As discussed in Chapter 3 (Cell Structure and Function) and Chapter 6 (Bacteria and Archaea), most bacterial cells contain a rigid cell wall composed of peptidoglycan, which protects the cell from rupturing in hypotonic environments. Young, growing cells must constantly synthesize new peptidoglycan and transport it to the wall (Figure 22.1). Agents such as penicillins and cephalosporins chemically react with the enzymes responsible for completing the peptidoglycan layer, thus preventing the assembly process. This disruption may occur at numerous different sites in the layer and at different points in the process, but in all cases it causes weaknesses at growth points in the layer, which in turn renders the cell vulnerable to lysis. In a hypotonic environment, water then enters the cell and eventually causes it to burst.

FIGURE 22.1 Peptidoglycan layer.
This illustration demonstrates the three-dimensional structure of the peptidoglycan layer.

Inhibition of Protein Synthesis

Most of the agents that inhibit protein synthesis involve disrupting the process of translation (see Chapter 3, Cell Structure and Function) at the ribosome–mRNA complex (Figure 22.2). The ribosomes of eukaryotic cells are structurally different from those of prokaryotic cells, and because of this human cells are usually not affected by the inhibitory action of these agents because they selectively act against bacteria. The specific chemical reactions that disrupt the translation of the mRNA vary and include the following:

FIGURE 22.2 Inhibition of translation.
The inhibition of translation can occur at a number of points, including the following: inhibition of peptide bond formation, interference with the attachment of transfer RNA (tRNA) to mRNA, and changing of the shape of the ribosome, thereby preventing translocation along the mRNA strand.

• Prevention of the initiation of synthesis

• Blocking of the formation of peptide bonds between amino acids on the transfer RNAs (tRNAs)

• Prevention of ribosome translocation along the mRNA strand

Whatever the specific point of attack, the result is the same: inhibition of the synthesis of necessary proteins. Antimicrobial agents that affect bacterial protein synthesis include tetracyclines, chloramphenicol, macrolides, and others.

Inhibition of Nucleic Acid Synthesis

The metabolic process involved in the synthesis of DNA and RNA is a long and complex series of enzyme-catalyzed reactions (see Chapter 3, Cell Structure and Function). The complexity of the process lends itself to disruption at many points along the way and inhibition at any point can block subsequent events in the pathway. As with the other mechanisms the specific target within the process is often dependent on the specific antimicrobial agent being used, but the end result is the same no matter where the point of attack is—disruption of the synthesis of nucleic acids. The interference with nucleic acid synthesis by an antimicrobial drug can be due to:

• Disruption of synthesis of the nucleotide component

• Inhibition of DNA replication

• Interference with transcription of the RNA

An interesting type of mechanism that is employed by sulfonamides and trimethoprim involves mimicking the normal substrate of an enzyme in a process called competitive inhibition. When these agents are supplied to the cell in high concentrations they will substitute for the true substrate of an important enzyme, thus preventing the enzyme from producing a needed product and causing the metabolism of the cell to slow or stop.

Disruption of Plasma Membrane

Damage to the cell membrane is a form of catastrophic damage for any cell. Not only can it affect the transport of substances required for metabolism both in and out of the cell, it is a major factor in the maintenance of the cell’s physical integrity. Most membrane–disrupting agents target the different types of lipids in the cell membrane, which lends to their specificity for a particular microbial group. Because all microorganisms (except for viruses) share the same basic plasma membrane structure, these agents are useful against both bacteria and fungi. Unfortunately, they can also be toxic to human cells.

Antibiotics, specifically polypeptides such as polymyxin B, adversely affect the membrane permeability of microbial cells, resulting in a loss of important metabolites. Antifungal drugs that disrupt fungal plasma membranes include nystatin, miconazole, ketoconazole, and amphotericin B.

Inhibition of Metabolic Pathways

Antimicrobial agents not only are able to disrupt the metabolic pathways involved in the synthesis of proteins and nucleic acids, but can affect numerous cellular metabolic processes that can lead to cell death. Disruption of crucial enzyme activity/production as well as blocking the synthesis of other essential metabolic compounds such as NAD or folic acid can be catastrophic to the overall metabolism of any cell, thus allowing use of these agents against a wide variety of microorganisms. The sulfonamides (sulfa drugs) and trimethoprim are broad-spectrum antimicrobial drugs that disrupt the synthesis of tetrahydrofolic acid, a precursor to nucleic acids, necessary for microbial metabolism.

Characteristics of Antimicrobial Agents

Almost all antimicrobial agents share a set of common characteristics that are important to remember when selecting a drug for treatment. These characteristics provide a great deal of information regarding how the agents work, and in some cases why they don’t work, in the treatment of an infection. These characteristics of an antimicrobial agent include the following:

• Its selective toxicity

• Whether it is microbicidal rather than microbiostatic

• How readily and easily the agent may be delivered to the site of infection

• Whether it is readily soluble in body fluids and will maintain its potency long enough to be effective

• How long the agent remains active in the body

• The degree of antimicrobial resistance to the agent

• Whether it complements or aids in host body defenses

• Is it nonallergenic?

• Does it have a long shelf life?

• Is it affordable/available to all patients who might need it?

Spectrum of Action

Most antimicrobial drugs do not inhibit the growth of all pathogens. Antimicrobial drugs have a spectrum of activity, which is the range of pathogen types against which a given drug is effective (Table 22.1). On the basis of the spectrum of activity, drugs can be classified as antimicrobials with a broad spectrum of activity and those that have a narrow spectrum of activity.

TABLE 22.1

Spectrum of Activity of Some Antimicrobial Drugs

Drug	Activity against:
Penicillin G	Gram-positive bacteria
Streptomycin	Gram-negative bacteria, mycobacteria
Tetracycline	Gram-negative bacteria, gram-positive bacteria, chlamydias, rickettsias
Isoniazid	Mycobacteria
Acyclovir	Viruses
Ketoconazole	Fungi
Mefloquine (malaria)	Protozoans
Niclosamide (tapeworms)	Helminths
Biltricide (flukes)	Helminths

• Drugs with a broad spectrum of activity are effective against a large variety of microorganisms. An example would be the sulfonamides, which are effective against both gram-positive and gram-negative bacteria, actinomycetes, chlamydias, and some protozoans. These drugs exert their effects on all cell components of the microbes. An advantage of using broad-spectrum antibiotics is the high possibility of efficacy against an unidentified pathogen. The disadvantage of using such a drug is the likelihood of also destroying the normal flora (see Chapter 9, Infection and Disease). Destruction of the normal flora can lead to disease if one organism of the normal flora is replaced by a pathogen. This then leads to what is referred to as a superinfection.

• Drugs with a narrow spectrum of activity, such as isoniazid and penicillin G, are effective only against a relatively small number of microbes, and generally avoid destruction of the normal flora. They target a specific component that is present only in certain bacteria.

• Drugs with a medium spectrum of activity are effective against some gram-positive and gram-negative bacteria, but not all of them.

