Antibiotics: Use And Abuse

Science, as well as all of mankind for that matter, is engaged in a relentless battle against bacteria. On the surface, it would seem that the human side has the advantage. Billions of dollars are available for research, and some of the best minds in the world are engaged in the fight against these tiny creatures that are visible only under a microscope. Yet, the tide of battle swings back and forth. Just when it seems that science has gained the upper hand with powerful new antibiotics, the sly bacteria create new defenses.

A case in point is found in human medicine: The science journal Nature recently published an article stating that an international team of scientists has reported that bacteria responsible for pneumonia, blood poisoning, and meningitis have become tolerant to what had been considered the antibiotic of last resort. The scientists state that Streptococcus pneumoniae, a germ common in the community and risky for children and the elderly, has genetically mutated into strains that no longer die when exposed to vancomycin, one of medicine’s most powerful antibiotics.

The article states that researchers from the United States and Sweden have confirmed the alarming development both in the lab and in cases involving three children and one adult, raising the specter of more chronic and fatal infections for ailments once thought to be curable. The researchers say that the bacteria’s tolerance to vancomycin is a precursor to Strep pneumoniae’s becoming completely resistant, meaning no drug would be able to stop it from reproducing.

Thus, they say, Strep pneumoniae has joined the ranks of bacteria that have learned to outwit the antibiotics that once killed them.

While the above appears to be all doom and gloom, there also is a bright spot. In the course of studying the genetic mutations of Strep pneumoniae, the researchers also pinpointed two genes that ultimately might serve as useful new targets to kill the bacteria. These genes appear to be essential in determining whether the bacteria grew, fell dormant, or died, and the scientists believe they might be present in a whole range of drug-resistant superbugs.

The hope is that new antibiotics can, in a sense, cause the bacteria to become suicidal. Scientists also are at work to develop a test that quickly will reveal whether bacteria resistant to vancomycin are present.

Such a test is highly important as was demonstrated with a young boy under the age of five who was being treated for meningitis at Le Bonheur Children’s Hospital in Memphis, Tenn. The youngster was administered vancomycin over a 10-day period, then removed from the drug. His infection, which at the time was not known to be the result of the superbug form of Strep pneumoniae, immediately returned, resulting in permanent hearing damage.

The problems involved in finding effective antibiotics to combat bacteria in human medicine are mirrored in equine medicine. It must be added that horse owners (and some practitioners) are at least partially responsible for the problem. Now, horse owners are experiencing deadly fallout from years of antibiotic misuse.

For the most part the misuse came about because of complacency and ignorance. To understand what has occurred, we must go back to the beginning.

Some scientists believe that for at least two billion years, bacteria were the only form of life on Earth and that all animals and plants are their descendants.

When man came upon the scene, he was relatively powerless against harmful bacteria. An infection or wound often proved fatal. It only has been in recent years that man has developed effective weapons against bacteria. As recently as the Civil War, a minor flesh wound could prove fatal if it became infected.

Then, particularly in the World War II period, science came up with what was considered to be the ultimate weapon in the battle against harmful bacteria: antibiotics.

First came penicillin. This powerful destroyer of harmful bacteria, developed from mold, began saving thousands of lives in the 1940s. Sulfa made an appearance at about the same time. That was only the beginning.

In the 1950s, aminoglycosides arrived. This is a group of antibiotics—including gentamicin and streptomycin—which interfere with the function of bacterial ribosomes.

It seemed man had triumphed over this age-old enemy. A "shot" of antibiotic was all that was needed for an infectious problem to be on its way out.

Unfortunately, this somewhat arrogant approach was the source of problems to come. With horses, antibiotics were sometimes over-prescribed. In other cases, horse owners failed to follow veterinary advice and often administered too little over too short a time frame or when the antibiotic was not needed.

A fictional example might be a horse suffering from an infection. The owner would be advised by the veterinarian to administer 10 ccs of penicillin per day over a five-day period. However, after three days, the owner observed that the condition appeared to have cleared and didn’t bother administering the other two days of medication that had been prescribed. That played directly into the bacteria’s "hands," so to speak. Instead of being killed, the bacteria only were damaged and quickly found ways to mount defenses to prevent that same damage.

