ANTIBIOTICS

What are antibiotics?

Antibiotics are medicines that help the body fight bacteria and viruses, either by directly killing them or by weakening them so that the immune system can fight and kill them more easily. The vast majority of antibiotics are bacteria fighters; although there are millions of viruses, we only have antibiotics for half-a-dozen or so of them. Bacteria, on the other hand, are more complex (while viruses must "live" in a "host", bacteria can live independently) and so are easier to kill. Strictly speaking, an "antibiotic" is a bacteria-fighting medicine that is derived from a biological source (plant, mold, or other bacteria).

Mechanism of Action of Antibiotics

Kinds of Antibiotics
Common Antibacterials (a) Penicillins and Cephalosporins In the early 20th century, Alexander Fleming discovered that a mold called Penicillium produces chemicals which kills most of the bacteria nearby. He was able to isolate these chemicals, which are now

known as "penicillins". Sometime later, another mold was found which produced a bacteria-killing chemical, and this chemical's molecule was found to be very similar to the penicillin molecule; this chemical and related chemicals were called "cephalosporins". The vast majority of antibiotics are either penicillins or cephalosporins; chemical changes have been made to the molecules over the years to improve their bacteria-fighting abilities and to help them overcome breakdown and "immunity" of resistant bacteria. Mechanism of Action: Penicillins and cephalosporins kill bacteria by messing up the wall-building system. Since we don't have cell walls, and plants have a different wall-building system, neither we, nor animals, nor plants are affected by the medicine. Disadvantage: There are a very few bacteria that don't have cell walls, either. These bugs are immune to penicillins and cephalosporins for the same reasons we are. Most bacteria do have cell walls, but many have changed their wall-building systems so that penicillins can't interfere, or have come up with ways to break down the medicines before the medicines can work. Side Effects: Penicillins and cephalosporins can cause mild side effects like diarrhea. Less common side effects include rashes and hives. The rarest -- and scariest -- side effect is anaphylactic allergy, in which the airway swells up when we take a dose of the medicine, sometimes to the point where we can't breathe. (b) Macrolides (Erythromycin and related drugs) Erythromycin is another antibacterial produced by a mold. There are a couple of drugs related to erythromycin (azithromycin and clarithromycin) that work the same way, but kill more bugs and have slightly fewer side effects. The erythromycin-like antibiotics are also known as macrolides. Mechanism of Action: Erythromycin works by blocking the bacterial cell's machinery for making new proteins. Since proteins both make up much of the cell's structure and make the enzymes that direct all the cell's chemical reactions, blocking protein manufacturing makes the cell unable to function. Erythromycin in low doses will stop bacteria from growing and multiplying, but we need a higher concentration to kill the bacteria. However, if we can stop growth until the immune system kicks in, that will help us get rid of the infection. Advantage: Since all protein making is affected, erythromycin can slow down or kill any bacteria, even those without cell walls.

Because of this, we use the erythromycins for several diseases, including bacterial bronchitis, chlamydia, and whooping cough, which penicillins and cephalosporins can't touch. Side Effects: Erythromycin and related drugs don't have anything like the allergy problems that are associated with the penicillins and cephalosporins, although there are rare people who have reactions to it. The biggest problem with these medicines is that they can irritate the stomach and this irritation seems to happen most often when someone tries to take the medicine on an empty stomach. Always take erythromycin with food or milk. The same goes for clarithromycin. Azithromycin doesn't irritate the stomach nearly as much as the others. Another problem with erythromycin - but not with azithromycin - is that it may cause enlargement of the pylorus, the muscle that serves as the valve at the outlet of the stomach - in infants. This condition is known as pyloric stenosis, and is a surgical emergency if it occurs since nothing can leave the stomach properly. (c) Sulfas The sulfas (more properly "sulfanilamides" or "sulfonamides") were the first antibiotics to be developed; they are actually completely man-made. Mechanism of Action: They interfere with bacterial DNA replication. Disadvantage: Sulfas can stop bacteria from growing, but they cannot actually kill the bacteria. When they were first used, sulfas worked against many kinds of bacteria. Unfortunately, as with penicillin, the more we used the sulfas the more bacteria became resistant to it. Side Effects: Sulfas also have a tendency to produce allergic reactions - different than those we see with the penicillins, for the most part, but including some that are rare but life-threatening. Because of this we don't use sulfas nearly as much we used to, and most often when we use sulfas it's in combination with another drug which attacks a different part of the bacteria (an attack on two fronts is usually better than an attack on one). The drugs we usually combine with sulfas are either erythromycin or "trimethoprim"; these combinations usually can kill bacteria rather than just slowing them down. One frequent use of "plain" sulfas is in antibiotic eyedrops used for conjunctivitis. (d) Trimethoprim-Sulfamethoxazole