Selective Toxicity

An ideal antimicrobial drug will kill harmful microorganisms without significant damage to the host. This principle is referred to as selective toxicity. The differences in structure and/or metabolism between the microbe and the host make selective toxicity possible. With greater differences between the pathogen and the host it is easier to develop an effective antimicrobial drug. Regarding toxicity, it is preferable to have a wide range between the toxic dosage level, which can cause damage to the host, and the therapeutic dosage level, which will eliminate the infectious pathogen over a prescribed period of time (see Chapter 21, Pharmacology).

Microbicidal versus Microbiostatic

Antimicrobial drugs that kill microorganisms are referred to as bactericidal; if they prevent microbes from growing they are called bacteriostatic. Ideally the drug being used would eliminate the pathogens by destroying them. Inhibition of microbial growth does not necessarily eliminate the pathogens already present and may require prolonged use of the drug to ensure that high-enough levels are maintained to keep populations from recovering and increasing. Because of the potential negative effects the drugs may have on the host, the use of a killing agent instead of an inhibitory one is not always a simple decision. Microbicidal agents can also kill natural flora in areas such as the healthy intestine, creating a potential digestion problem because the normal resident flora are vital to proper digestion. The destruction of the normal flora population anywhere in or on the body may also create an advantage for competing pathogens that would normally be kept in check by the resident population (superinfection).

Delivery to the Site of Infection

To be effective, drugs need to be easily and effectively delivered to the site of infection. Therefore, an important criterion for the effectiveness (efficacy) of a drug is its ability to cross biological barriers (see Chapter 21, Pharmacology). Potential barriers may be physiological, such as the lining of the body compartments and the blood–brain barrier, or those induced by inflammation and disease. Abscess walls, exudates, and necrotic material are classic examples of host reactions to pathogens and can impede the transport of drugs to the invading microorganisms.

Furthermore, if the antimicrobial drug is not sufficiently soluble or becomes too dilute once in solution, the effectiveness of the drug is greatly diminished. In addition, if the means of delivery and/or transport of the agent does not efficiently and rapidly deliver the antibiotic to the site of infection, the drug will not have the opportunity to fight the pathogen even if it is in solution and in the correct concentration. For example, some agents are effective against a particular infection but are not lipid soluble. Therefore, these compounds are not able to cross the blood–brain barrier, rendering them ineffective against an infection in the central nervous system, such as meningitis. Whereas most antibiotics cannot cross the blood–brain barrier, some third-generation cephalosporins (cefotaxime, ceftizoxime, and ceftriaxone) and metronidazole can.

Time of Activity

It is desirable for an antimicrobial drug to be active over a long period of time for an optimal effect. As covered in Chapter 21 (Pharmacology), the duration of action time is a major consideration when evaluating the overall effect of a drug on an infection/pathogen. If the destruction of a population of pathogens requires a sustained concentration of agent over a specified period of time, any shortening of this time may significantly decrease the effectiveness of the treatment. By subjecting the organisms to the agent for a time that proves to be nonlethal to many of them, the risk of producing a resistant population is increased.

Not Subject to Antimicrobial Resistance

The ideal antimicrobial drug is an agent that is not subject to the development of antimicrobial resistance. If the nature of the agent and its mechanism is such that populations of pathogens are less likely to develop resistance to the agent, its effectiveness and scope of use would be dramatically increased. Because of microbial genetic mutations as well as the acquisition of resistance genes from other cells, viruses, and the environment; it is difficult to develop an antibiotic against which microbes will not eventually develop some resistance (see Resistance to Antimicrobial Drugs).

Complements/Aids in Host’s Own Defenses

The natural defenses of a host, including barriers at portals of entry, protective cells and environments within the host, and an acquired immune system (both active and passive), do an excellent job in fighting off infections in the healthy host (see Chapter 20, The Immune System). When these layers of defense are compromised, antimicrobial drugs need to be administered in order to aid the immune system. Any time a foreign substance is introduced into a host there is a risk of upsetting this complex balance of defenses and actually inhibiting the body’s natural response to pathogens. For example, if an antibiotic harms an organ or system it may adversely affect the natural defenses of the host, causing such things as excessive damage to the kidneys.

Nonallergenic

Certain antimicrobial agents are capable of inducing a hypersensitivity reaction (Chapter 20, The Immune System) in certain individuals. Patients with allergies to specific agents such as penicillin must be careful to inform medical personnel about their allergy, or the shock that may result from receiving penicillin could be fatal.

Dilution/Minimal Inhibitory Concentration Method

In the dilution/minimal inhibitory concentration method a given quantity of the pathogen culture is added to a series of tubes containing decreasing concentrations of a specific antibiotic. The tubes are then incubated and examined for growth. Turbidity (cloudiness) indicates bacterial growth; lack of turbidity signifies that bacterial growth is either inhibited or the organisms have been killed by the antimicrobial agent (Figure 22.4). The goal is to identify the tube with the lowest concentration of drug that inhibits visible growth. This concentration is referred to as the minimal inhibitory concentration (MIC) for a specific agent acting on a selected microorganism. In the past this test was performed in individual test tubes. However, kits are now available wherein the test is performed in shallow wells on standard testing plates. This test is widely used in hospitals and clinics today; however, there are also shortcomings with this method. As with the Kirby-Bauer method, the basic test procedure will not indicate whether an antibiotic is microbicidal or microbiostatic. A second test using this method can be added to determine whether the organisms are being inhibited or killed. In this test a sample from the tube with the lowest concentration showing no growth is subcultured in order to see whether there are any organisms still surviving in the tube. This lowest concentration containing no living organisms is called the minimal bactericidal concentration (MBC).

FIGURE 22.4 Minimal inhibitory concentration.
The minimal inhibitory concentration (MIC) for a specific agent is indicated by the absence of growth in the tube containing the lowest drug concentration.

Serum Killing Power

In the serum killing power method a sample of a patient’s blood is obtained while they are receiving an antibiotic. The blood is then processed to extract the serum, which will contain the drugs that are in the bloodstream. A bacterial suspension is then added to a measured quantity of the patient’s serum. If the bacteria grow in the tube of serum this indicates that the antibiotic is ineffective, whereas no growth indicates it is effective. Using serial dilutions, the lowest concentration that still provides effective serum killing power can be easily determined.

Side Effects

All drugs are potential poisons (see Chapter 21, Pharmacology) and the administration of therapeutic drugs can possibly lead to side effects that can be potentially serious. Drugs can adversely affect the liver (hepatotoxic), kidneys (nephrotoxic), gastrointestinal tract, cardiovascular system, red bone marrow (hemotoxic), nervous system (neurotoxic), respiratory system, integument, bones, and teeth. The administration of drugs involves a previous assessment of the risks and benefits. This type of assessment is referred to as the therapeutic index (see Chapter 21).

The liver is responsible for the metabolism and detoxification of chemical substances in the blood. Liver damage can occur due to a drug or its metabolic by-products. The kidneys are in charge of the excretion of drugs and drug metabolites. Both drugs and their metabolic by-products have the potential to damage the structures of the nephron and therefore are capable of interfering with the filtration and reabsorption ability of the nephron.