Before long, horse owners and veterinarians were finding that more and more antibiotic had to be administered to clear up certain infections. Instead of the 10 ccs per dose over a specified period of time to compromise a bacteria severely, 30 ccs per dose over the same time frame might be needed. This has happened in just the last 10-15 years!

There have been other problems through the years, says James Orsini, DVM, a professor of surgery and a staff surgeon at New Bolton Center, University of Pennsylvania, and the author of a number of articles and papers on bacteria and the drugs being developed to combat them. Often in the past, Orsini said, a combination of drugs was administered for a particular condition without knowledge of just how they worked within the animal’s system.

"Many times," he says, "these drugs had different rates of absorption, distribution, and excretion. One drug might have been administered in an appropriate dosage while the other was inappropriate. The drug administered inappropriately stirred the pot or tweaked the bacteria just enough for it to develop resistance."

Economics also has been a factor. Sometimes the decision on which antibiotic to use and how much to administer was dependent on how much the horse owner wanted to spend.

While all of this was going on, the wily bacteria were mounting their own defenses ever more effectively against antibiotics.

Orsini and his colleagues provided disturbing evidence to this effect in a five-year study concerning the resistance of bacteria to two aminoglycosides at New Bolton Center. One of the popular aminoglycosides was the powerful bacteria fighter gentamicin. It was used heavily at New Bolton Center and around the country.

However, the bacteria it was designed to fight began erecting barriers of resistance and, as the study revealed, gentamicin was losing the battle. At the same time, however, another aminoglycoside—amikacin—was holding its own against the same bacteria that were overpowering gentamicin.

In the New Bolton study, antimicrobial susceptibility of 1,244 Gram-negative equine isolates was obtained between July 1, 1985, and June 30, 1990. These were the first cultures submitted on 693 medical and surgical patients admitted to the hospital with suspected infection. Medical records were available for 480 of the 693 cases from which cultures were taken. Of these, 393 received antibiotic treatment. The 190 cases that received their first treatment on the day the culture was taken were selected for examination of isolates and in vitro antibiotic susceptibility of the isolates.

Susceptibility to gentamicin and amikacin was analyzed for the six most frequently isolated Gram-negative pathogens—Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus spp., Pseudomonas spp., and Pasteurella spp.

The results of the study were revealing, and sobering.

Overall, amikacin had a susceptibility rate (its ability to kill the bacteria involved) of 94.3%, while the susceptibility rate for gentamicin was only 77.7%.

Orsini had this to say about the study results:

"In our study, a substantial number of Gram-negative isolates were found to be resistant to gentamicin, a result that has important implications for clinical use. On the basis of the data from our hospital, one-third or more of the isolates from Gram-negative infections in hospitalized horses may be gentamicin resistant. Indiscriminate use of gentamicin could result in continued increase in the number of infections caused by resistant strains."

One of the reasons that bacteria are taking the measure of gentamicin, he says, involves the production by the bacteria of enzymes that inactivate gentamicin.

Amikacin had a better track record during the five-year study, perhaps because it was developed specifically to evade enzymatic mechanisms of resistance. However, the researchers also found that certain bacteria are already eroding amikacin’s effectiveness.

In the above discussion, there was frequent mention of Gram-negative bacteria. There are two basic types of bacteria—Gram-negative and Gram-positive.

They carry the "Gram" name in honor of the Danish microbiologist, Hans Christian Gram, who developed the "Gram stain" to identify certain disease-causing bacteria. Gram-positive bacteria possess a single, thick cell wall that retains the Gram stain within the cell, causing the stained cells to appear purple under the microscope.

Gram-negative bacteria have more complex cell walls. Because the walls are thinner (lipopolysaccharide), they do not retain stain. Generally speaking, the Gram-negative bacteria are the more resistant of the two to antibiotics. In most cases, Gram-negative bacteria are associated with the more virulent infectious diseases.

The attack on Gram-positive bacteria by penicillin and other antibiotics is relatively straightforward. The entire cell wall of a Gram-positive bacterium is composed of a relatively simple structure, made up of repeating units that are linked chains of amino acids. Antibiotics act on these bacteria by blocking the cross-linking reaction. Cell walls without cross linking have no strength and rupture when the cell reproduces.