Trimethoprim (TMP) is another man-made antibiotic. Mechanism of Action: Like the sulfas, trimethoprim blocks an important step in the bacteria's system for making new DNA. Advantage: By itself, TMP can kill bacteria, but very slowly. Usually, though, we use TMP in combination with sulfamethoxazole (SMX), and the combination of TMP and a sulfa kills bugs better. In fact, bacteria that are partly resistant to either TMP or SMX can still be killed by the combination of the two. Side Effects: The side effects of the combination are the same as those of the two separate components. Other Antibacterials (a) Nitrofurantoin Nitrofurantoin is another synthetic antibiotic, used mainly for urinary tract infections (UTIs; since it is excreted in the urine, it concentrates in the bladder very nicely). Nitrofurantoin stops bacteria from growing, and can kill bacteria with a high enough level, by blocking the bacteria's ability to use energy it makes by digesting nutrients like sugar, and by blocking other chemical reactions that use the same system. It is not usually used for infections other than UTIs, and there are several side effects (ranging from stomach upset to (very rarely) malfunctioning nerves) which limit its use. (b) Aminoglycosides The aminoglycosides are drugs which stop bacteria from making proteins; they work by attaching permanently to the protein machinery. Since they attach permanently, the bacterial cell will die if it gets enough of the drug. They can be used by themselves, or along with penicillins or cephalosporins to give a two-pronged attack on the bacteria. Aminoglycosides work quite well, but bacteria can become resistant to them. Since aminoglycosides are broken down easily in the stomach, they can't be given by mouth and must be injected or given IV (although we can use them as eyedrops for conjunctivitis). When injected, their side effects include possible damage (temporary or permanent) to the ears and to the kidneys; this can be minimized by checking the amount of the drug in the blood and adjusting the dose so that there is enough drug to kill bacteria but not too much of it. Generally, aminoglycosides are given for short time periods.

(c) Quinolones The quinolones, of which the best known is ciprofloxacin (Cipro), interfere with an enzyme called DNA gyrase that is essential for duplication of bacterial DNA. (DNA gyrase is the DNA unwinding enzyme.) This interference is completely different from the interference of other antibiotics with bacterial "machinery", and so bacteria that are resistant to other antibiotics may be sensitive to the quinolones. However, bacteria can develop resistance to the quinolones, too. Also, researchers have noticed that young animals given quinolones can have damage to their cartilage (the hard but slippery material that connects some bones and covers the slding surfaces of joints). In the past we have avoided using quinilones in children because of this finding, but we sometimes have to give some children quinolones when there is no alternative antibiotic available. (d) Polymyxin B Polymyxin B is an antibacterial that is produced by another bacterium. It kills bacteria by damaging the cell wall chemically -- just the way soap does. It can't be taken internally, but it's very useful for skin infections and for conjunctivitis. (e) Tetracyclines Tetracyclines are yet another family of antibiotics oringinally found in bacteria. They also block the protein-making machinery of certain bacteria. One of the tetracyclines, doxycycline, is often used to treat certain sexually transmitted diseases (such as chlamydia and gonorrhea) in older patients. One known side effect of the tetracyclines is that they affect development of bone and of tooth enamel in young children, and because of this we do not usually give tetracyclines to children under age 8 years. However, tetracycline may be the best antibiotic for some life-threatening infections, such as cholera and anthrax, and in such cases we may use tetracycline to treat a young child (tetracycline often leaves a permanent brown stain on developing teeth, but that's better than death...). Antifungals Some microorganisms, known as fungi,, are cells that are biologically more similar to animal cells than to bacteria. Since many of the antibacterial antibiotics take advantage of the difference between bacterial cells and animal cells, the fungi's similarlity to animal cells