One of the most common side effects to antimicrobial therapy is diarrhea, which may progress to severe intestinal irritation and colitis. Most often these irritations occur because of disruption of the normal intestinal flora. The organisms in the normal flora of the skin, intestine, urogenital tract, and oral cavity are with a few exceptions harmless and also prevent the colonization of potentially harmful organisms. However, with the use of broad-spectrum antibiotics these harmless microbes can be destroyed, allowing resistant organisms to overgrow, resulting in a superinfection.

For example, the use of a broad-spectrum cephalosporin for the treatment of Escherichia coli–induced urinary tract infections can also destroy lactobacilli in the vagina. Lactobacilli and Candida albicans are both part of the normal vaginal flora. Lactobacillus will be killed by the broad-spectrum antibiotic, allowing Candida albicans to flourish and cause a yeast infection. Similar superinfections by Candida can also occur in the oral cavity (thrush) and the large intestine.

Antibiotic-associated colitis, a serious and potentially fatal condition, can be caused by oral administration of:

• Tetracyclines

• Clindamycin

• Broad-spectrum penicillins

• Cephalosporins

The condition is a result of the overgrowth of Clostridium difficile, an antibiotic-resistant and endospore-forming bacterium. The organism invades the intestinal mucosa, where it releases toxins (enterotoxins) that result in diarrhea, fever, and abdominal pain. Other drug-induced side effects may involve the skin, either because of an allergic reaction or by interaction of the drugs with sunlight, causing photodermatitis.

The antibiotic tetracycline is contraindicated in children from birth to 8 years of age, because the drug causes permanent discoloration of tooth enamel in this age group. The drug also should be avoided during pregnancy because of its capacity to cross the placenta, followed by its deposition in the developing fetal bones and teeth.

Certain antiparasitic drugs are potentially toxic to the heart, causing irregular heartbeat and in severe cases even cardiac arrest. Other antimicrobial drugs can directly affect the brain, resulting in seizures. Aminoglycosides and some other antimicrobials can cause nerve damage resulting in dizziness, deafness, and motor and sensory disorders.

When using different drugs at the same time, toxic effects can occur that do not come about when the drugs are given alone. Another possibility is that one drug can potentially neutralize another. For example, it has been reported that certain antibiotics can neutralize the effect of contraceptive pills.

Another example of an unwanted side effect is when an individual develops a hypersensitivity (allergic) reaction. Allergic reactions have been reported for most antimicrobial drugs, with penicillin accounting for the majority of antimicrobial drug–induced allergies, followed by sulfonamides. Individuals allergic to these drugs become sensitized during the first exposure, not showing any symptoms. After sensitizing the immune system, a second exposure will result in hives, respiratory problems, and occasionally anaphylaxis that may become fatal (see Hypersensitivity Reactions in Chapter 20, The Immune System). For pregnant women the U.S. Food and Drug Administration (FDA) has identified and classified antibiotics that present no evidence of risk to the fetus.

Resistance to Antimicrobial Drugs

One of the major challenges in healthcare today is the problem caused by bacteria that are already resistant to antimicrobial drugs as well as those that are acquiring resistance at an alarming rate. The evolution of bacteria toward antibiotic resistance, including multidrug resistance, represents an aspect of the general evolution of bacteria and most likely cannot be stopped. Bacterial drug resistance goes beyond the traditional evolutionary mechanisms, because bacteria can pass on drug resistance without having to inherit it. This process occurs via plasmids, the nonchromosomal DNA of bacteria (see Genetics in Chapter 6, Bacteria and Archaea). Furthermore, these plasmids can also be transferred to different species of microorganisms.

Development/Acquisition of Drug Resistance

Resistance of a microorganism to an antibiotic means that the organism is no longer susceptible to the agent’s effects as it had previously been. The development of resistant organisms is a special problem when developing and prescribing microbiostatic agents that are specifically designed not to kill the microbes but just to inhibit their growth.

Microorganisms and specifically bacteria usually acquire their resistance by changes in their genetics, but there are also nongenetic mechanisms that can contribute to resistance. One of these nongenetic means of resistance is a method known as evasion, and is as simple as the pathogens infecting tissue that is out of reach of specific antimicrobial agents (such as the blood–brain barrier). Another method involves alteration of the cell wall into the l-form, (a form of bacterial cell without a developed cell wall), thus modifying the wall enough to prevent antibiotics from attacking the cell wall.

Genetic resistance to antibiotics involves changes in the genes of the microorganisms followed by natural selection favoring these organisms. Those mutations that result in a resistant organism can quickly increase their frequency in a population because many microorganisms have a relatively short generation time and they have a potential survival advantage over organisms that do not have resistance to an antibiotic. The antibiotics themselves do not induce genetic mutations but they instead create a chemical environment that will greatly favor the growth of microbes that have in fact mutated and are resistant.

Any large population of microorganisms, especially bacteria, contains a few cells that are already resistant due to prior transfer of plasmids or by mutation. When the drug is not present in the environment the resistant forms will remain small in numbers, but when the drug is administered, the nonresistant organisms will die and the resistant ones will flourish and multiply (Figure 22.5). This natural selection of drug-resistant forms is common and takes place in a variety of natural habitats, laboratories, and medical environments, as well as in individuals during drug therapy.

FIGURE 22.5 Acquisition of drug resistance.
As drug exposure increases nonresistant cells are eliminated, eventually producing a population consisting only of resistant cells.

In addition to underuse or misuse of antimicrobials, poor patient compliance also adds to the development of resistant strains. The use of antimicrobials for any infection, in any dose, and over any time period, forces microorganisms to adapt or die. This phenomenon is known as selective pressure and the organisms that adapt and survive will pass on the resistant gene.

Mechanisms of Resistance

Once a mutation occurs in bacteria that results in a resistance gene or genes, there are a number of natural mechanisms that can allow the resistance genes to be acquired by nonresistant organisms. The three mechanisms are transduction, transformation, and conjugation (see Chapter 3, Cell Structure and Function). Some cells contain resistance genes on a plasmid called a resistance or R plasmid and may contain as many as six or seven genes, each of which may confer resistance against a number of different antibiotics. Even plasmids can be transferred from one strain or species to another, widening the distribution of the resistance genes even further. These resistance genes confer a variety of different mechanisms of resistance to the microorganisms that possess them.

Several basic mechanisms have been identified and include the following: change in membrane permeability, increased drug elimination, change in the target of the agent (drug receptors), change in some part of the microbial metabolic pathway, change in a previously inhibited enzyme, and the development of enzymes that can destroy or inactivate antimicrobial agents.

• Change in membrane permeability: Changes in the proteins of the plasma membrane interfere with the transport mechanisms and this may prevent some antibiotics from crossing the membrane to enter the cell.

