Nothing has contributed more towards the health of modern man than vaccines and antibiotics. It is likely that either you or a close family member of yours is alive only because an antibiotic has overwhelmed an otherwise fatal bacterial infection sometime in his or her life.

But these magic bullets--often dubbed as the most useful chemicals ever developed by man--are losing their charm. So much so that many people have begun asking the frightening question: Has the antibiotic era come to an end? Are we reverting to the pre-antibiotic age when we were at the mercy of ruthless microbes?

The first successful drug to treat Staphylococcus aureus became available to clinicians in 1930s with the introduction of sulfonamide. But the bacteria soon developed resistance towards the drug and the doctors had to turn to penicillin, which had become widely available in 1940s. Within a span of only a few years, strains of Staphylococcus aureus emerged that were resistant to penicillin. Then other drugs came and went--streptomycin, tetracycline cephalosporins--and the victor in every war was the sturdy Staph. Today, the last arrow in the antibiotic armamentarium of the modern medical practitioner against Staphylococcus aureus is vancomycin. And already reports are coming telling of strains of the bacteria that are resistant even to vancomycin. In May 1998, one of these super-strains of vacomycin-resistant staphs claimed their first scalp, a man in New York.

Until the pharmaceutical scientists develop another class of antibiotics for Streptococcus aureus very soon, it is not difficult to imagine who is going to have the last laugh in the battle with the pathogen.

And a growing number of pathogens are marching on the way to become unstoppable killers. The death rates of such diseases as TB that were thought to be conquered long ago--at least in the developed world--are rising alarmingly.

What is the nature and extent of the problem and how did we manage to end up in this situation? And what we can do to fight back in this seemingly losing battle? These are the basic questions that I will try to answer in this article.

MECHANISMS OF RESISTANCE

Bacteria turn themselves immune to the action of antibiotics in a number of ways. Following is a summary of the major mechanisms that bacteria have adopted over the years to combat various antibiotics.

Antibiotic- Degrading Enzymes

Process

Bacteria produce enzymes that breakdown the antibiotic so that is no longer effective against the bacteria. In enterococci produce ribosomally mediated production of inactivating enzyme against aminoglycoside.

Examples

Staphylococci produce an enzyme b-lactamase that cleaves the b-lactam ring of penicillins. Since the b-lactam ring is essential for the antibiotic action of the penicillins, its breakdown renders the drugs useless.

Efflux Pumps

Process

This is a highly specialized procedure by which bacteria synthesize antibiotic efflux pumps. These pumps expel antibiotic molecules as soon as they enter the bacterial cell and thus spare themselves from the harmful action of the antibiotic.

Example

Pseudomonas aeruginosa has developed extremely efficient membrane efflux pumps that deport ß-lactam antibiotics, ciprofloxacin, tetracycline, chloramphenical and some other antibiotics out of the cell. This makes the bug antibiotic proof against the above mentioned drugs.

Alteration of Receptors

Process

Every drug acts by binding to some kind of receptor. The three dimensional shape of a particular drug molecule and its corresponding receptor is as crucial as the shapes of a key and its lock. Certain bacteria change the steric structure of its molecule that serves as receptor for the drug action. With the lock altered, the key is unable to perform its function.

Example

Macrolide antibiotics (erythromycin, clarithromycin, azithromycin, etc.) act by interfering with ribosome function in susceptible bacteria. Resistant Bacteria change the site on the 50S subunit of their ribosome so that macrolides cannot bind to and inhibit protein synthesis. Enterococci also transform their target sites to render aminoglycosides invalid.

Change in Metabolic Pathways

Process

Some bacteria evolve a new pathway and are thus no more dependent on the pathway through which the antibiotic acts.

Example

Sulfonamides act by entering into, and interfering with, the enzymatic pathway that manufactures folic acid from PABA. Certain bacterial strains have developed alternatives by virtue of which they no longer depend on synthesizing folic acid but collect it from the environment instead, just like humans do. Thus the sulfonamides become redundant.

Alterations in Membrane Permeability

Process

Antibiotics must seep into the bacterial cell to exert its effects. What about holding the antibiotic molecules at the gate? No drug at the site of action and thus no antibacterial action.

Example

Tetracycline resistant bacteria do not allow the protein synthesis-inhibitor antibiotic to enter through their cell walls by modifying the structure of proteins either in the membrane transport system or in the pores. Likewise, some aminoglycosides and polymyxins also encounter the problem of being stopped at the bay.

