Chapter 9: Antimicrobial Therapy

            When it comes to chemicals, disinfectants are too harsh to use on a human body. Antiseptics can be used, but are only safe when used externally. To treat infections, chemicals are needed which can be taken into the body and can kill the offending microbes without hurting the host. This is the principle of SELECTIVE TOXICITY. Most of our chemotherapeutic agents (drugs used for treatment) are effective against bacteria, because they have targets that are the most different from us (their ribosomes are different, we have no peptidoglycan to be damaged, etc).  Against fungi and protozoa, we have fewer effective drugs, because they are eukaryotes like us; more drugs that would hurt them may also hurt us too.  Drugs that work against various worms are even fewer in number, because worms are classified as animals like us.  Viral infections are very hard to treat because viruses use our own cells. Worst of all are cancer cells; they ARE our cells, but gone bad.

            When considering any kind of drugs, remember that all drugs will have some effect or side effect at some concentration. Typically, as you increase the concentration of a drug, it will go from having no effect to have a useful clinical effect, to have undesirable side-effects (toxicity).  An ideal drug (in particular, one that works against microbes) will have the properties listed on p 124 in your text: be effective against a wide variety of pathogens (disease-causing microbes), not be toxic for the patient (at the effective concentration), be difficult for bacteria to become resistant to, not be something people easily get allergic to, and not interfere with normal host defenses.  In reality, there are always trade-offs, and no drug is perfect.

            Antimicrobials have 5 primary modes of action (how they work). These are a) inhibition of cell wall synthesis, b) inhibition of protein synthesis, c) interference with the use of DNA, d) damage to cell membranes, and e) anti-metabolite activity (interfering with metabolic enzymes).

            There are several important families of antimicrobial drugs. Some are antibiotics (natural substances made by other microorganisms).  Most are semi-synthetic antibiotics (chemical modifications of a natural substance), and a few are synthetic, meaning not produced by living things (except people in a factory).  Here are the families of drugs I want you to remember and some representative examples. You must also learn how each of these families work against bacteria.

Sulfa drugs (sulfonamides)

These are synthetic drugs that act as antimetabolites.  They interfere with the enzymes that make the vitamin folic acid.  The drugs don’t hurt us because we can’t make folic acid anyway, we must have it in our diet. Bacteria that make it themselves are stopped, and can’t grow without it (the drug is bacteriostatic).  Two currently used examples are drugs used in combination: sulfamethoxazole and trimethoprim.  These 2 sulfa drugs block two separate steps in the folic acid pathway, making it very hard for bacteria to mutate and become resistant to both drugs (sold in a combination called Bactrim and other brand names).

Penicllins

Penicillin was the first antibiotic. This family works by inhibiting peptidoglycan synthesis (cells commit suicide as described in class; drugs won’t work against cells that aren’t growing.)  There is now a whole family of penicillins because the drugs have improved to a) allow being taken by mouth instead of injected, b) active against more Gram negative bacteria (more broad spectrum), and c) be more resistant to penicillinases (also called beta-lactamases because they cut the beta-lactam ring which is part of the important chemical structure of the molecule) which some bacteria make to destroy the drug.  There are no particular members of this family for you to remember; any drug whose name ends in –cillin is a penicillin family drug.

Aminoglycosides

These drugs inhibit protein synthesis by binding to the ribosomes and causing problems. One of the very earliest antibiotics, streptomycin, is in this family. All the drugs in this family end in –mycin, unfortunately, completely unrelated drugs, especially brand names, ALSO end in –mycin, so you can’t trust that!  These drugs are somewhat toxic, must be given by injection (for example, i.v. drip), and the concentration in the blood must be monitored.

Tetracyclines

Includes tetracycline and any drug that ends in –cycline (but brand names may end in –mycin!).  These drugs also inhibit protein synthesis and are broad spectrum, working against many kinds of bacteria.  They do have side-effects, however, and because they are broad spectrum, they can kill off many of the normal bacteria (microbiota), causing problems.

Macrolides

This family also ends in –mycin and includes erythromycin and azithromycin (Zithromax). Although often given to patients who are allergic to penicillin, these drugs inhibit protein synthesis.  The book doesn’t say, but in a certain portion of the population, these drugs cause stomach upset. How true! The whole family of drugs makes me puke; I can’t take them.

Cephalosporins

These drugs are similar to the penicillins in that they have the beta-lactam ring structure which allows them to inhibit cell wall synthesis. Cephalosporins were developed in waves (first generation, second, third) with the later generations of drugs geared against enteric bacteria (like E. coli) and Pseudomonas.  Newer drugs of this family are rather expensive.  All the drugs are easy to recognize because their names start with the prefix Cef- or Ceph-. 

Glycopeptides

This is a smaller group, but worth mentioning because of the main group member, vancomycin.  This drug inhibits cell wall synthesis and until recently was the “last line of defense” against drug resistant Staph. aureus. 

Quinolones

These drugs have been in the news a lot lately, although you don’t recognize the family name. To understand how these work, you need some quick background information. In bacterial cells, the DNA is tightly wound up, supercoiled. There is an enzyme named gyrase that is responsible for winding and unwinding DNA so that it can be used or copied. These drugs inhibit that enzyme, preventing the DNA from being used.  Drugs in this family end in the suffix –floxacin.  The drug ciprofloxacin became famous for being the drug of choice to fight Bacillus anthracis, the cause of anthrax. (Other drugs work well against the anthrax bacterium also).

Some drugs work well against bacteria but are too toxic to use internally. Typical over the counter medications for fighting infection have 3 of these drugs (for example Neosporin brand ointment). The three drugs are: neomycin (aminoglycoside, which is identified above as somewhat toxic), bacitracin (interferes with cell wall synthesis, is in a group by itself), and polymyxin (disrupts cell membranes; how’s that for a molecule that’s probably not selectively toxic; I mean afterall, all cells have a cell membrane). This combo is applied topically (meaning on the skin) and each of the 3 has a different mode of action.

            When antibiotics first came on the scene, they were truly wonder drugs, saving lives against bacteria that most of us now take for granted.  We became cavalier about them though, using some in agriculture to make livestock grow faster and to use them on ourselves for every sore throat, cough, and sniffle. The unfortunate consequence is an epidemic of antibiotic resistance among the bacteria.  How does this happen?

            The use of antibiotics results in selective pressure (remember selective media?). Bacteria that aren’t resistant are killed, but those that are resistant and aren’t killed reproduce, and all their descendants are also resistant! Bacteria can mutate (undergo changes in their DNA) that, by several different mechanism, can result in resistance. Also, bacteria readily exchange DNA by conjugation, and plasmids (called “R plasmids”) that may carry information for resistance to several antibiotics are transferred among bacteria.  As long as those plasmids are a ticket to survival, the bacteria will keep them (and use them!)  We humans have cooperated in this.  Virus infections aren’t cured by antibiotics, but we expect to get antibiotics when we are sick regardless. Every time we take the antibiotics, we promote the growth of mutant or plasmid-carrying bacteria that are resistant. When we do need antibiotics, some people take them until they feel better, then stop.  This succeeds in killing off the most susceptible pathogens, leaving behind the more resistant ones so the next infection will take more antibiotic to treat.