• Increased drug elimination: Resistance to tetracycline can arise through plasmid-encoded proteins that pump the drug out of the cell. Aminoglycoside resistance develops through changes in drug permeability caused by point mutation, affecting proteins in the membrane transport system. Many bacteria have multidrug-resistant pumps capable of actively transporting chemicals, including drugs, out of the cell. These protein pumps are encoded in plasmids or chromosomes; they are not selective and are capable of removing a variety of antimicrobial drugs, detergents, and other substances toxic to the microbe.

• Change in the target (receptor) of the agent: The majority of antimicrobial drugs act on a specific target (receptor) such as a protein, RNA, DNA, or a structure within the plasma membranes. Microbes can avoid attack by antimicrobials by altering the drug target. In other words a change in the DNA can occur and a protein important to the functioning of the target site is altered and antibiotics can no longer bind to and disrupt this target protein. For example, bacteria can become resistant to aminoglycosides by changing ribosomal binding sites. Alterations of binding sites in the cell wall of a bacterium can result in resistance to penicillin by Streptococcus pneumoniae and methicillin by Staphylococcus aureus. Some enterococci have developed resistance to vancomycin by a similar mechanism.

• Change in a metabolic pathway: Microbes can develop an alternative metabolic pathway or enzyme that allows the bypassing of a metabolic reaction that could be inhibited by an antibiotic.

• Change in a previously inhibited enzyme: Modifying an enzyme that was previously being inhibited may prevent a reaction or series of reactions in a bacterial cell. With modification of the enzyme this inhibition by the antibiotic may be prevented and the reactions may occur unhampered.

• Development of defensive enzymes: Bacterial enzymes may be developed that are capable of destroying or inactivating antibiotics before they can act on the bacterial cell. A prominent example of this mechanism is the production of β-lactamase, that is, penicillinase, by some bacteria, which breaks the β-lactam ring in penicillin and destroys its effectiveness. Another β-lactamase, cephaloporinase, disrupts the structure of cephalosporin molecules.

Multiple Resistances

Antimicrobial resistance is a global problem. Historically, antimicrobials were regarded as wonder drugs and have been inappropriately used for infections that did not require the use of antibiotics. Furthermore, antibiotics often were not used for the appropriate length of time to ensure their bactericidal effect. Consequently, antibiotic-resistant bacterial strains emerged. For many years this resistance was overcome by the use of newer, more effective antibiotics. However, the development of new drugs has slowed down and multiple antimicrobial resistant (MAR) strains have emerged. The development of MAR is a serious concern in both human and animal communities as MAR compromises treatment and can potentially lead to increased morbidity and mortality.

The development of multiresistant strains occurs primarily in hospitals, nursing homes, and other healthcare facilities. In these environments the constant use of many different types of antimicrobial agents eliminates sensitive cells while encouraging the development of resistant cells. Multiple drug–resistant strains are often called “superbugs” and are usually resistant to three or more antimicrobial agents. At present, multiresistant organisms include strains from Staphylococcus, Streptococcus, Enterococcus, Pseudomonas, Mycobacterium, and the malaria-causing protozoan Plasmodium. In addition, resistance to only one type of drug unfortunately also may allow resistance to a similar drug by a phenomenon called cross-resistance.

MEDICAL HIGHLIGHTS

Antibiotic Resistance Due to Overuse

Many public health agencies, including the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), have warned about the overuse of antibiotics for infections that do not require them. As a result of misuse, drug-resistant bacterial strains have developed worldwide. One of the most publicized and a dangerous resistant organism is methicillin-resistant Staphylococcus aureus (MRSA), a strain that is resistant to most of the commonly used antibiotics. MRSA infections most frequently occur in people with a weak immune system, usually in patients in healthcare facilities (nosocomial). However, MRSA infections have occurred in otherwise healthy people who have not been hospitalized or had any medical procedures within the past year. These infections are known as community-associated MRSA infections, usually starting as skin infections such as abscesses, boils, and other pus-filled lesions. Infection control is the key to stopping MRSA in hospitals and to prevent community-associated MRSA.

Preventing Drug Resistance

Since the discovery of antibiotics and other antimicrobial drugs, they have been widely used for more than 50 years and over time microbes have developed resistance to many of the agents on the market. This resistance has been determined to be one of the world’s most pressing public health problems. To prevent the spread of antimicrobial drug-resistant microbes and to minimize the evolution of antimicrobial resistance among pathogens the following guidelines should be considered:

• Healthcare professionals and providers should wash their hands thoroughly between patient visits.

• Physicians should not grant patients’ demands for antibiotics when not warranted for the particular infection. Consumers should not demand antibiotics from a physician because the infection may be other than bacterial (e.g., common viral infections).

• Antibiotics when prescribed should target a narrow range of microbes whenever possible.

• Antibiotics may be used in combination in order to kill pathogens that are resistant to one antimicrobial but will be killed by the other (see synergism, discussed previously).

• Hospital and nursing home patients with multidrug-resistant infections should be isolated.

• Physicians should be familiar with local data on antibiotic resistance.

• Patients, when given antibiotics, should take them exactly as prescribed and complete the full course of the treatment to avoid the development of resistant strains.

• Antimicrobials should not be hoarded for later use. Leftover medication should be discarded after completion of the prescribed course of treatment.

• Individuals should not take antimicrobials that have been prescribed to someone else. This may lead to a delay in the correct treatment and also allow bacteria to multiply.

• Antimicrobial soaps and lotions should be used only when protecting a sick individual with a weakened immune system. This will:

• Prevent disruption of the normal flora

• Avoid selecting for resistance

• Prevent the inadvertent selection of naturally resistant bacterial types, which may become emergent pathogens. The human immune system is generally effective at controlling the majority of microbes dominating the environment. The overuse of antimicrobial soaps/lotions may change the composition of microbes in the environment, allowing resistant strains to become dominant.

In 1996 the National Antimicrobial Resistance Monitoring System (NARMS) was implemented to track the emergence of any antimicrobial drug–resistant organisms and strains. Furthermore, the WHO Global Strategy for Containment of Antimicrobial Resistance provides a framework of action for effective containment at various levels.

LIFE APPLICATION

Use of Antibiotics in Livestock

For more than 40 years farmers have used antibiotics in the feeding of poultry, cattle, and pigs to prevent disease and to speed growth. An estimated 9 to 13 million kilograms of antibiotics are used in the United States annually for livestock. The vast majority of antibiotics produced in the United States are used by livestock producers. These large amounts of antibiotics are believed to end up in animal manure that is commonly applied to agricultural land and also may end up in the water supply. It is implied by several agencies that this overuse of antibiotics in livestock contributes to the development of antibiotic-resistant bacterial strains, which is becoming a global crisis threatening human health. The U.S. Food and Drug Administration (FDA) first called for some restrictions in the use of antimicrobials in feed in 1977. While the medical community is trying to educate healthcare providers and patients on the overuse of antibiotics, the debate on the use of antibiotics in animal feed is still ongoing.

Specific Antimicrobial Drugs

A great number of antimicrobial drugs are marketed in the United States. Drug companies market the drugs through physicians, and lately also directly to the consumer via television and Internet advertisements. Although a wide variety of commercial names are used, most of them are variants of a small number of drug families. However, different drug companies assign different trade names to the same generic drug (see Chapter 21, Pharmacology). Antimicrobials can be classified as antibacterial, antiviral, antifungal, antiprotozoan, and antihelminthic agents.