ORIGINS OF RESISTANCE

Resistance is a natural

Bacteria are one of the oldest life forms on Earth. During eons of evolutionary processes, they have developed an amazing array of tricks and gadgets that make them adapt the to the harshest of living conditions. From the scalding geysers to the frosty Antarctica to the extremely unfriendly human stomach, they inhabit every imaginable niche present on earth.

From the bacterial point of view, the human body is just another habitat to populate and antibiotics are just another environmental hazard to overcome.

THE ROOTS

Bacteria can acquire resistance to antibiotics in a number of ways, both genetic and non-genetic. Since genetic resistance is more important, we will discuss it in detail.

Genetic origins of resistance can be divided into two sub types:

Vertical evolution

Vertical evolution works on the Darwinian principle of natural selection. A spontaneous mutation occurs in a bacterium's genome that makes it resistant to the action of a particular antibiotic. The antibiotic kills all the susceptible population, leaving behind only the resistant mutant, which then proliferates and an entire colony is produced that is immune to the antibiotic.

Vertical evolution is not of much clinical significance, partly due to the fact that this kind of mutation usually makes bacteria less pathogenic. However, vertical evolution is consequential in mycobacterial infections (tuberculosis and leprosy).

Horizontal evolution

By far the most dangerous type of acquisition of resistance, horizontal evolution involves the transfer of genes between different bacteria. The problem, from human point of view, is that the gene-donating bacteria may be of the same strain as well as of different strains and even different species.

A dramatic example of horizontal evolution and its significance to antibiotic resistance sprung up in 1955 when an epidemic of bacterial dysentery was noticed. The bacteria behind this outbreak was Shigella dysenteriae that was resistant to chloramphenical, streptomycin, sulfanilamide and tetracycline at the same time.

It was found later that the pathogens acquired the resistance genes by exchanging resistance plasmids through a process called conjugation.

Conjugation

Conjugation can be likened to bacterial sex. Two bacteria come close, make a cell-to-cell contact, build a bridge (called pilus) between the cells and exchange genetic material. Much larger quantities of information can be transferred by this method as compared with transformation and transduction.

Other processes of gene transfer under horizontal evolution are transformation, where bacteria scavenges shards of DNA from the environment (perhaps left by a dead bacterial cell) and incorporates them to its own genome; and transduction, in which certain viruses, called bacteriophages, play the role of carrier of genetic information from one bacterial cell to another. Staphylococci and streptococci use transduction for transferring resistant genes between their strains.

PLASMIDS

Plasmids are small, circular loops of DNA that lie outside the main chromosomal DNA. Plasmids, ranging in size from two to several hundred thousand bases, are mobile genetic elements and play a vital role in the propagation of resistance genes through conjugation. These kinds of plasmids are called resistance plasmids.

Resistance Plasmids

Resistance plasmids are specialized plasmids that carry genes for antibiotic resistance. They are composed of two parts: resistance genes and a resistance transfer factor (RTF), which is responsible for transfer of resistance gene from one bacterium to another. One resistance plasmid may carry genes for resistance to several antibiotics simultaneously, giving rise to multiple-drug-resistant bacteria. An RTF is capable of disseminating resistance genes even to a bacterium of a different species.

Transfer of resistance plasmids is of great medical concern since it is the major pathway through which resistance to drugs spreads in a very short period of time.

ONE WAY TICKET

Another headache in the problem of antibiotic resistance is the fact the acquisition of resistance is irreversible. Once a resistance gene is selected, it cannot be unselected and bacteria are unlikely to lose the gene even the antibiotic is withdrawn.

HOW RESISTANCE SPREADS

However ironic it might seem, but actually it is the antibiotics that are to be blame the most for the spread of resistance to them. An antibiotic kills the bacteria that are susceptible to it but leaves behind all those that are resistant --handing them over a great advantage over their vulnerable cousins. The resistant bugs proliferate in leaps and bounds and a whole colony of bacteria springs up that is antibiotic resistant.

Moreover, antibiotics commit another type of hara-kiri by indiscriminately killing non-pathogenic bacteria as well. Those bacteria that compete with the pathogenic strains for nutrients and thus can keep their growth in check.

Unwarranted use of antibiotics also incites non-pathogenic commensals to become virulent. For instance, the use of cephalosporins has turned the once innocuous intestinal bacteria E. faecalis into a nasty pathogen, especially in hospital settings.