However, this approach on the part of penicillin and other antibiotics does not work with the more complex Gram-negative bacteria because they have a tough outer membrane that is less permeable to antibiotics. Unfortunately, for scientists seeking to outwit the two types of bacteria, both have the ability to change genetically.

"Bacteria, generally, are quite capable of change in their genetic code to resist antibiotics," Orsini says. "The two main mechanisms of bacterial resistance are prevention of the antimicrobial agent (antibiotic) from reaching the target site and bacterial production of enzymes. The Gram-negative bacilli exemplify the first mechanism. They generally are less sensitive to antimicrobials because of the presence of an outer membrane that is less permeable than other membranes of the bacteria to antimicrobial agents. A drug, such as erythromycin, is inactive against Gram-negative bacilli because of its inability to penetrate the cell wall."

The other method of resistance—the manufacture of enzymes that inactivate the antibiotic—is a bit more sophisticated. This is the route of attack bacteria have taken against gentamicin. The enzymes used to combat the antibiotic might be compared to laser beams that render the antimicrobial helpless.

The "bacterial enzyme production approach" becomes even more sophisticated. Bacteria have the ability to acquire new genetic determinants for the production of new enzymes to inactivate the antibiotic being administered. There are three ways this is done—transformation, transduction, and conjugation.

It works like this, according to Orsini:

"There are three ways in which genetic material can be passed from one cell to another. In transformation, the cell disrupts and the material lies free of the cell, with the possibility of a piece entering another cell. In transduction, a virus infecting a bacterial cell is capable of taking up some genetic material and passing it on when other cells are infected. In conjugation, or mating, there is direct contact between cells; a large amount of DNA material (plasmids) can be transferred at one time. Bacteria such as Escherichia coli and Salmonella spp. transfer drug resistance from one species to another by conjugation. These plasmids can transfer resistance for multiple microbrials."

New Weapons

In reviewing what has appeared in the foregoing, it would seem that bacteria are on the winning side in this battle. However, _science has brought some new weapons and approaches to bear that are proving effective against the smartest of the harmful bacteria. The new drugs carry names that are not exactly household words for most horse owners—aztreonam, imipenem, and third-generation cephalosporins, for example.

These are Beta-lactam antibiotics that are highly effective against bacteria that have become resistant to other antibiotics. Some of them have a broad spectrum, while others have highly specific activity for one or more particularly sensitive species.

Here, in capsule form is how the three previously mentioned Beta-lactams work:

Aztreonam—This antibiotic is a synthetic monobactam, a new class of Beta-lactam antibiotic synthesized by soil bacteria. It acts by inhibiting synthesis in the bacterial cell wall. It is effective against many aerobic Gram-negative bacteria.

Imipenem—This is one of the most exciting of the new class of Beta-lactams, known as carbapenems, and is the first of the carbapenems to enter clinical use. It has the broadest anti-bacteria spectrum of the Beta-lactam agents, encompassing virtually all clinically significant species, including both Gram-positive and Gram-negative species. "Its excellent activity against Pseudomonas aeruginosa and aminoglycoside-resistant Enterobacteria," says Orsini, "makes it potentially quite valuable in the treatment of serious nosocomial (pertaining to originating in a hospital) and opportunistic infections in animals."

Third Generation Cephalosporins—These antimicrobials differ from the first and second generations primarily because of their wider spectrum of activity. The role for which the third-generation cephalosporins are best suited, says Orsini, is the treatment of resistant Gram-negative infections in particularly compromised cases.

Also in the category of new and powerful drugs are the fluoroquinolones. Their method of attack against bacteria is the inhibition of an enzyme necessary for synthesis of bacterial DNA and RNA in aerobic Gram-negative and Gram-positive strains. Although the drug interferes with the bacteria’s DNA by impairing important reactions, including synthesis and repair, it does not seem to have a negative effect on the host animal’s DNA.

In veterinary medicine, fluoroquinolones provide a potent weapon against aerobic Gram-negative infections of the genitourinary and gastrointestinal tracts, Gram-negative respiratory tract infections, bone infections, and certain types of skin and soft tissue infections, as well as external auditory canal infections.

