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Drug interaction studies should be considered for drugs that are likely to be administered concomitantly to large numbers of patients. The drugs may be indicated for the same disease process, and their use in combination is considered therapeutically rational. Alternatively, the drugs may have different indications, but the two disease processes occur frequently in the same population. Drugs involved in interactions are divided into precipitant drugs (drugs that cause a change in the pharmacokinetics or pharmacodynamics of another drug) and the object drug (drug affected by the precipitant drug). A drug can act as a precipitant drug and an object drug at the same time when two drugs affect each other during concomitant administration. [ABSTRACT FROM AUTHOR]

There are numerous opportunities for drug interactions involving antimicrobial agents. The potential for drug interactions encountered in clinical practice continues to grow as the number of different antimicrobial classes expands, the number of specific agents within these drug classes increases, and antimicrobial drug regimens become more complex (e.g., treatment of mycobacterial infection and human immunodeficiency virus [HIV] disease). In addition, antimicrobials are commonly used in certain patient populations (e.g., critically ill, elderly, or HIV-infected patients) for whom many drugs of various classes are used, and the potential for drug interactions therefore increases as a function of the number and types of drugs present. Many interactions are of minimal clinical importance and often ignored. However, other interactions are associated with substantial risk of adverse pharmacokinetic or pharmacodynamic interactions, resulting in decreased therapeutic efficacy, increased incidence of drug toxicities, or potential for increased antimicrobial resistance. Thus, the ability to prevent or minimize adverse drug interactions is of vital importance in optimizing the appropriate and effective use of antimicrobials and enhancing patient outcome. [ABSTRACT FROM AUTHOR]

The term drug-cytokine interaction was proposed to describe the interactions between the mediators of the acute-phase response (APR) and drug metabolism (1). This potential for drug-cytokine interactions has been appreciated in the laboratory since at least 1966 (2) and in clinical practice since the late 1970s (3,4). The APR (5) to infection or injury, with its complex cascade of cytokines, endocrine hormones, free oxygen radicals, arachidonic acid metabolites, catecholamines, reactive oxygen species, and nitric oxide, can have multiple effects on the pharmacokinetic and pharmacodynamic properties of many drugs. Disturbances in drug disposition and action can be caused by many physiological changes, including alterations in protein binding, expansion of extracellular fluid volume, end-organ dysfunction (liver and kidney), changes in organ perfusion, hemodynamic compromise, hypoxia, and alterations in receptor availability or responsiveness (6). A report put a novel twist on the drug-cytokine interaction definition. Brooks et al. (7) reported that the β-lactam antibiotic benzylpenicillin conjugated with interferon-γ and reduced the cytokine's immune responses. [ABSTRACT FROM AUTHOR]

Drug-food interactions can be a major source of patient inconvenience and nonadherence through disruptions in a patient's daily schedule. Unless advised to the contrary, patients often take drugs with meals as a suitable adherence reminder and to lessen gastrointestinal (GI) side effects. Lack of knowledge of potentially significant drug-food interactions can lead to poor clinical outcomes. This chapter describes mechanisms of drug-food interactions and US Food and Drug Administration (FDA) guidelines for drug-food interaction studies. Antimicrobial drug-food interactions based on drug classes and pharmacokinetics are described, as are the recommended dosing guidelines. In addition, anti-infectives and the disulfiramlike reaction and two case studies are included. [ABSTRACT FROM AUTHOR]

This chapter discusses the interactions of antibiotics that may be the only available agents from a class of antibiotics that is used clinically today. Chloramphenicol and tetracycline are older agents that are less frequently prescribed; so many clinicians may not be familiar with their interactions with other medications. Many of the interacting agents also are less frequently prescribed, such as first-generation oral hypoglycemic agents. Because many of the interactions in this chapter are based on single case reports, it is difficult to determine the mechanism of the interaction and if a true interaction exists. The existence of some interactions may be questioned because of other potential causes that may have been present when the interaction was discovered. [ABSTRACT FROM AUTHOR]

During the past several decades, fungi have become increasingly common pathogens, particularly among critically ill or immunosuppressed patients. Until recently, advances in antifungal therapy had not kept pace with this trend. Historically, antifungal development significantly lagged behind that of antibacterial therapy. For many years, there were few choices for the treatment of systemic mycoses. However, the recent past has seen the development of a new class of antifungal agents (the echinocandins); safer or more bioavailable formulations of marketed antifungal agents (itraconazole oral and iv solution, lipid formulations of amphotericin B); and a new addition to an existing class of agents (voriconazole). Today, antifungal agents differ sufficiently in terms of activity, toxicity, and drug interaction potential so that clinicians now have the luxury of considering these characteristics when tailoring therapy to treat a specific systemic fungal infection. Systemically acting antifungal agents can cause drug—drug interactions by a variety of mechanisms. Therefore, they have the potential to interact with a vast array of medicines. Given the patient populations in whom systemic mycoses typically occur, the increased use of antifungal therapy, and the growing but still relatively limited selection of antifungal agents, clinicians must understand the drug interaction profile of this small but increasingly important class of drugs. [ABSTRACT FROM AUTHOR]

The β-lactam antibiotics are a large class of diverse compounds used clinically in both the oral and parenteral forms. The β-lactam antibiotic agents have become the most widely used therapeutic class of antimicrobials because of their broad antibacterial spectrum and excellent safety profile. Reports of drug-drug interactions with the β-lactam antimicrobials are a relatively rare phenomenon, and when interactions do occur, they are generally minor. This chapter describes the drug-drug interactions of the β-lactam antibiotics: penicillins, cephalosporins, carbapenems, and monobactams. [ABSTRACT FROM AUTHOR]