Antibacterial Agents

Antibacterial agents can be subdivided into natural antibiotics, semisynthetic drugs, and synthetic drugs.

• A natural antibiotic is a chemical substance that is produced by a microorganism and has the capacity to either destroy bacteria or inhibit their growth.

• A semisynthetic antibiotic drug is an antibiotic that has been chemically modified for greater efficacy.

• Synthetic drugs are agents produced in the laboratory rather than by a microorganism, but can act identically to antibiotics. Sulfonamides, trimethoprim, and quinolones are man-made drugs and therefore are not considered to be antibiotics, but synthetic antibacterial agents.

Synthetic Drugs

Sulfonamides, or sulfa drugs were the first antimicrobial agents that used the metabolic disruption mechanism successfully against bacteria. Since its discovery by Domagk (see “Why You Need to Know”) many sulfonamides have been developed including sulfadoxine, sulfadimidine (short acting), sulfamethoxazole (intermediate acting), sulfametopyrazine (long acting), sulfasalazine (poor absorption by the gastrointestinal tract), and sulfamethoxazole in combination with trimethoprim. This group of antibacterial agents is manufactured synthetically The mechanism of action is to compete with a metabolic intermediate in the folic acid synthesis pathway in bacteria. Folic acid is essential to the synthesis of purines and pyrimidines, which are the bases used in the construction of nucleic acids and other cellular components in both bacteria and mammals (see Chapter 2 [Chemistry of Life] and Chapter 3 [Cell Structure and Function]). Sulfonamides are selectively toxic to bacteria, which must synthesize folic acid because they are unable to obtain it from the environment. In contrast, humans acquire folic acid from dietary sources; therefore the disruption of the folic acid synthesis pathway will not affect the host. The effectiveness of sulfonamides has been seeing some decline as more bacteria have been developing resistance. Mild to moderate side effects include nausea, vomiting, headache, and mental depression. Its use is also limited because of some allergenic reactions, which are experienced by about 5% of patients. These side effects may include rashes, fever, or hives.

Trimethoprim was introduced in 1969 as a combination with sulfonamides. The agent synergizes sulfonamide activity and minimizes bacterial resistance. Trimethoprim is chemically related to pyrimethamine, an antimalarial drug. Both agents are folate antagonists. Trimethoprim is given orally and is bacteriostatic against most common bacterial pathogens. Because sulfonamides inhibit the same bacterial metabolic pathway, they can potentiate the action of trimethoprim. Side effects of trimethoprim include nausea, vomiting, blood disorders, and skin rashes. Folate deficiency, a toxic effect of the drug, can be prevented by the administration of folinic acid.

Quinolones, also referred to as fluoroquinolones, are broad-spectrum synthetic drugs used to treat a wide variety of bacterial infections. Nalidixic acid was the first quinolone developed but a family of these drugs is being developed, such as ciprofloxacin and doxycycline, which have gained fame as the drugs of choice for treating anthrax. Quinolones are effective against both gram-negative and gram-positive bacteria and are used in treating urinary tract infections, sexually transmitted diseases, gastrointestinal infections, respiratory tract infections, skin infections, and osteomyelitis. The mechanism used by these agents is the disruption of nucleic acid synthesis through binding to the DNA gyrase complex. This enzyme complex is responsible for the unwinding of DNA for replication, repair, transcription, and other DNA cell processes. Quinolones are divided into generations based on their spectrum of activity. In general, the earlier generations have a narrower spectrum of activity than the later generations (Table 22.2). Some side effects may be experienced including gastrointestinal problems and, in some rare cases, seizures or other neural disturbances.

TABLE 22.2

Generations of Quinolones Based on Their Spectrum of Activity

Generation	Generic Name	Trade Name(s)
First generation	Cinoxacin	Cinobac
	Flumequine	Flubactin (veterinary use)
	Nalidixic acid	NegGam, Wintomylon
	Oxolinic acid	Cistopax
	Piromidic acid	Panacid
	Pipemidic acid	Dolcol
Second generation	Ciprofloxacin	Ciprobay, Cipro, Ciproxin
	Enoxacin	Enroxil, Penetrex
	Fleroxacin	Megalone (withdrawn)
	Lomefloxacin	Maxaquin
	Nadifloxacin
	Norfloxacin	Lexinor, Noroxin, Quinabic, Janacin
	Ofloxacin	Floxin, Oxaldin, Tarivid
	Pefloxacin
	Rufloxacin	Uroflox
Third generation	Balofloxacin
	Grepafloxacin	Raxar (withdrawn)
	Levofloxacin	Cravit, Levaquin
	Pazufloxacin mesylate
	Sparfloxacin	Zagam
	Temafloxacin	Omniflox (withdrawn)
	Tosufloxacin
Fourth generation	Clinafloxacin
	Gemifloxacin	Factive
	Moxifloxacin	Avelox
	Gatifloxacin	Tequin (withdrawn), Zymar
	Sitafloxacin
	Trovafloxacin	Trovan (withdrawn)

Antibiotic (Nonsynthetic) and Semisynthetic Antibacterials

Antibiotics are chemotherapeutic agents naturally produced by some microorganisms. Semisynthetic agents, on the other hand, are natural products that have been chemically modified in the laboratory to improve the effectiveness (efficacy) of the antibiotic, expand the spectrum of activity, reduce side effects, and decrease the development of drug resistance.

Penicillin, a natural product produced by the fungus Penicillium chrysogenum, was the first widely used antibiotic. The discovery of penicillin initiated the development of an extensive family of semisynthetic drugs. Penicillins G and V are the most broadly used natural forms of penicillin. The semisynthetics include drugs such as ampicillin and methicillin. Regardless of the derivative, the functional structure common to almost all is the β-lactam ring, which appears to be crucial to the activity of the molecule. The penicillins are effective against sensitive, gram-positive cocci as well as some gram-negative bacteria. Each member of the penicillin family of drugs each has a specific target, such as penicillin G, which is used against Streptococcus and Staphylococcus, or ampicillin, which has a broader spectrum of activity against a number of gram-negative bacteria. The mechanism used by the penicillins is the disruption of cell wall synthesis. Although the exact details of the process are not completely understood, the disruption involves blocking the formation of the chemical bonds that cross-link the layers of peptidoglycan in the cell wall. By preventing the complete assembly of the cell wall, the cell becomes vulnerable to osmotic lysis. Unfortunately, an increasing number of bacteria have developed resistance to penicillin drugs. Many of these resistant organisms synthesize an enzyme called penicillinase, which hydrolyzes a bond in the β-lactam ring, rendering it ineffective. Penicillins have proven to be a relatively safe family of antibiotics although there is a small percentage of the human population, about 1% to 5%, that is allergic to them.