While highly effective against aerobic bacteria, the fluoroquinolones do not work well against anaerobic bacteria.

Many of the new antibiotics are produced synthetically, and this provides science with another weapon. The materials used are foreign to the bacteria and because of that, bacteria will have a difficult time developing resistance.

One of the "hottest" topics in the area of antimicrobials at present, says Orsini, is the method of their administration. Traditionally, antibiotics have been administered either orally, intramuscularly, or intravenously.

The problem with this approach is that the antimicrobial is distributed throughout the horse’s system. In some cases, a particular antibiotic might be harmful to kidneys, liver, or some other organ. To avoid this sometimes dangerous fallout, scientists have been working on methods to deliver the antimicrobial directly to the site of infection. The theory is that intense concentrations of the antibiotic can be directed against the bacteria on-site without being carried through the horse’s system.

One method, described by Orsini, involves an implant. The title of the study was "Antibiotic-impregnated polymethyl methacrylate (methacrylate is a plastic material used in dentistry and as the basis for an acrylic bone cement in orthopedic surgery) of an open, infected radial fracture in an adult horse."

"In that report, implants were prepared by adding one gram of cefazolin (a third generation cephalosporin) and one gram of amikacin (an aminoglycoside) to separate 20-gram batches of polymethyl methacrylate powder. After the liquid antibiotic was mixed with the powder, the polymethyl methacrylate was then folded into cylinders two to six centimeters long and 0.5 centimeter in diameter.

"The cylinders were placed in the soft tissues surrounding the fracture. Cylinders have an advantage over beads in that they are easier to locate and remove at a later time, should this become necessary. Implantation can be temporary or permanent. For example, antibiotic-impregnated polymethyl methacrylate may be placed adjacent to an infected plate fixation with an unhealed fracture. If the plate has to be removed after the fracture heals, it is likely that some or all of the polymethyl methacrylate would also be removed. If the fracture and soft tissues heal and plate removal is not necessary, it is unlikely that polymethyl methacrylate removal would be needed.

"The antibiotics slowly elute from the polymethyl methacrylate and diffuse into the surrounding tissues to produce relatively high concentrations locally for several days to several months. The rate of release of antibiotic from the implant varies with the drug."

Thus, one can conclude, localized administration allows the practitioner to place the antibiotics exactly where they are needed and avoid negative systemic reactions.

In an effort to avoid past mistakes that have produced present-day problems with antibiotics, Orsini adds some advice to his colleagues and the horse world in general. The advice involves knowing just what form of bacteria has been encountered and the most pertinent antibiotic to use against it.

"In a discussion of antibiotics, the importance of culture and sensitivity testing cannot be overemphasized," says Orisini. "Although there is good general knowledge of the organisms that are likely to be encountered in horse infections, guided therapy is more likely to be successful.

"All practitioners have experienced cases in which their standard regimen was not effective, only later to identify a resistant strain or an unusual organism. Whenever possible, Gram stains should be performed on samples submitted for culture. This practice often gives some immediate guidance to therapy while culture results are pending and may provide the only information in the event that no organisms are isolated. There is usually good correlation between Gram stain and culture results.

"In some patients, clinical response to antibiotic treatment may be a better therapeutic guide than laboratory results. If the laboratory results indicate that the organism is sensitive to the drug, but the patient is not responding, one should ensure that the drug is not being underdosed."

So, it would seem, we are left with a message that contains both positive and negative elements. Harmful bacteria have not, and likely never will be, defeated. However, in the equine world, there are some powerful allies in the form of new antimicrobials and exciting new approaches to their administration.

There also is a message of caution. We, as horse owners, are implicated in the problem we face involving antibiotic-resistant bacteria. Let’s make certain history isn’t repeated.

We will leave the discussion with these words of observation and advice from Orsini:

"Antimicrobials are powerful and, as a rule, very effective drugs that must be used selectively based on culture and sensitivity results. Their use should be monitored carefully, especially when dealing with drugs known to have toxic side effects. When possible, the clinician should treat with a single drug and should use medications compounded of multiple drugs only when they are essential.

About the Author

Les Sellnow

Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.

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