War with the Superbugs ith respect to antimicrobial drugs, the future challenge is already upon us. The challenge is to maintain the effectiveness of antimicrobials by (1) preventing the continued spread of resistance, and (2) developing new drugs that have even more desirable properties. New ways must be developed to fight infections caused by the ever greater numbers of bacterial strains that are resistant to the effects of conventional antimicrobial drugs. Several strategies are being used to develop potential weapons against these new "superbugs."

One way to combat resistance is to continue developing modifications of existing antimicrobial drugs. Researchers constantly work to modify drugs chemically, trying to keep at least one step ahead of bacterial resistance. Another method to foil drug resistance is to interfere with the resistance mechanism itself, as is done currently in using f-lactamase inhibitors in combination with f-lactam drugs to protect the antimicrobial drug from enzymatic destruction. Likewise, it may be possible to thwart resistance using other mechanisms—-for example, developing chemicals that can be used to inactivate or interfere with bacterial efflux systems.

Other researchers are focusing on developing new drugs that are entirely unrelated to conventional antimicrobials. One example is a class of compounds called defensins, which are short peptides, approximately 29 to 35 amino acids in length, produced naturally by a variety of eukaryotic cells to fight infections. Various defensins and related compounds are being intensively studied as promising antimicrobials.

Accumulating knowledge of the genetic sequences of pathogens and identification of genes associated with pathogenicity may allow development of antimicrobials that interfere directly with those processes. The "master switch" that controls expression of virulence determinants is one such potential target. Nucleotide sequence information and determination of the three-dimensional conformation of proteins may uncover new targets for antimicrobial drug therapy.

Future Challenges 529

Table 21.5 Characteristics of Some Antiprotozoan and Antihelminthic Drugs

Causative Agent/Drug


Intestinal protozoa Iodoquinol Nitroimidazoles Metronidazole Quinacrine

Plasmodium (Malaria) and Toxoplasma

Folate antagonists

Pyrimethamine, sulfonamide Quinolones

Chloroquine, mefloquine, primaquine, tafenoquine

Trypanosomes and Leishmania


Heavy metals

Melarsoprol, sodium stibogluconate, meglumine antimonate


Intestinal and Tissue Helminths

Avermectins Ivermectin


Mebendazole, thiabendazole, albendazole


Niclosamide Piperazines Piperazine, diethylcarbamazine

Pyrazinoisoquinolines Praziquantel

Mechanism unknown. Poorly absorbed but taken orally to eliminate amebic cysts in the intestine.

Activated by the metabolism of anaerobic organisms. Interferes with electron transfer and alters DNA. Does not reliably eliminate the cyst stage. Metranidazole is also used to treat infections caused by anaerobic bacteria.

Mechanism of action is unknown, but it may be due to interference with nucleic acid synthesis.

Interferes with folate metabolism. Used to treat toxoplasmosis and malaria.

The mechanism of action is not completely clear. Chloroquine is concentrated in infected red blood cells and is the drug of choice for preventing or treating the red blood cell stage of the malarial parasite. Its effects may be due to inhibition of an enzyme that protects the parasite from the toxic by-products of hemoglobin degradation. Primaquine and tafenoquine destroy the liver stage of the parasite and are used to treat relapsing forms of malaria. Mefloquine is used to treat infections caused by chloroquine-resistant strains of the malarial parasite.

Used to treat infections caused by some types of Trypanosoma. It inhibits the enzyme ornithine decarboxylase.

These inactivate sulfhydryl groups of parasitic enzymes, but they are very toxic to host cells as well. Melarsoprol is used to treat trypanosomiasis, but the treatment itself is often lethal. Sodium stibogluconate and meglumine antimonate are used to treat leishmaniasis.

Widely used to treat acute Chagas' disease; it forms reactive oxygen radicals that are toxic to the parasite as well as the host.

Ivermectin causes neuromuscular paralysis in parasites. It is used to treat infections caused by Strongyloides and tissue nematodes.

Mebendazole binds to tubulin of helminths, blocking microtubule assembly and inhibiting glucose uptake. It is poorly absorbed in the intestine, making it effective for treating intestinal, but not tissue, helminths.Thiabendazole may have a similar mechanism, but it is well absorbed and has many toxic side effects. Albendazole is used to treat tissue infections caused by Echinococcus and Taenia solium.

Absorbed by cestodes in the intestinal tract, but not by the human host.

Piperazine causes a flaccid paralysis in worms and can be used to treat infections caused by Ascaris. Diethylcarbamazine immobilizes filarial worms and alters their surface, which enhances killing by the immune system.The resulting inflammatory response, however, causes tissue damage.

A single dose of praziquantel is effective in eliminating a wide variety of trematodes and cestodes. It is taken up but not metabolized by the worm, ultimately causing tetanic contractions of the worm.

Tetrahydropyrimidines Pyrantel pamoate, oxantel

Pyrantel pamoate interferes with neuromuscular activity of worms, causing a type of paralysis. It is not readily absorbed from the gastrointestinal tract and is active against intestinal worms including pinworm, hookworm, and Ascaris. Oxantel can be used to treat Trichuris infections.

530 Chapter 21 Antimicrobial Medications

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