Cephalosporins are a class of β-lactam antibiotics that are structurally similar to penicillins because of the presence of similar β-lactam rings. They also resemble the penicillins because they also inhibit the successful assembly of peptidoglycan in the cell wall. They tend to be more stable than penicillins and have a broader spectrum of activity. Furthermore, cephalosporins are often given to treat infections in patients with penicillin allergies. Another advantage over penicillin is that they resist hydrolysis by penicillinase, an enzyme secreted by a number of bacteria. Four generations of cephalosporins exist and each generation is more effective against gram-negative bacteria (Table 22.3). In general, each generation has a broader spectrum of activity than the previous one, and typically have improved dosing schedules and fewer side effects.

TABLE 22.3

Generations of Cephalosporins Based on Their Spectrum of Activity

Generation	Generic Name	Trade Name(s)
First generation	Cephacetrile	Cephacetrile
	Cefadroxil	Cefadroxil; Duricef
	Cephaloglycin	Kafocin
	Cefalonium	Cephalonium
	Cephaloridine	Cephaloradine
	Cephalothin	Cephalothin; Keflin
	Cephapirin	Cephapirin; Cefadyl
	Cefatrizine	Axelorax
	Cefazolin	Cephazolin; Ancef, Kefzol
	Cephradine	Cephradine; Velosef
	Cefroxadine
	Ceftezole
Second generation	Cefaclor	Ceclor, Distaclor, Keflor, Raniclor
	Cefonicid	Monocid
	Cefprozil	Cefprozil; Cefzil
	Cefuroxime	Zinnat, Zinacef, Ceftin, Biofuroksym
	Cefmetazole
	Cefotetan
	Cefoxitin
Third generation	Cefcapene
	Cefdaloxime
	Cefdinir	Omnicef
	Cefditoren
	Cefetamet
	Cefixime	Suprax
	Cefmenoxime
	Cefodizime
	Cefoperazone	Cefobid
	Cefotaxime	Claforan
	Cefpimizole
	Cefpodoxime	Vantin
	Cefteram
	Ceftibuten	Cedax
	Ceftiofur
	Ceftiolene
	Ceftizoxime	Cefizax
	Ceftriaxone	Rocephin
Fourth generation	Cefclidine
	Cefepime	Maxipime
	Cefluprenam
	Cefoselis
	Cefozopran
	Cefpirome
	Cefquinome

• First-generation drugs have proven to be more effective against gram-positive than gram-negative bacteria.

• Second-generation drugs are effective against gram-positive as well as many gram-negative organisms.

• The third-generation drugs are particularly effective against gram-negative bacteria and are capable of crossing the blood–brain barrier to treat infections in the central nervous system. Furthermore, this generation shows activity against enteric bacteria that produce β-lactamases.

• Fourth-generation cephalosporins have the widest range of activity, are also effective with both gram-positive and gram-negative bacteria, and are rapidly microbicidal.

Tetracyclines are a family of antibiotics with a common four-ring structure to which a number of different side chains are attached. These are broad-spectrum antibiotics that include both naturally produced and semisynthetic drugs. As broad-spectrum agents, these antibiotics are active against both gram-negative and gram-positive bacteria, chlamydias, rickettsias, and mycoplasmas. The mechanism of action is the inhibition of protein synthesis and is typically bacteriostatic and not bactericidal. The host immune response and resistance to the pathogen is ultimately responsible for eliminating the infection. Possible side effects may include nausea, diarrhea, discoloration of teeth, and damage to the liver and kidneys. The first drug of the tetracycline family was introduced in 1948.

Aminoglycosides antibiotics are naturally produced agents with considerable variation in their structure; however, all contain the common characteristics of amino sugars and a cyclohexane ring. These antibiotics are bactericidal and are primarily active against gram-negative organisms. The mechanism of action is the direct disruption of protein synthesis as well as the misreading of mRNA. Some aminoglycosides such as streptomycin are now less effective because of the development of resistance by some target bacteria. It is still effective against tuberculosis and the plague. The aminoglycosides are rather toxic and side effects may include deafness, kidney damage, loss of balance, nausea, and a variety of allergenic reactions.

Macrolides antibiotics are both naturally produced agents such as erythromycin, as well as semisynthetics such as azithromycin. These drugs are composed of a 12- to 22-carbon ring that is linked to one or more sugars. Macrolides are broad-spectrum, bacteriostatic agents with relatively low toxicity. They are effective against gram-positive bacteria, mycoplasmas, and a few select gram-negative bacteria and are useful when fighting infections in patients who are allergic to penicillins. They are also effective in the treatment of whooping cough, diphtheria, gastroenteritis caused by Campylobacter, and pneumonia from Legionella. Newly developed macrolides are being used to treat infections caused by Staphylococcus and Bacteroides. Azithromycin is especially effective against Chlamydia. The mechanism of action is the disruption of protein synthesis by preventing peptide chain elongation at the ribosome.

Chloramphenicol is a potent broad-spectrum, bacteriostatic antibiotic. Originally this agent was produced naturally, but is now manufactured through chemical synthesis. Chloramphenicol has a nitrobenzene structure and its mechanism of action is much like that of the macrolide erythromycin in that it disrupts protein synthesis at the ribosome. Because of the toxicity of this antibiotic its uses are restricted. It is used primarily to treat typhoid fever, brain abscesses, and rickettsial and chlamydial infections. The side effects can be severe and may include the following:

• Allergic reactions

• Neurotoxic reactions

• Irreversible bone marrow damage leading to a fatal form of aplastic anemia

Bacillus Antibiotics Bacitracin and the polymyxins are relatively narrow-spectrum peptide antibiotics that are naturally produced by bacteria of the genus Bacillus. Both bacitracin and polymyxins are topically applied antibiotics that are effective in combating superficial skin infections by Staphylococcus and Streptococcus. The mechanism of action for bacitracin is the disruption of cell wall synthesis, and polymyxins disrupt the cell membrane structure, causing leakage of metabolites. These agents are typically used for the treatment of surface infections, but can be administered internally when the patient can be closely monitored, because of the potential for kidney damage or respiratory arrest.

HEALTHCARE APPLICATION
Antibacterial Agents

Organism	Infection	Drug of Choice	Commercial (Trade) Name(s)
Escherichia coli	Urinary tract infections	Cefotaxime (cephalosporin)	Claforan
Staphylococcus aureus	Abscess, toxic shock syndrome	Penicillinase-resistant penicillin
		Vancomycin	Vancocin, Vancoled, Vancor
		Cephalosporin
Streptococcus pyogenes	Strep throat, rheumatic fever	Penicillin
		Cephalosporin
		Erythromycin	Benzamycin, EryDerm, Erycette, Erygel, Erymax, Ilotycin, Robimycin, Sansac, Staticin, Theramycin Z
Streptococcus pneumoniae	Pneumonia	Penicillin
		Cephalosporin
		Erythromycin
Bacillus	Anthrax	Penicillin
		Doxycycline	Doxycin, Monodox, Apo-Doxy, Vibramycin, Periostat
		Ciprofloxacin	Cipro, Ciloxan
Clostridium	Tetanus, gas gangrene	Penicillin
		Cephalosporin
		Clindamycin	Cleocin, Dalacin, Clinda-Derm
Corynebacterium	Diphtheria	Penicillin
Corynebacterium	Diphtheria	Erythromycin
Mycobacterium	Tuberculosis	Isoniazid	Isotamine, Nydrazid, Rimifon, Laniazid, Stanozide
		Rifampin	Rifadin, Rifamate, Rifater, Rimactane, Rofact
		Pyrazinamide	Tebrazid
		Ethambutol	Etibi, Myambutol
		Streptomycin

