Antimicrobial agents are used to kill or suppress the growth of microorganisms and are used widely both to treat and prevent infection. In order to understand how antimicrobial drugs work it is necessary to understand the anatomy and structure of microorganisms.

An antimicrobial is defined as a drug that kills, prevents, or inhibits the growth of any type of microorganism (1). These drugs originate from a variety of sources, including microorganisms, plants, animals, and can be semi-synthetic or synthetic. Antimicrobials can be antibacterial, antimycobacterial, antifungal, antiparasitic and antiviral (2). Strictly speaking, the term ‘antibiotic’ refers to an agent produced by a microorganism that kills another microorganism; it does not include synthetic substances (3). However, this specific meaning is often not emphasised in clinical practice. Therefore, in this book, the terms antibacterial and antibiotic will be used interchangeably.

WITH THE continuing development of clinical drug resistance among bacteria and the advent of resistance to the more recently released agents quinupristin/dalfopristin and linezolid, the need for new, effective agents to treat multidrug-resistant gram-positive infections remains important. With treatment options limited, it has become critical to identify antibiotics with novel mechanisms of activity. Several new drugs have emerged as possible therapeutic alternatives. This chapter focuses on agents newly introduced and those currently in clinical development for the treatment of skin and skin structure infections. In addition, novel antifungal agents will be reviewed, as will novel dosing of antiviral agents for herpes labialis.

NOVEL ANTIBACTERIAL AGENTS

There has been an alarming increase in the incidence of gram-positive infections, including resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and drug-resistant pneumococci. Although vancomycin has been considered the drug of last defense against gram-positive multidrug-resistant bacteria, strains of vancomycin-resistant bacteria, including vancomycin-resistant enterococci (VRE), began to emerge by the late 1980s. More recently, strains of vancomycin-intermediate-resistant S. aureus (VISA) have been isolated.

Gram-positive bacteria, such as S. aureus and Streptococcus pyogenes, are often the cause of both uncomplicated and complicated skin and skin structure infections. Uncomplicated infections are mild, localized to the skin, and responsive to topical or systemic antibiotics. This category includes simple abscesses, impetiginized lesions, furuncles, and cellulitis. Complicated infections are those involving deeper soft tissues and requiring surgical intervention or associated with significant systemic disease or comorbidities.

Antimicrobials have revolutionised clinical care, but their use and misuse has contributed to the current drug-resistance emergency. The prescription of antimicrobials demand that prescribers demonstrate technical skills such as knowledge about pharmacokinetic and pharmacodynamics, up-to-date awareness of emerging infections and understanding of local and national drug susceptibility. In addition to these skills, prescribers must also demonstrate optimal and effective communication with patients, particularly when antibiotics are not warranted. These ‘softer’ skills are essential to balance the influence of social or cultural factors on decisions by all stakeholders involved in antibiotic usage. To balance these demands, prescribers can engage in systematic decision making that reflects upon the need and benefits of using antimicrobials. This will ensure that optimal diagnostic and imaging tests inform such decisions; following recognised guidance and best practice, whilst acknowledging the local drug susceptibilities and available resources; and engage and support patients and families to share decisions about antibiotic use and follow-up care.

The factors that must be assessed before choosing antimicrobial therapy are shown in Figure 42.1.

INTRODUCTION – PRINCIPLES OF ANTIMICROBIAL USE

Pharmacokinetics and Pharmacodynamics

Many factors affect the choice of an antimicrobial agent in the acute care setting. Selection of an agent with in vitro activity against the infecting pathogen is necessary but not sufficient. Pharmacokinetic (distribution of the drug in the body) and pharmacodynamic (effect of the drug on its target) factors must also be taken into account. The most important pharmacokinetic consideration is the concentration of the drug at the site of infection. The physicochemical properties of antimicrobials determine their distribution throughout the body, and these properties may be unfavorable for the penetration of certain tissue compartments.

Sites of particular concern for the adequate penetration of antimicrobials include bone, compartments of the eye, and the central nervous system. Additionally, abscess cavities are poorly penetrated and should be drained regardless of whether systemic antimicrobial therapy is to be used. Even treatment of pulmonary and urinary tract infections depends on site-specific penetration, and recommendations for standard therapies reflect this. Thus, clinicians should rely on standard therapy or use alternative drugs that are documented to achieve effective concentrations at the site of interest. Unfortunately, data as to the relative penetration of different drugs may be lacking, although predictions based on physicochemical characteristics (e.g., protein binding) can be made.

An important pharmacodynamic distinction is whether a drug's activity is bactericidal or bacteriostatic.

Prevention

Chemoprophylaxis is the use of an antimicrobial agent to prevent infection. Chemoprophylaxis is often administered after exposure to a virulent pathogen or before a procedure associated with risk of infection. Chronic chemoprophylaxis is sometimes administered to persons with underlying conditions that predispose to recurrent or severe infection. Antibiotics can also be used as pre-emptive therapy (sometimes referred to as secondary prophylaxis) to prevent clinical disease in persons infected with a microorganism such as Mycobacterium tuberculosis. Immunization, another excellent means of preventing infection, is discussed in Chapter 115. For information on prophylaxis of bacterial endocarditis, see Chapter 37, Endocarditis of natural and prosthetic valves: treatment and prophylaxis; for information on prophylaxis in persons infected with the human immunodeficiency virus (HIV), see Chapter 102, Prophylaxis of opportunistic infections in HIV disease; for malaria prophylaxis, see Chapter 200, Malaria; for prophylaxis related to transplant recipients and neutropenic patients, see Chapter 89, Infections in transplant recipients, and Chapter 85, Infections in the neutropenic patient; and for surgical prophylaxis, see Chapter 114, Surgical prophylaxis.

Several concepts are important in determining whether chemoprophylaxis is appropriate for a particular situation. In general, prophylaxis is recommended when the risk of infection is high or the consequences significant. The nature of the pathogen, type of exposure, and immunocompetence of the host are important determinants of the need for prophylaxis. The antimicrobial agent should eliminate or reduce the probability of infection or, if infection occurs, reduce the associated morbidity. The ideal agent is inexpensive, orally administered in most circumstances, and has few adverse effects. The ability to alter the normal microbiota and select for antimicrobial resistance should be limited. The emerging crisis of antibiotic-resistant bacteria underscores the importance of rational and not indiscriminate use of antimicrobial agents.