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Overview of Chemotherapeutics


Treatment with any chemotherapeutic agent involves an understanding of the interrelationships among the host animal, the pathogen, and the drug. These relationships comprise the chemotherapeutic triangle (seefigure). The advent of professional flexible labeling places further emphasis on consideration of these factors when selecting a dosing regimen. That the FDA struggles to identify the most reasonable method of approving antimicrobials while maintaining high standards of proof of efficacy and safety and clinician flexibility in the design of dosing regimens is a testament to the complex host, drug, and microbial interactions associated with infections.

Fig. 1

The chemotherapeutic armamentarium includes antibacterial, antiviral, antifungal, antiparasitic, and antineoplastic compounds. The basic mechanisms through which many of these agents exert their effects against pathogens are known. More importantly, the methods by which harmful organisms may protect themselves against the action of specific drugs are also becoming better understood. The pharmacologic modulation of these processes has added new dimensions to modern chemotherapeutics.

Chemotherapeutic agents may be selectively toxic for invading micro- or macro-organisms, but in many cases, they can also result in adverse effects in the host. This is particularly true when the infecting microbe is eukaryotic (eg, fungal organisms) compared to prokaryotic (eg, bacterial). To avoid toxic manifestations, particularly for antifungal drugs, the dose rate often becomes critical; additionally, the clinical condition of the animal and concurrently administered drugs can be responsible.

Factors related to the animal, the antimicrobial agent, and the pathogenic organism all play significant roles in therapeutic success with antimicrobial agents. Chemotherapeutic agents that are absorbed or injected into the body are eliminated by the same processes as with other xenobiotics. Differences in how the body handles these drugs can impact efficacy. The effect that disease may have on the absorption, distribution, biotransformation, and excretion of a therapeutic agent also may be of notable clinical significance.

The effect of the pathogen on the host and its response to infection are also important components of the chemotherapeutic triangle. The pathogenesis of the disease, the pathophysiologic reactions, and the resultant lesions may have important bearings on clinical management; in addition to appropriate chemotherapy, supportive and adjunctive treatment may be crucial for success. Therapeutic measures such as fluids, blood transfusion, antisera, anti-inflammatory drugs, positive inotropic agents, and bronchodilators could well be life-saving, depending on the particular case.

The microbe itself can profoundly impact therapeutic success, beyond its ability to cause infection, through production of toxins (exo- or endo-) or other chemicals that induce a host inflammatory response. Production of protective materials such as glycocalyx (a biofilm) may alter the ability of the drug to penetrate the microbe.

Also, nonspecific and specific immune mechanisms play a vital role as part of the animal's response to an invading pathogen. The immunocompetence of the animal should always be assessed, recognizing that extraneous factors, stress, disease, malnutrition, and the effects of concurrently administered drugs may influence the animal's ability to resist infection. Host defense systems are seriously compromised in bone marrow depression, hypogammaglobulinemia, conditions in which alveolar macrophages are incapacitated, tracheobronchitis, necrotic enteritis, starvation, and other conditions. In addition, immunosuppressants (eg, corticosteroids and antineoplastics) compromise immune response. Any depression of immune capabilities can be expected to modify the effectiveness of many antimicrobial agents, especially those for which only bacteriostatic activity is achieved at the site of infection. Host defense mechanisms should be sustained by whatever means possible when treating an infectious or parasitic disease; otherwise, protracted recovery or relapses are likely inevitable. Minimizing stress, providing quality nutritional support, administering specific immunoglobulins, and using immunopotentiators are some of the approaches that may be used. These general principles apply to all classes of chemotherapeutic agents.

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP

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