Drug-drug interactions can be categorized into those originating from pharmacokinetic mechanisms and those originating from pharmacodynamic mechanisms. Pharmacokinetic interactions are those that result in alterations of drug absorption, distribution, metabolism, and elimination; pharmacodynamic interactions occur when one drug affects the actions of another drug. This chapter deals only with the pharmacokinetic and pharmacodynamic interactions of fluoroquinolone (hereafter referred to as quinolone) with non-antimicrobial agents. Additive, synergistic, or antagonistic antimicrobial activity interactions between quinolones and other antimicrobials are not discussed. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains one of the most prevalent infectious killers on the planet. Given the broad range of interactions associated with rifamycins, it is highly likely TB patients will be at risk of drug interactions. Since TB and human immunodeficiency virus (HIV) often co-exist as infections, it is inevitable that drug interactions will occur in this population. [ABSTRACT FROM AUTHOR]

As outlined in Chapter 5, drug interactions in human immunodeficiency virus (HIV) are encountered frequently, particularly with protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). In a retrospective chart review of 165 HIV patients newly prescribed a protease inhibitor, at least one potential drug interaction was identified in 82 (49.7%) of the patients (1). In total, 111 interactions were identified, but only 22 (19.8%) were recognized at the time of protease inhibitor therapy initiation. An additional 12 drug interactions were later identified at follow-up, but 77 (69.3%) were never recognized. At the time this study was conducted, only three protease inhibitors (saquinavir, ritonavir, and indinavir) were available. More recently, in a chart review of 189 ambulatory HIV patients, 466 interactions were identified in 153 subjects for an average of 2.46 interactions per patient (2). [ABSTRACT FROM AUTHOR]

More than 20 years of research in human immunodeficiency virus (HIV) infection has led to remarkable scientific breakthroughs in drug development. Although the use of highly active antiretroviral therapy (HAART) has dramatically altered survival rates, these complex regimens remain challenging to use, even to the experienced practitioner. In no other disease state does the management and exploitation of drug interactions play such a critical role as it does in HIV disease. Because there are so many potential drug interactions in HIV-infected patients, this book includes two chapters pertaining to HIV/AIDS (acquired immunodeficiency syndrome). This chapter describes the clinically important interactions associated with the four classes of antiretrovirals and discusses management strategies to improve patient outcome. Chapter 6 discusses interactions with antiretroviral agents and agents for opportunistic infections. [ABSTRACT FROM AUTHOR]

Regulatory review scientists have been interested in the impact of drug interactions on the safety and efficacy of drugs for many years; however, a number of regulatory actions highlight the importance of the issue. The withdrawals of terfenadine, astemizole, and cisapride were related, in part, to safety concerns when drug interactions with cytochrome P450 (CYP) 3A inhibitors led to higher plasma drug concentrations. Mibefradil is a CYP3A inhibitor that was withdrawn because of drug interactions that led to markedly increased concentrations of CYP3A substrates. In 2002, a Food and Drug Administration (FDA) advisory committee recommended against approval of pleconaril for the treatment of the common cold partly because of the potential for drug interactions (1). Pleconaril is a CYP3A inducer, and its administration may decrease plasma concentrations of CYP3A substrates, including some contraceptive steroids (2). We can reflect on these examples when we consider the appropriate timing of drug interaction evaluations and the appropriate methods to communicate the risk of drug interactions. [ABSTRACT FROM AUTHOR]

Drug interactions continue to be an important consideration for patients receiving antimicrobial chemotherapy. The clinical significance of drug interactions in patients receiving anti-infectives has been spotlighted by numerous reports of drug interactions among patients taking antiretroviral therapy (1). As a result, considerable progress has been made in describing the mechanisms by which drug interactions occur; this has led to increased ability to recognize and manage clinically significant drug interactions. Although much of the success in managing drug interactions can be attributed to increased knowledge of cytochrome P450 (CYP)-mediated drug metabolism, drug transport mechanisms are increasingly recognized as a means by which clinically relevant drug interactions occur among anti-infective agents (2). [ABSTRACT FROM AUTHOR]

Each year, 150 million outpatient prescriptions for antibiotics are dispensed in the United States (1). In institutional settings, 25 to 35% of hospitalized patients receive antibiotic treatment for active infections or to prevent infections (2). Given that antibiotics represent global sales of approx $20 billion of a $370 billion pharmaceutical market, one can assume that many patients who are prescribed antibiotics are also receiving other agents (3). Therefore, the potential for drug interactions is significant. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV), more than any other disease, is responsible for the renewed interest in drug interactions by physicians, pharmacists, nurses, scientists, and regulatory agencies. The importance of managing drug interactions in infectious diseases moved to the forefront as more drugs spanning the different classes of infectious disease agents became available to treat HIV and prevent or treat opportunistic infections and HIV-related malignancies. This has led to recognition of the potential for and impact of drug interactions in other infectious diseases and with a variety of anti-infective drug classes. Recent reviews (1-4), including those in this volume, and the development of computerized drug interaction databases (5) further attest to the revived interest and importance of drug interactions in the different therapeutic areas of infectious diseases. [ABSTRACT FROM AUTHOR]