makes them immune to the antibacterial antibiotics. However, there are antibiotics available for fungi such as Candida. These include nystatin, the azoles (including fluconazole, ketoconazole, and similar antibiotics), and amphotericin B. These work by disrupting the fungal cells machinery. Some of these antibiotics may be applied to the skin or taken by mouth, while others must be given IV. Antivirals Since viruses can't live outside the person or animal they infect, they are much harder to kill off. Our immune system can find and kill many of the viruses that attack us, but sometimes a virus can multiply and overwhelm the immune system before the immune system comes up to full speed. Unfortunately, since viruses are completely dormant outside a host, they can't be attacked biologically unless they infect someone. Once the virus is in the body, however, all we can do is let the immune system do its work, and in very rare cases (perhaps half-adozen viruses at most) give drugs that slow down the infection so that the body can clear it out more easily. (a) Acyclovir One often-used antiviral medicine is acyclovir; ganciclovir and valciclovir are similar to acyclovir. These medicines slow down infections with viruses of a certain family, which include both varicella (chickenpox and shingles) and the herpes viruses. Acyclovir slows down the virus multiplication and therefore slows down the infection.. (b) AZT and other Reverse-Transcriptase Inhibitors Another very well-known antiviral is triazidothymidine, better known as zidovudine or AZT. This drug, and others like it, are used to inhibit an enzyme called "reverse transcriptase" which HIV uses to "copy" its own genes into the genes of the cells it infects. Once the HIV genes are copied, the infected cell and all its offspring can produce more HIV. (This is why an AIDS patient cannot actually get rid of all of the virus once infected: the virus may lie dormant as inactive genes for months or years, and the anti-AIDS drugs cannot get to the gene copies.) Like bacteria, viruses can mutate, changing their structure so that drugs that used to work no longer help; this explains why AZT and other reverse-transcriptase inhibitors eventually lose their effectiveness in many patients. (c) Protease Inhibitors

A newer class of anti-AIDS drugs, the protease inhibitors, work by blocking a different HIV enzyme. HIV uses reverse transcriptase to copy its genes into the cell it's infecting; it uses "protease" (an enzyme that breaks down protein) to get into the cell in the first place. Many people with AIDS have been able to eliminate the virus from their bloodstream -- or almost eliminate it -- by using both reversetranscriptase inhibitors and protease inhibitors at the same time. However, since the virus has copied itself into cells where neither kind of drug can attack it, a patient must keep taking the drugs forever to keep the virus from reactivating.

Antibiotic Resistance
Bacteria and viruses learn how to survive even with antibiotics around. There are several ways that bacteria can become resistant. All of them involve changes in the bacteria's genes.

Bacterial genes mutate (change), just like the genes of larger organisms (including humans) mutate. Some of these changes happen because of chemical or radiation exposure; some just happen randomly, and no one's sure quite why. If bacteria with a changed gene is less susceptible to an antibiotic, and that antibiotic is around, the less susceptible (and more resistant) version of the bacteria is more likely to survive the antibiotic and continue to multiply. This is particularly likely to happen if the amount of antibiotic around isn't quite enough to kill all of the bacteria quickly -- as can happen if you don't take enough of the antibiotic to keep its level in your body high, or if you stop taking the antibiotic too early. Although there are many different species of bacteria, some bacteria can "trade" genes with other bacteria. If you have a relatively harmless bacteria in you -- say, in your mouth or your intestines (both places are chock full of bacteria) -- and you've used (or overused or misused) antibiotics some of those harmless bacteria will become resistant to the antibiotics you've (over-, mis-)used. They can then give the resistance genes they have developed to other, harmful bacteria. There are viruses around that attack bacteria rather than plants, animals, or people. Most of these viruses just kill the bacteria, but sometimes the viruses can copy genes -- like the antibiotic resistance genes -- from one kind of bacteria to another.