Furthermore, the antibiotics convert commensals into resistance gene banks, from where inter-species gene transfer can take place. Vancomycin resistance can be imparted to deadly S. aureus by E. faecalis by this process.

Societal Drugs

Antibiotics are perhaps the only class of drugs that affect the person who takes them but also his family, his community and the whole society. The antibiotic does not just target the individual but the entire bacterial flora in the patient's environment, disturbing the ecological balance. When a resistant gene arises in the patient, it is immediately diffuses in the environment and is readily taken up by other bacteria as described earlier.

By the same token, heavy use of antibiotics in hospitals and farms (where antibiotics are given to livestock to improve their performance) produces a resistant-gene pool, which spreads to healthy persons. These resistance-conferring genes, thanks to ever-increasing volume of international travel, reach far and wide on the globe. For example, a strain of multi-drug resistant Streptococcus pneumoniae has been reported to hitchhike from Spain to the USA, UK and South Africa. Likewise, travelers to Pakistan bring with them an unwanted souvenir: multi-drug resistant M1 type of Salmonella typhi. In the USA, too, concern is growing over the increased spread of Salmonella enterica Serotype Typhimurium DT 104, mostly brought by travelers from other parts of the world

Some years ago, data from various research agencies showed the transfer of a resistance genes to and from enterococci and the major gram-positive bacterial species. A similar phenomenon was also reported in E. coli, found to be transferring and obtaining genes different gram-negative species.

It has now been learned that mycobacteria have picked up tetracycline resistant genes originally developed by enterococci and staphylococci.

WHAT CAN BE DONE?

Where the developed world is now paying close attention to the problem of antibiotic resistance, nothing has been done in Pakistan, and for that matter, the whole third world. Even the extent of the problem is largely unknown due to non-existence of any kind of national surveillance and a crippling lack of data. As mentioned earlier, this is a societal problem. Therefore, every component of the society should strive to stop it --before it is too late to do so.

Following are some proposals for adopting strategies to beat the bad bugs:

PHARMACEUTICAL INDUSTRY

• Make newer and better antibiotics, which are harder for the bacteria to circumvent
• Make vaccines to stop the evil before it causes trouble

HEALTHCARE PROFESSIONALS

Prevention is better than cure

The first rule for prescribing antibiotic should be: Don't prescribe antibiotics as far as possible. It has been seen in Pakistan that doctors tend to prescribe antibiotics to patients with common cold or to ones with a viral infection where antibiotics are useless. In Canada, it has been estimated that about half of the 26 million annual antibiotic prescriptions are unnecessary.

Think rational

The choice of an antibiotic should be based upon solid knowledge of the likely causative organism and the most suitable antibiotic, route of administration, dose and duration of therapy should be prescribed for that organism. Use the common antibiotic first. Newer drugs should be saved for more serious cases. Greater emphasis should be given to susceptibility testing. Try to avoid empiric use of antibiotics as far as possible.

Think narrow

Use the most specific antibiotic available. The much-hyped "broad spectrum" antibiotics kill the causative bacteria only efficiently as a narrow spectrum one would, as well as disturb "innocent bystanders" --the bacteria that do not cause disease but can spread resistance

Educate patients

Patient education cannot be over-emphasized. Try to make them understand how important it is to take the drug in the right dose for the right period of time.

Reduce nosocomial infections

Hospitals all over the world are the breeding grounds for resistant organisms, and much more so in our country where the conditions of hospitals is pathetic, to say the least. Some prevention strategies:

• Avoid excessive surgical prophylaxis
• Adhere to the infection control guideline
• Don't use antibiotics as antipyretics
• Aim to minimize pre-hospital stay
• Replace shaving hair with clipping wherever possible
• Use the narrowest spectrum antibiotics possible
• Try to kill bugs before they infect a person: use better aseptic and hygienic conditions.
• Adhere strictly to hand washing policies
• Cohort patients with similar resistant organisms

PHARMACEUTICAL INDUSTRY

• Make newer and better antibiotics, with narrower spectra of activity aimed at known and new molecular targets.
• Make vaccines to stop the evil before it causes trouble

PATIENTS

• When antibiotics are prescribed, complete the full course of therapy. Follow the instructions exactly.
• Don't give your antibiotics to anybody. Never take antibiotics without the prescription of a medical practitioner.
• Wash fruits and vegetables thoroughly.
• Avoid antibacterial soaps and other such products.