The incorrigible bugs

With current antibiotics losing (or having already lost) their effectiveness against common and serious pathogens, and problems like lack of awareness and over the counter availability of antibiotics looming over our heads, alarm bells have started shrieking. Aashruti Kak discusses how this disturbing development is resisting the industry's resolve to treat and eradicate the 'superbugs'

As soon as the next generation of antibiotics were developed to overcome problems of resistance against available antibiotics, bacteria displayed their creativity by developing new mechanisms to evade the newer antibacterials as well. Once curable diseases are becoming difficult to treat, and other already killing diseases are conveniently strengthening their protection gear in the form of evolving resistance. Years ago the scientific community found a 'miracle drug', penicillin, and decades later, it seems that we are still looking for it.

Emerging pathogens

For many years, antibiotic resistance has been largely seen in hospital-acquired infections. Highly resistant isolates of bacteria such as Staphylococcus aureus, Enterococci, Enterobacter, Pseudomonas, penicillin-resistant Streptococcus pneumoniae (PRSP), Clostridium difficile and Acinetobacter are becoming even more prevalent in hospitals. Methicillin-resistant Staphylococcus aureus (MRSA) is the leading 'bad bug' globally. Increasingly, community-acquired infections are also showing resistance (e.g, PRSP, MRSA).

"Basic pathogens are classified into gram negative and gram positive. The gram positive ones are Staphylococcus aureus, which is vancomycin resistant. Sometimes we have Enterococci in the gram positive, which may be also resistant to vancomycin (Vancomycin Resistant Enterococcus-VRE), and is not so common in India," says Dr Khusrav Bajan, Consulting Physician and Intensivist, Hinduja Hospital.

"In gram negative, which is our main problem, we have ESBLs (Extended Spectrum Beta Lactamases), the common ones being Kiebsiella and Escherichia coli, which are resistant to almost every antibiotic and require very strong treatment with carbapenems," he adds. Another one is a multi drug resistant (MDR) gram negative bacterium, usually Pseudomonas. He continues, "For Pseudomonas you need antibiotics like colistin (cheap antibiotic, but only one that is effective against MDR gram negative bacteria) as they are also resistant to carbapenems."

What triggers the resistance?

"When we speak about resistance, we mean selection pressure," says Bajan. When a lot of antibiotics have been under use/misuse for a long time, they select out the defenceless bacteria and leave behind the resistant strain. These bacteria multiply million times a day and become very predominant. Bajan gives an example. When 20 years ago ciprofloxacin or quinolones came into the market, they were used for every patient of Pseudomonas across hospitals, clinics, etc. And that led to resistance of Pseudomonas to quinolones, after which, only ceftazidime could be used for the next five to seven years. Later, one could not even get ceftazidime sensitivity, and therefore, we grew ESBL.

There are three to four mechanisms through which a microbe becomes resistant to antibiotics. The first one is through intrinsic resistance where the drug becomes impermeable. The second mechanism is due to alteration in the target molecules. "The drug alters the entry channel (called porins) into the microbe from where the antibiotic is supposed to enter. Hence, the next time the antibiotic is administered, it will not be able to enter through the porins and the microbe will become resistant," explains Bajan. In the third mechanism, the antibiotic is rejected by the microbe through the formation of enzymes (beta lactamase) like production of penicillinase in bacteria, which will make the microbe resistant to penicillin. Bajan continues, "The fourth mechanism is through efflux, in which the antibiotic enters the porins, there is no production of any enzyme, unlike the second mechanism, but the antibiotic is pushed out through the same porin the moment it enters."

Each pathogen has a different drug. "For Staphylococcus aureus, if vancomycin is not effective we can use drugs like teicoplanin (marketed by Sanofi-Aventis under the trade name Targocid) and linezolid (marketed under the trade name Zyvox by Pfizer). Same appears for Enterococci." He continues, "For ESBLs you need to use a carbapenem--imipenem or meropenem. If it's not a very severe infection we can also sometimes use a combination of a beta-lactam antibiotic and a beta-lactamase inhibitor (BL+BLI). The available combinations are cephalosporin with tazobactam or sulbactam." Cefoperazone and sulbactam or piperacillin and tazobactam (marketed by Wyeth under the trade name Tazocin or Zosyn), and ticarcillin and clavulanic acid (marketed by GalxoSmithKline under the trade name Timentin) are some other common combinations that can be used. "But in severe life threatening ESBLs you would need to use a carbapenem at the first shot because about 50 percent of the ESBLs are resistant to the above mentioned combinations," says Bajan.