Antiviral Agents

Because viruses depend on host cells for replication, it has been a difficult challenge to develop drugs that will destroy or inhibit a virus without also severely affecting the host cell. However, there has been some promise in the development of antiviral drugs that target specific points in the life cycle of viruses. Although this form of treatment for viral infections has shown some success, the agents developed still are limited in their effectiveness and usefulness. Most of these new compounds have modes of action that involve the following:

• Preventing complete penetration of the virus into the host cell

• Blocking transcription and translation of viral molecules

• Steps to prevent maturation of the virus

Unfortunately, most of these drugs are unable to affect viruses in the extracellular environment or when the virus is in a latent state.

Synthetic Antiviral Agents

The search for antiviral agents has resulted in the discovery and development of a number of drugs, such as acyclovir for the treatment of herpes simplex, and azidothymidine for the treatment of AIDS. Additional molecular targets for chemotherapeutic intervention of viral infections have been identified, and novel classes of synthetic antiviral agents have been and are still being discovered.

Purine and pyrimidine analogs are agents involved in the substitution of normal purines and pyrimidines. The molecular analogs results in erroneous genetic information being incorporated into the nucleic acid being synthesized for viral replication. One of the premier drugs in this group is acyclovir (Zovirax), which is an analog of guanine. The agent is rapidly incorporated into cells that are infected with a virus, and it is less toxic than other analogs. Acyclovir is widely used in the treatment of genital herpes, in which it not only interferes with the replication of the virus but also promotes healing of the lesions produced by herpes and is also effective in reducing pain.

Amantadine, a tricyclic amine, is used to prevent influenza A viruses from penetrating cells. As a drug that blocks penetration and uncoating of the virus, it is usually given prophylactically to prevent disease and has proven to be 50% to 80% effective. Side effects include dizziness, confusion, and insomnia.

Azidothymidine (AZT) is an analog group drug that can be designated in its own group, as it is used primarily in the treatment of AIDS. It is an analog of thymidine that inhibits reverse transcriptase, thus blocking DNA synthesis by the retrovirus HIV. This drug does not cure AIDS and is not able to eliminate the latent HIV DNA that may reside in memory T cells and macrophages. AZT is often used along with other antiviral agents in a “cocktail” that is given in relatively high doses to prevent the development of drug resistance.

Interferons are a group of antiviral drugs consisting of proteins produced by cells that are infected with a virus. These naturally produced chemicals induce neighboring cells to produce antiviral proteins that prevent these cells from becoming infected. Some of them are now being genetically engineered to increase their effectiveness. They have shown some positive results in the control of viral hepatitis, warts, and cancers such as Kaposi’s sarcoma and even as a treatment for the “common cold.”

Antifungal Agents

Fungal infections are becoming more frequent because of their opportunistic behavior in immunocompromised individuals, such as those with AIDS and those cancer patients receiving chemotherapy. Moreover, the widespread use of broad-spectrum antibiotics causes the elimination or decrease of the normal, nonpathogenic flora that competes with the fungal population.

Because fungi are eukaryotic cells, unlike bacteria, they present a different challenge when combating infections with chemical agents. Antimicrobial agents designed to combat bacteria are usually ineffective against fungi. The similarities between fungal and human cells make it difficult to develop drugs that are toxic to the fungus but not to the human host. The main groups of drugs currently in use against fungal infections include the following:

• Macrolide polyene antibiotics

Therapeutic antifungal agents can be broadly classified as naturally occurring antifungal agents and synthetic drugs. Most fungal infections are superficial and therefore many preparations are topical. Antifungal medications are toxic to humans and animals, and therefore when systemic therapy is required these agents are used under strict medical supervision.

Synthetic Azoles

Synthetic azoles are broad spectrum, synthetically produced, and designed primarily for use on superficial fungal infections such as athlete’s foot and oral and vaginal candidiasis. The mechanism of action for these agents is the disruption of cell membrane permeability by inhibiting the synthesis of membrane sterols. Some select drugs in this group, such as ketoconazole, can also be administered orally to treat systemic fungal infections. Side effects may include skin irritations when using topical agents, and possible drug interactions with antihistamines and immunosuppressants can occur.

Flucytosine

Flucytosine is a broad-spectrum, synthetic agent that is used to combat systemic fungal infections and some cutaneous mycoses. It can be taken orally and is quickly dissolved in the blood and cerebrospinal fluid. The mechanism of action involves transformation and substitution of flucytosine for uracil in the RNA, thus disrupting RNA function. It is often used in combination with amphotericin B because of the increase in fungi that are resistant to flucytosine. Some side effects may include skin rashes, diarrhea, nausea, aplastic anemia, and liver damage.

Macrolide Polyene Antibiotics

Macrolide polyene antibiotics are naturally produced agents and include amphotericin B and nystatin; the latter are products of the genus Streptomyces. Amphotericin B is arguably the most versatile and effective antifungal agent that is commonly used against systemic mycoses. The mechanism of action is the disruption of cell membrane permeability, causing leakage of metabolites by binding to the sterols. This agent is poorly absorbed from the digestive tract and is therefore administered intravenously. Amphotericin is quite toxic and the side effects can be severe. These effects include abnormal skin sensations, fever and chills, nausea and vomiting, headache, depression, kidney damage, anemia, abnormal heart rhythms, and in some cases blindness.

Griseofulvin

Griseofulvin is a naturally produced, relatively narrow-spectrum agent used primarily to combat localized dermatophyte infections such as athlete’s foot. It is taken orally; deposits in the hair, nails, and epidermis; and is fungistatic. The agent will accumulate in new replacement cells in the area of infection, thus interfering with any further fungal growth. The mechanism of action involves impairing mitotic cell division by disrupting the mitotic spindle apparatus. The eradication of a fungal infection using griseofulvin usually takes from 4 weeks to sometimes over a year. This agent may damage the kidneys and has additional possible side effects of mild headaches, and some gastrointestinal problems.

Echinocandins

Echinocandins are made of a ring of six amino acids, linked to a lipophilic side chain.

Echinocandins inhibit the synthesis of glucan in the cell wall of fungi; they do not have a target in mammalian cells. Their spectrum of activity is rapidly fungicidal against most species of Candida, fungistatic against Aspergillus spp., and can be useful as prophylaxis against the cyst form of Pneumocystis carinii. Echinocandins are administrated intravenously and do represent a major development in the treatment of systemic fungal infections.

