Most modern antibiotics come from microorganisms that normally reside in the soil; these include species of the bacteria Streptomyces and Bacillus, and the eukaryotic fungi Penicillium and Cephalosporium. To commercially produce an antibiotic, a carefully selected strain of the appropriate species is inoculated into a broth medium and incubated in a huge vat. As soon as the maximum antibiotic concentration is reached, the drug is extracted from the medium and extensively purified. In many cases, the antibiotic is chemically altered after purification to impart new characteristics such as increased stability. These chemically modified compounds are called semisynthetic. In some cases, the entire drug can be synthesized in the laboratory. By convention, these partially or totally synthetic chemicals are still called antibiotics because microorganisms naturally produce them. A multitude of antimicrobial drugs is now available, each with characteristics that make it more or less suitable for a given clinical situation. Hundreds of tons and many millions of dollars' worth of antibiotics are now produced each year.
Medically useful antimicrobial drugs exhibit selective toxicity, causing greater harm to microorganisms than to the human host. They do this by interfering with essential biological structures or biochemical processes that are common in microorganisms but not in human cells.
While the ideal antimicrobial drug is non-toxic to humans, most can be harmful at high concentrations. In other words, selective toxicity is a relative term. The toxicity of a given drug is expressed as the therapeutic index, which is the lowest dose toxic to the patient divided by the dose typically used for therapy. Antimicrobials that have a high therapeutic index are less
510 Chapter 21 Antimicrobial Medications toxic to the patient, often because the drug acts against a vital biochemical process of bacteria that does not exist in human cells. For example, penicillin G, which interferes with bacterial cell wall synthesis, has a very high therapeutic index. When an antimicrobial that has a low therapeutic index is administered, the concentration in the patient's blood must be carefully monitored to ensure it does not reach a toxic level. Drugs that are too toxic for systemic use can sometimes be used for topical applications, such as first-aid antibiotic skin ointments.
Antimicrobial drugs may either kill microorganisms or inhibit their growth. Those that inhibit growth are called bacteriosta-tic. These drugs depend on the normal host defenses to kill or eliminate the pathogen after its growth has been inhibited. For example, sulfa drugs, which are frequently prescribed for urinary tract infections, inhibit the growth of bacteria in the bladder until they are eliminated during the normal process of urination. Drugs that kill bacteria are bactericidal. These drugs are particularly useful in situations in which the normal host defenses cannot be relied on to remove or destroy pathogens. A given drug can be bactericidal in one situation yet bacteriostatic in another, depending on the concentration of the drug and the growth stage of the microorganism.
Antimicrobial drugs vary with respect to the range of microorganisms they kill or inhibit. Some kill or inhibit a narrow range of microorganisms, such as only Gram-positive bacteria, whereas others affect a wide range, generally including both Gram-positive and Gram-negative organisms. Antimicrobials that affect a wide range of bacteria are called broad-spectrum antimicrobials. These are very important in the treatment of acute life-threatening diseases when immediate antimicrobial therapy is essential and there is no time to culture and identify the disease-causing agent. The disadvantage of broad-spectrum antimicrobials is that, by affecting a wide range of organisms, they disrupt the normal flora that play an important role in excluding pathogens. This in turn can leave the patient predisposed to other infections. Antimicrobials that affect a limited range of bacteria are narrow-spectrum antimicrobials. Their use requires identification of the pathogen, but they cause less disruption to the normal flora. ■ normal flora, pp. 375,461
Tissue Distribution, Metabolism, and Excretion of the Drug
Antimicrobials differ not only in their action and activity, but also in how they are distributed, metabolized, and excreted by the body. For example, only some drugs are able to cross from the blood into the cerebrospinal fluid, an important factor for a physician to consider when prescribing a drug to treat meningitis. Drugs that are unstable in acid are destroyed by stomach acid when taken orally, and so these drugs must instead be administered through intravenous or intramuscular injection. ■ meningitis, p. 664
Another important characteristic of an antimicrobial is its rate of elimination, which is expressed as the half-life. The halflife of a drug is the time it takes for the body to eliminate one-half of the original dosage in the serum. The half-life of a drug dictates the frequency of doses required to maintain an effective level in the body. For example, penicillin V, which has a very short half-life, needs to be taken four times a day, whereas azithromycin, with a half-life of over 24 hours, is taken only once a day or less. Patients who have kidney or liver dysfunction often excrete or metabolize drugs more slowly, and so their drug dosages must be adjusted accordingly.
Combinations of antimicrobials are sometimes used to treat infections, but care must be taken when selecting the combinations because some drugs will counteract the effects of others. When the action of one drug enhances the activity of another, the combination is called synergistic. In contrast, combinations in which the activity of one interferes with the other are called antagonistic. Combinations that are neither synergistic nor antagonistic are called additive.
As with any medication, several concerns and dangers are associated with antimicrobial drugs. It is important to remember, however, that antimicrobials are extremely valuable drugs that have saved countless lives when properly prescribed and used.
Some people develop hypersensitivities or allergies to certain antimicrobials. An allergic reaction to penicillin or other related drugs usually results in a fever or rash but can abruptly cause life-threatening anaphylactic shock. For this reason, people who have allergic reactions to antimicrobials must alert their physicians and pharmacists so that alternative drugs can be prescribed. A bracelet or necklace that records that information should also be worn in case of emergency. ■ anaphylactic shock, p. 444
Several antimicrobials are toxic at high concentrations or occasionally cause adverse reactions. For example, aminoglycosides can damage kidneys, impair the sense of balance, and even cause irreversible deafness. Patients taking these drugs must be closely monitored because of the very low therapeutic index. Some antimicrobials have such severe potential side effects that they are reserved for only life-threatening conditions. For example, in rare cases, chloramphenicol causes the potentially lethal condition aplastic anemia, in which the body is unable to make white and red blood cells. For this reason, chloramphenicol is usually used only when no other alternatives are available.
The normal flora plays an important role in host defense by excluding pathogens. When the composition of the normal flora is altered, which happens when a person takes an antimicrobial, pathogens normally unable to compete may multiply to high numbers. Patients who take broad-spectrum antibiotics orally sometimes develop the life-threatening disease called antibiotic-associated colitis, caused by the growth of toxin-producing strains of Clostridium difficile. This organism is not usually able to establish itself in the intestine due to competition from other bacteria. When the normal intestinal flora are inhibited or killed, however, C. difficile can sometimes flourish and cause disease.
I normal flora, pp. 375,461 ■ Clostridium difficile, p. 601
Just as humans are assembling a vast array of antimicrobial drugs, microorganisms have their own genetic toolbox of mechanisms to avoid their effects. In some cases, certain types of bacteria are inherently resistant to the effects of a particular drug; this is called innate or intrinsic resistance. For example, members of the genus Mycoplasma lack a cell wall, so, not surprisingly, they are resistant to any drug such as penicillin that exerts its action by interfering with cell wall synthesis. Many Gram-negative organisms are intrinsically resistant to certain drugs because the lipid bilayer of their outer membrane excludes entry of the drug. In other instances, previously sensitive organisms develop resistance through spontaneous mutation or the acquisition of new genetic information; this is called acquired resistance. The mechanisms and acquisition of resistance will be discussed later.
While the price of a drug is not a concern from a purely scientific standpoint, it can significantly affect the overall expense of health care. In general, newly introduced drugs are far more expensive than their traditional counterparts. For example, one relatively new addition to the family of penicillins is 20 times as costly as the original version. This higher price partially reflects the inherent expense of the research and development of new drugs. Unfortunately, the rapidly increasing resistance of microorganisms to traditional antimicrobials is affecting the cost of health care.
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