"The major cause of pathogens to become resistant is heavy reliance on few drugs as treatment, which naturally led to continuous use of the similar class of drugs, for example beta-lactam antibiotics (penicillin, methicillin), glycopeptide antibiotics (vancomycin, teichoplanin)," says Dr Somesh Sharma, Chief Scientific Officer, Nicholas Piramal India (NPIL). "The drugs developed in the course of time involved were mostly the second or third generation of the earlier molecules (e.g.cephalosporin analogues, glycopeptides)," he says. Other available drugs for such resistant bacteria are daptomycin (Cubist Pharma) and tigecycline (Wyeth Labs). However, resistance has been now also been reported for Linezolid, as well as daptomycin. Other than the above mentioned factors, resistance is further encouraged by lack of education, use of antibiotics in agriculture (as resistant bacteria may be found in the flesh of animals and on fruits and vegetables), certain environmental factors (natural production in soil and fresh water), usage in household cleaning products, etc.

Lethal remedies

To devise strategies and new innovations, one needs to really know what one is fighting against. Sadly, it seems that most pharma companies find it very difficult to deviate their attention from profits, to making the right scientific combinations of antibacterials. "Now-a-days, we have combinations for these indications coming out every now and then, which make no sense. I would really implore the pharma industry not to bring out illogical combinations," says Bajan. He elaborates, "Sometimes what they do is combine any beta-lactam and a beta-lactamase inhibitor group and make a combination which is very dangerous. Because many of the beta-lactams have a 12 hour life span and the beta-lactamase inhibitors have a six hour life span/duration of action, they cannot be combined. It is wrong to combine them." According to him, there should be a scientific combination. "Unfortunately, the wrong combinations are being used by most of the doctors because they have been marketed in such a way. A very small example is of ceftriaxone with sulbactum. Sulbactum has six hour duration of action and ceftriaxone has 12-24 hours duration of action, so ideally, it should not be combined. It is such prevalence of incorrect combinations that also leads to resistance," he says. "Do not make a product which is meant for resistant organisms readily available to the general practitioner so that they can misuse it," he adds.

Faltering pace?

The first class of antibiotic, based on enzymatic activity, was followed in 1944 by a second one, composed mainly of amino acids--the peptide antibiotics, says Sharma. In the meantime, several other classes have followed, namely, methicillins, vancomycins, aminoglycosides, macrolides, cephalosporins, quinolones, lipopeptides, glycopeptides, etc. "They are all based on a mere 15 compounds, such as the beta-lactams, to which penicillin and the cephalosporins belong. All currently used antibiotics were introduced between 1940 and 1962. After a gap of 38 years, the new class of oxazolidinones followed in 2000, trailed by daptomycin in 2003, and the very recent tigecycline in 2005," he says.

Bajan feels that there definitely is enough research happening, but it's still not good enough to outsmart the bugs. "In the last 50 years there have hardly been four new compounds of antibiotics that have been developed or invented. All the others are hovering around them. It's a very stagnant output and the bugs are becoming smarter and smarter," he says. Sharma presents the other side of the coin, "Companies working in antibiotic discovery do come up with one or two drugable antibiotic candidates per year which could be taken ahead for development." However, he says, it is the trend of final US-FDA approvals of the antibacterial agents that is to be blamed. (Figure 1) "The plethora of discovery programmes initiated in the post genomic and combinatorial chemistry period have failed to lead to an easy or rapid source of such new antibacterials. The most logical way to accept development of a drug that is less likely than other antibiotics to develop resistance is to search for new scaffolds, which the microbes are hardly exposed to," he says.

For instance, Sharma explains that NPIL has always returned to natural sources (microbial and plants) as source of new scaffolds to overcome resistance problems. He says, "We are one of few industrial R&D organisations that have a collection of about 40,000 microbes (actinomycetes, myxobacteria and fungi) from diverse sources in India, as well as about 5,600 plant extracts representing rich flora and fauna of India." He further says that the microbial sources are pursued further in different ways so as to yield different metabolites. This approach has been successful in terms of the isolation of very potent antibacterial and antifungal agents.

Their strategic collaborations with CSIR laboratories such as National Institute of Oceanography (NIO) and Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, have also helped in providing additional resources. "We have one potent anti-gram positive drug (PM181104) especially active against all kinds of MRSAs and VREs at nanogram level. We discovered this antibiotic from a marine bacterium, which was obtained from sponge. This was carried out in collaboration with National Institute of Oceanography (NIO). Further, we have strong pipeline of potent antibacterial and antifungals, which are acting against resistant bacteria and fungi respectively," he adds. India, owing to the large variations in climatic conditions and geographical extremes, is a rich source of diverse bacteria. Hence, one of the best ways to access this diverse micro flora is to collaborate with DBT labs, which are well skilled and close to such microbial resources. Sharma says, "Our collaborations with NIO have already proven that our natural product approach is successful in discovering biologically active molecules from bacteria. Also we are well equipped with anti-infective discovery, its scaling up and development." Bajan concurs, "Collaborations are always welcome as each one will have his own views. And we need much more research and scientific background to discover new molecules, because every time we find one molecule, for the next 10-15 years we are just trying to make more and more products from them." Other molecules which are in very late phase of development are Oscient Pharmaceuticals' gemifloxacin, Replidyne's faropenem, Peninsula Pharmaceuticals' doripenem and Intermune's oritavancin.