HEALTHCARE APPLICATION
Antifungal Drugs

Organism	Infection	Drug of Choice	Commercial (Trade) Name(s)
Aspergillus	Aspergillosis	Amphotericin B	Abelcet, AmBisome, Amphotec, Amphocin, Fungizone
		Azoles
		Flucytosine	Ancobon, Ancotil
Candida albicans	Thrush, vaginal infections	Amphotericin B
Candida albicans	Thrush, vaginal infections	Fluconazole	Diflucan
Blastomyces	Blastomycosis	Ketoconazole	Nizoral
Blastomyces	Blastomycosis	Amphotericin B
Pneumocystis	Pneumonia	Pentamidine	Nebupent, Pentacarinat, Pentam, Pneumopent
Pneumocystis	Pneumonia	Sulfamethoxazole-trimethoprim
Microsporum	Athlete’s foot	Griseofulvin	Fulvicin, Grifulvin, Grisactin
Candida spp.	Candidiasis	Echinocandins	Caspofungin
Aspergillus spp.	Invasive aspergillosis	Echinocandins	Micafungin

Antiprotozoan Agents

Antiprotozoan agents are used in the treatment of parasitic protozoans, which can infect a number of body systems. Although often effective at controlling or even curing these infections, some of these agents have some dramatic and unpleasant side effects due to the fact that the treatment is against eukaryotes, just like human cells. Another inherent difficulty in treating protozoan infections is that many of the organisms have several stages in their life cycles, which may require treatments involving different agents being administered at different stages of the infection. With the exception of quinine, most antiprotozoan drugs are synthetic.

Chloroquine and Primaquine

Synthetically produced chloroquine and primaquine are derived from quinine, a drug obtained from the bark of the cinchona tree, and are widely used in the treatment of the protozoan parasite Plasmodium, which causes malaria. Chloroquine interferes with protein synthesis, particularly in red blood cells, which are the cells infected with the protozoan. The mechanism is not fully understood, but may involve accumulation of the drug in the vacuole of the parasite, which prevents it from metabolizing hemoglobin. A combination of chloroquine and primaquine can be used to protect people who are in regions where malaria occurs by reducing the risk of infection. The regimen involves use of the drugs both before and after entering a malarial zone.

Metronidazole

The synthetic drug metronidazole has been proven to be effective in treating Trichomonas vaginal infections as well as gastrointestinal infections caused by amoeba and Giardia. Its mechanism of action is to disrupt the helical structure of DNA, subsequently inhibiting transcription and protein synthesis. Although effective, it does exhibit some unwanted side effects such as diarrhea, nausea, and “black hairy tongue.” Furthermore, it has been shown to cause some forms of cancer.

Pyrimethamine

Pyrimethamine has been used to both prevent and cure malaria and, when used with sulfanilamide, it can treat other infections such as toxoplasmosis. The mechanism of action involves disruption of the synthesis of folic acid, which is required in the synthesis of DNA and other nucleic acids. Side effects may include nausea, loss of appetite, headaches, dry mouth, and dizziness.

Quinine

Quinine, a nonsynthetic drug, is extracted from the bark of the cinchona tree and has been used for centuries in the treatment of malaria. In the 1940s the widespread use of quinine as a malarial treatment declined because of the development of less toxic agents. It is still in use today in severe cases or when the organism has become resistant to other drugs. The theorized mechanism of action involves the disruption of the parasite’s ability to fully metabolize hemoglobin, which it uses as an energy source. The side effects of quinine may include hearing loss, headaches, nausea, vomiting, diarrhea, confusion, anaphylactic shock, birth defects, and in some cases death due to cardiotoxicity.

HEALTHCARE APPLICATION
Antiprotozoan Drugs

Organism	Infection	Drug of Choice	Commercial (Trade) Name(s)
Giardia lamblia	Giardiasis	Quinacrine
Giardia lamblia	Giardiasis	Metronidazole	Flagyl, Helidac, RTU, Metrolotion, Metrogel, Metromidol, Nidagel, Noritate, Protostat, Satric, Trikacide, Novonidazol
Plasmodium	Malaria	Chloroquine	Aralen
		Primaquine
		Quinine
Trypanosoma cruzi	Chagas’ disease	Nifurtimox	Available only through the CDC
Entamoeba histolytica	Amebiasis	Metronidazole
		Tetracycline
		Paromomycin	Humatin
Toxoplasma gondii	Toxoplasmosis	Pyrimethamine	Daraprim, Fansidar
Toxoplasma gondii	Toxoplasmosis	Sulfadiazine	Lantrisul, Neotrizine, Sulfaloid, Terfonyl, Sulfose
Trypanosoma brucei	Sleeping sickness	Suramin	Available only through the CDC
Trypanosoma brucei	Sleeping sickness	Pentamidine	Nebupent, Pentacarinat, Pentam, Pneumopent

CDC, Centers for Disease Control and Prevention.

Antihelminthic Agents

Numerous helminths can infect humans as pathogenic parasites. The agents used to eliminate these organisms once an infection begins present the same problems faced when using antifungal agents: The agent is aimed at eukaryotic cells, which can have a negative effect on the host body cells. Those agents designed to suppress a metabolic process target those processes that are more important to the helminth than the host. Other agents inhibit the movement of the worm and prevent it from remaining in a specific organ. Some representative agents are presented in the following sections.

Niclosamide

Niclosamide prevents ATP formation and also causes the parasite to release large amounts of lactic acid through interference with carbohydrate metabolism. The lactic acid also appears to inactivate substances made by the worm that resist host proteolytic enzymes.

Mebendazole

Mebendazole blocks the uptake of glucose by the worm. This agent will damage a fetus and is therefore not prescribed for pregnant women.

Piperazine

Piperazine is a strong neurotoxin that paralyzes the body wall muscles of a roundworm, thus paralyzing the worm and allowing it to be expelled in the feces. Typically the drug exerts its effect in the intestine, but if it is absorbed it can travel into the nervous system. This penetration into the nervous system can cause convulsions, especially in children.

Ivermectin

Ivermectin blocks nerve transmission, thereby paralyzing the worm, and is used to treat heartworm infections in dogs as well as river blindness in humans.

HEALTHCARE APPLICATION
Antihelminthic Drugs

Organism	Infection	Drug of Choice	Commercial (Trade) Name(s)
Ascaris lumbricoides	Roundworm	Piperazine	Entacyl
Trichuris trichiura	Whipworm	Mebendazole	Vermox
Enterobius vermicularis	Pinworm	Piperazine	Entacyl
Necator americanus	Hookworm	Piperazine	Etacyl
Necator americanus	Hookworm	Mebendazole	Vermox
Strongyloides stercoralis	Threadworm	Thiabendazole	Mintezol
Trichinella spiralis	Trichinosis	Mebendazole	Vermox
Wuchereria bancrofti	Elephantiasis	Diethylcarbamazine	Hetrazan
Schistosoma mansoni	Schistosomiasis	Praziquantel Metrifonate	Biltricide
Taenia	Tapeworm	Niclosamide	Niclocide
Onchocerca volvulus	River blindness	Ivermectin	Mectizan Stromectol