealing with the diseses. This may include use of substances that are known to strengthen immune system as advocated by Max Chartrand earlier, (vii) Non-antibiotic antimicrobial substances, such as, ascorbate as imphasized by Sydney Bush should be explored, developed and used, (viii) Inspite of all this, we would still need antibiotics to save life, there is no denying to that. So the new generation or the novel antibiotics must be developed based on our understanding of the mechanism of resistance (Laura Piddock can guide us here) so that the new antibiotics are not affected by the resistance pathways and also they should be such that the microbes find it difficult to develop resistance against.

I would like to invite comments and criticism from the participants of this discussion in an attempt to evolve a global consensus from the very best in the field for dealing with the threat of emergence of antibotic resistance in pathogens.

Excellent summary, Ashok! You brought into one comment the highlights of each of us, I believe. We do have crises around us now, as evidenced by the CDC's constant vigilance in documenting antibiotic resistant strains of staph, and the microbial cousins in amoeba, protozoa, and other microbes that seem to be developing almost exclusively in our nation's hospitals. In my research and subsequent models of behavior therefrom, I have long noted specific public health trends that are fostering much of what we see today: declining cellular pH, reduction in cellular oxygen (and hemoglobin), growth of certain microbes (anaerobic psuedomonas, for example) as a result of this--and still largely unrecognized and undiagnosed at the PCP level.

Education is the key here, as well as research: How do raise the population's cellular pH and oxygen (as migh be measured on the A1C score), reduce inflammation (as measured on the Gelactin-3 test), and help make human immune systems stronger rather than weaker. I have very specific ideas on all of this, and we espouse them generously in our multipdiscipliary practice, but we also note a general lack of enthusiasm among health professionals to promote what we see as the only hope of turning back the tide of clearly declining health in advanced nations. Diabetes mellitus, for instance, is on the rise everywhere, as is cancers of all types, CVD--all sharing similar pH sensitive pathophysiological pathways. Getting to stronger albeit more toxic antibiotics may not be as necessary if we can everyone on the same immunological page.

Max, thanks for your complement and observations. Immune system is a key component in health and disease. Therefore, it should receive due consideration by the Physicians diagnosis and treatment of diseases. Have you made any specific observation about change in cellular pH, oxygen concentration, and inflammation markers in an event of microbial infection? If so, is there any specific relationship? Any reference will be greatly appreciated.