Overview of Chemotherapeutics
Treatment with any chemotherapeutic agent involves an understanding of the complex interrelationships among the host animal, the infecting pathogen, and the drug, the interactions of which comprise the chemotherapeutic triangle. The advent of resistance places further emphasis on consideration of these factors when selecting a dosing regimen. That the FDA struggles to identify the most reasonable way to approve antimicrobials while maintaining high standards of proof of efficacy and safety as well as clinician flexibility in the design of dosing regimens is a testament to the complex host, drug, and microbial interactions associated with infections.
Chemotherapy is the use of chemical agents in treatment or control of disease. However, the term is most often used in the context of controlling harmful pathogens through their chemical destruction. As such, the chemotherapeutic armamentarium includes antibacterial, antiviral, antifungal, antiparasitic, and antineoplastic compounds.
Chemotherapeutic agents may be selectively toxic to invade micro- or macroorganisms, but in many cases, they can also result in adverse effects in the host. This is particularly true when the infecting pathogen is eukaryotic (eg, fungal organisms, cancer cells) versus prokaryotic (eg, bacterial). To avoid toxic manifestations, particularly for drugs targeting eukaryotes, the dose rate often becomes critical; additionally, the clinical condition of the animal and concurrently administered drugs can be responsible for adverse events.
This discussion of chemotherapeutic agents focuses on infecting bacterial pathogens; fungal and viral pathogens are discussed in their respective chapters. Any time a drug is used with the intent to kill the target, multiple factors impact therapeutic success. The most obvious is that the target organism will implement mechanisms whereby it can avoid harm, the most notable being resistance mechanisms. However, microbes in particular are associated with numerous virulence factors and other mechanisms for self-protection, often also making the host sick at the same time. Likewise, host factors, which seemingly should help the host fend off infection, can become detrimental to therapeutic success. For most infections, a functional immune system is paramount to therapeutic success. Drug factors also influence therapeutic success, most notably because drugs must be able to penetrate any body tissue to successfully kill the microbe. These include the interactions between the three points of the chemotherapeutic triangle: host, microbe, and drug. If the goal of antimicrobial therapy is to simply resolve clinical signs of infection, then attention may not be given to the critically important aspects of therapy. In general, the use of an antimicrobial to which an isolate is susceptible will reduce the size of the infecting innoculum but is likely to leave behind a residual, yet resistant, inoculum. Immunocompetent animals are more likely to eradicate this residual population, but at-risk animals may not. As such, the population may regrow to a size capable of once again causing clinical signs (eg, 103–105 CFU in the urinary tract). Much of the following discussion is intended to support the design of dosing regimens (appropriate choice of drug, dose, and interval) that maximize antimicrobial efficacy while minimizing the risk of emergent antimicrobial resistance.