Market woes

The global anti-infective market is currently valued at $66.5 billion, with antibacterial agents accounting for over 50 percent of sales, says Sharma. "The antibacterial market is set to grow to over $45 billion by 2012, driven by newer antibacterial agents such as glycopeptides and carbapenems, which demonstrate resistance to MRSA and VRE, as well as other emerging strains," he adds. It was once felt that Big Pharma is really going away from antibiotic due to the attractiveness of chronic therapy, and that antibacterial drug discovery has declined in many large pharmaceutical companies, shifting to small pharma companies in the process. However, Sharma says, some giants like Merck are again 'in' antibiotic seriously. Pfizer's acquisition of Vircuron's dalbavancin and Johnson & Johnson investment in both doripenem and ceftobipole brings much needed investment to the antibacterial sector and a commitment to combating serious hospital infections. "The antibacterial market is huge and rising, but is not as speedy as other sectors. Now, especially after 2002, the problem of resistant bacteria has become more aggressive, and the market seems to be accelerating in comparison to the last decade," he says.

Preserving effectiveness

To overcome the problem of resistance, there should be more antibiotics in the market with similar potency so that the physician would have a choice instead of recommending only few antibiotics over the years. "The potent antibiotics developed for harmful bugs like MRSA, PRSP should not be considered for development as OTC ointment for general antiseptic use and their use should be tightly controlled by dispensing only through prescription written by physicians," says Sharma. He also says that a curative, prophylactic and leisure use of such ointments may support prevalence of resistance in bugs, which may hinder further parenteral use of such a drug.

Reducing, or better, eradicating the overuse or misuse of the antibiotics, can really help in countering such infections. "If we give antibiotics for more than the days indicated, it will lead to the overuse or the misuse of antibiotics. Unfortunately, most of the fever cases that we get after being to the general practitioners or family doctors treating them are always given a quinolone, and that increases the chance of an ESBL drastically," says Bajan. Hence, it is best to avoid using quinolone for every infection as OTC and prescription. Bajan says that there are certain antibiotic policies/techniques that can help in tackling antibiotic resistance. One such way is through de-escalation therapy. "If we do not have the correct microbe, we make a wild guess from the patient's condition and hit these patients hard with the strongest antibiotics. So we might start with a carbapenem or with a gram positive coverage like vancomycin, and then two or three days down the line when the culture comes in and you find out that it is not a very bad bug, then you can hit it with something cheaper and smaller and de-escalate by slowly bringing down the therapy. If you give a very small antibiotic in the beginning then the bug may become more resistant," says Bajan. The other technique that can be used is rotation or cycling of antibiotics. "Every one month or two you may change the use of an antibiotic in your ICU. But there is no evidence to prove that cycling of antibiotics helps," he adds.

Also, it is not right to price antibiotics too low as well. They should be a bit exotic in some way because they should be used only by patients who need them, otherwise more diverse bacteria will be exposed to antibiotics. If people start using carbapenems in their clinics and start giving injections and asking them to come back the next day, that is going to worsen the situation immensely. The cost issues are not too bad as far as antibiotics are concerned. "Obviously, the notion that the most expensive antibiotic is the best and most effective, does not hold true at all. They should only be encouraged to be used with the correct knowledge of microbes," says Bajan. He adds that doctors should know the anti-biogram in their hospitals or local possibilities of resistance patterns, and then, accordingly, use the antibiotics, because the same microbe may have a different sensitivity pattern in different hospitals. "The most expensive antibiotic, according to me, is that antibiotic which does not save a life," he says.

Realising objectives

There has been considerable disappointment over the failure of genomics and high-throughput screening to produce the breakthroughs they were expected to deliver, but the antibacterial R&D business is showing signs of rejuvenation, both because of medical necessity and business opportunity, says Sharma. "The steady rise of antibiotic resistant pathogens is dictating a need for new products, and hence, this therapeutic category is ripe for true breakthrough products. Since there are too many varieties of resistant bacteria and fungi that would be taken care by single antibacterial or antifungal, the demand for specific categories of antibiotics would always continue," he adds.

According to Sharma, one way to keep close watch on this development could be to study periodically hospital derived bacteria and fungi for resistance soon after the new antibiotic has been launched. Also, as alluded to previously, they should be dispensed only by prescription from a qualified physician. Self-medication of antibiotics should not be allowed. Bajan adds, "Also, there should be more seminars and programmes propagating awareness and education amongst the doctors and patients on a massive scale. Bugs are always smarter; they have been there since amoeba's age, so eventually, they will succeed in outsmarting the antibiotics, sooner or later."

aashruti.kak@expressindia.com