Porth's Essentials of Pathophysiology, 4e

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Mechanisms of Infectious Disease

C h a p t e r 1 4

are interference with a specific step in bacterial cell wall synthesis (e.g., penicillins, cephalosporins); inhibition of bacterial protein synthesis (e.g., aminoglycosides, tet- racyclines); interruption of nucleic acid synthesis (e.g., fluoroquinolones, nalidixic acid); and interference with normal metabolism (e.g., sulfonamides, trimethoprim). Of great concern is the increasing prevalence of bacte- ria resistant to the effects of antibiotics. The mechanisms by which bacteria acquire resistance to antibiotics include the production of enzymes that inactivate antibiotics, such as β -lactamases; genetic mutations that alter antibiotic binding sites; alternative metabolic pathways that bypass antibiotic activity; and changes in the filtration qualities of the bacterial cell wall that prevent access of antibiot- ics to the target site in the organism. It is the continuous search for a “better mousetrap” that makes anti-infective therapy such a fascinating aspect of infectious diseases. Antiviral Agents Until recently, few effective antiviral agents were avail- able for treating human infections. The reason for this is host toxicity; viral replication requires the use of eukaryotic host cell enzymes, and the drugs that effec- tively interrupt viral replication are likely to interfere with host cell reproduction as well. Almost all antiviral compounds are synthetic and, with few exceptions, their primary target is viral RNA or DNA synthesis. Like antibiotics, antiviral agents may be active against RNA viruses only, DNA viruses only, or occasionally both. A common class of antiviral drugs is the nucleoside analogs, which include agents such as acyclovir. These mimic the nucleoside building blocks of RNA and DNA. During active viral replication, the nucleoside analogs inhibit the viral DNA polymerase, preventing duplication of the viral genome and thus limiting the spread of infectious viral progeny to other susceptible host cells. In response to the AIDS epidemic, there has been mas- sive, albeit delayed, development of antiretroviral agents capable of targeting the replication of HIV, a retrovirus (see Chapter 16). These include the nucleoside analogs such as zidovudine as well as nonnucleoside inhibitors, which impair the synthesis of the HIV-specific enzyme reverse transcriptase. This key enzyme is essential for viral replication and has no counterpart in the infected eukaryotic host cells. Another class of antiviral agents developed solely for the treatment of HIV infections are the protease inhibitors. These drugs inhibit an HIV- specific enzyme that is necessary for late maturation events in the virus life cycle. Antifungal Agents The target site of the two most important families of antifungal agents is the cytoplasmic membranes of yeasts or molds. Fungal membranes differ from human cell membranes in that they contain the sterol ergos- terol instead of cholesterol. The polyene family of

antifungal compounds (e.g., amphotericin B, nystatin) preferentially binds to ergosterol and forms holes in the cell membrane, causing leakage of the fungal cell con- tents and, eventually, lysis of the cell. The imidazole class of drugs (e.g., fluconazole, itraconazole) inhibits the synthesis of ergosterol, thereby damaging the integ- rity of the fungal cytoplasmic membrane. Both types of drugs bind to a certain extent to the cholesterol compo- nent of host cell membranes and elicit a variety of toxic side effects in treated patients. A new class of antifungal agents known as the echi- nocandins (e.g., caspofungin, micafungin, and anidula- fungin) inhibit synthesis of the glucan in the cell wall, preventing the fungal cell wall from cross-linking. The lack of cross-linking causes the cell wall to become unstable and eventually lyse. The echinocandins are pri- marily active against Candida and Aspergillus. Surgical Interventions Before the discovery of antimicrobial agents, surgical removal of infected tissues, organs, or limbs was occa- sionally the only option available to prevent the demise of the infected host. Today, medicinal therapy with antibiotics and other anti-infective agents is an effective solution for most infectious diseases. However, surgi- cal intervention is still an important option for cases in which the pathogen is resistant to available treatments. Surgical interventions may be used to hasten the recov- ery process by providing access to an infected site by antimicrobial agents (drainage of an abscess), cleaning the site (débridement), or removing infected organs or tissue (e.g., appendectomy). In some situations, surgery may be the only means to a complete cure, as in the case of endocarditis resulting in an infected heart valve, in which the diseased valve must be replaced with a mechanical or biologic valve to restore normal function. In other situations, surgical containment of a rapidly progressing infectious process such as gas gangrene may be the only means of saving a person’s life.

SUMMARY CONCEPTS

■■ The goal for treatment of infectious disease is complete removal of the infectious agent from the host and restoration of normal physiologic function to damaged tissues. ■■ Treatment methods include the use of antimicrobial agents and, when necessary, surgical interventions that provide access to an infected site by antimicrobial agents (drainage of an abscess), clean the site (débridement), or remove infected organs or tissue (e.g., appendectomy).