enicillin, the miracle antibiotic of the 20th century hailed for its strength and its generic bacterium-killing capability, quickly became the drug of choice for treating infections of the skin, wounds, and bone, as well as many hospital-acquired diseases. However, this star performer and its successors have increasingly been losing effectiveness as resistant bacteria emerge. The limitations of the pharmaceutical industry in the development of new antibiotics are widely known. The 1970s saw a greater number of new antibiotics than the 1990s did, and the number continues to drop.

Researchers have developed more potent antibiotics - while the cunning microbes have evolved concurrently to become ever hardier. An environment with sub-optimal concentrations of antibiotics provides a platform for the generation of resistant bacterial mutations, explains Paul Tambyah, an infectious-disease clinician at the National University of Singapore/National University Hospital.

One of the best-known cases is methicillin-resistant Staphylococcus aureus, or MRSA, which is widespread in Singapore hospitals and many other parts of the world. MRSA acquires resistance to semi-synthetic penicillin and a host of other antibiotics via the acquisition of a single gene, the mecA. For Singapore at least, most of the so-called community-acquired MRSA is actually healthcare-acquired; people somehow related to healthcare facilities may bring these resistant bacteria out of the hospital and into the community.

Antibiotic resistance in the community is not that big a problem except for certain pathogens such as Streptococcus pneumoniae, the most common cause of community-acquired pneumonia, and then particularly in certain groups such as the day-care-centre population. This microorganism has to alter four penicillin-binding proteins to become completely resistant to penicillin, so sometimes this can be overcome with higher doses of penicillin. Gram-negative organisms like Klebsiella and Escherichia coli, which cause urinarytract or intra-abdominal infections, have acquired enzymes that digest many common antibiotics, often by means of mobile genetic elements.

Some Singapore researchers have documented the spread of antibiotic resistance. They include SENTRY Antimicrobial Surveillance, a multinational cooperative group providing the first worldwide, longitudinal surveillance program to offer physicians, researchers, and public health officials comprehensive, timely data on the most pervasive and devastating infectious diseases, including those of the bloodstream, respiratory tract, urinary tract, and wounds, using standardised reference testing methods; and ANSORP (Asian Network for Surveillance of Resistant Pathogens), a very influential group that studies multidrugresistant S. pneumonia. Ti Teow Yee of the NUS Department of Pharmacology/Medicine, a member of ANSORP, works on therapeutic and preventative strategies against antibiotic-resistant pneumococci.

Doctors dealing with drug resistance face many problems. Tambyah has highlighted one issue - the control of antibiotic resistance - that must be seen as a national or even global concern. According to him, NUS/NUH has detected resistance to antibiotics that have not yet even entered the hospital formulary, mainly owing to the widespread use and abuse of antibiotics in the community or in other healthcare settings. The traditional approach to countering drug resistance depends on the pharmaceutical industry's coming up with newer and more potent - and usually more expensive - drugs. The stream seems to have dried up in the last few years, and the industry needs to develop some creative strategies.

Some countries have had success in controlling drug resistance. The Netherlands' MRSA rate stays very low, but the cost involved is tremendous. Health administrators worldwide are often reluctant to part with money for prevention rather than treatment.

An important emerging technology that tackles drug resistance embraces the newer drug delivery systems that ensure high doses of antibiotics reach the sites of infection. Drug resistance is often the result of bacteria exposed to sub-optimal concentrations of antibiotics, but these concentrations are the highest that can be achieved using techniques such as taking a pill or running an intravenous infusion.

Novel drug delivery techniques using special "magic bullets" which can go straight to the site of infection might be able to achieve high levels of anti-infectives at the actual site of infection without unpleasant side effects in other parts of the body. This approach does not allow a small population of "superbug survivors" to remain that can mutate and/or acquire the means to avoid the next antibiotic onslaught. The whole field of pharmacodynamics is rising to the challenge of optimising drug dosing to reduce the emergence of resistance.

Promising Therapies

Perhaps more promising in the short term is the use of newer therapies to prevent infection in the first place so that antibiotics can be "saved" for more serious infection. This strategy has been exemplified in some areas of hospital-acquired infection, in particular reducing the risk of infection with the use of coated urinary catheters. Newer therapies to prevent infection in the first place include the use of antiseptic-coated catheters (both intravenous and urethral), better skin preparation before surgery, the use of intelligent systems to ensure that peri-operative prophylactic antibiotics are delivered appropriately, and better systems for ventilators which are designed to reduce ventilatorassociated pneumonias. So are humans inadvertently encouraging drug resistance by means of their practices, habits, and ways of treating disease? Tambyah muses, "Although it is tempting to blame physicians for abusing antibiotics, often no alternative is available if resistant strains have already become established in hospitals!"

Scientists are sometimes seen as modern-day Dr Frankensteins who create super-resistant pathogens by over-manipulating genes and tampering with nature. Tambyah points out that no concrete evidence exists that genetic engineering has given rise to drugresistance problems. However, he admits that the use of antibiotics as growth promoters in animal feed, as well as the use of antibioticresistant genes as markers in the production of genetically modified food, does present cause for concern.

Sometimes it seems that humanity is not making any headway in the battle against pathogens since it gets caught unawares each time a new variety rears up, such as the severe acute respiratory syndrome (SARS) virus. Tambyah ponders: "As we take small steps forward, microorganisms keep several steps ahead of us. I alluded to this fact in an editorial for the April 2003 issue of Singapore Medical Journal. Unless we devote huge amounts of resources to surveillance and detection of emerging infections, we shall continue to be caught flatfooted by novel pathogens. Our world has become ever smaller, making dissemination of these pathogens very quick. A single infected individual on the ninth floor of a hotel can shortly lead to SARS epidemics in four countries on three continents, triggering worldwide alarm."

The clinician feels that the main lesson that Singapore can learn from the incident is that resources need to be devoted to infection control and, more important, to the surveillance and detection of emerging infectious agents. NUH, on its part, has also learned valuable clinical and epidemiological lessons from the few SARS patients who have passed through its doors.

Tambyah concludes with some food for thought. "We also need to think long and hard about some assumptions we have made regarding our healthcare system - about putting patients together in crowded wards, making them wait in crowded corridors outside various diagnostic and treatment suites, pressuring doctors and nurses so that they feel they must go to work even when ill because their colleagues will not be able to manage without them, and many other issues."

For more information contact Paul Tambyah at mdcpat@nus.edu.sg