Resistance development

Development of Resistance. One of the principal disadvantages of sulfonamide therapy is the emergence of dmg-resistant strains of bacteria. Resistance develops by several mechanisms overproduction of PABA (38) altered permeabiUty of the organisms to sulfonamides (39) and reduced affinity of dihydropteroate synthetase for sulfonamides while the affinity for PABA is retained (40). Sulfonamides also show cross-resistance to other sulfonamides but not to other antibacterials. In plasmodia, resistance may occur by means of a bypass mechanism in which the organisms can use preformed foHc acid (41). 

Of increasing concern is the development of mutant strains of tuberculosis that are resistant to many of the aiititubercular drug s currently in use. Bacterial resistance develops, sometimes rapidly, with the use of anti-tubercular drag s. Treatment is individualized and... 

In addition, naturally growing plants resist plant pathogen and Insect attack because resistance develops over time via natural selection (35). Also, most natural and crop plants have, as a part of their basic physical and chemical makeup, a wide array of mechanisms that help them resist pest attack. These Include chemical toxicants, repellents, altered plant nutrients, hairiness, thorns, and diverse combinations of these (35). 

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

In this chapter we describe the current insights into the evolution of viruses under pressure of antiviral therapy and the potential impact on viral fimess. As most recent work in this field has been done in the field of human immunodeficiency virus (HIV), we use the evolution of this virus as the basis for the chapter. Subsequently, we describe resistance evolution for Hepatitis B virus (HBV), where large progress has been made in recent years. Furthermore, we describe the resistance development for Hepatitis C virus (HCV), for which a very active drug development program is undertaken by several pharmaceutical companies. Finally, we discuss resistance evolution for Influenza. 

Initially, it was assumed that the HlV-1 population is infinite, evolution is deterministic, and antiretroviral resistance development is definite (Coffin 1995). However, our research amongst others has demonstrated that the effective population size, defined as the average number of HIV variants that produces infectious progeny is relatively small (Leigh Brown 1997 Leigh Brown and Richman 1997 Nijhnis et al. 1998). This can be explained because the majority of virus particles that are produced harbor deleterious mutations resulting in noninfectious virus. Also limited target cell availability and inactivation of potentially infectious viruses by the host... 

Resistance development is not an all-or-nothing phenomenon and in general gradually increases over time. Overall, three phases in the evolution of antiretroviral drug resistance can be discerned (Fig. 1). 

Oleandomycin, its ester (triacetyloleandomycin) and spiran rdn have a similar range of activity as erythromycin but are less active. Resistance develops only slowly in chnical practice. However, cross-resistance may occur between all four members of this group. 

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