Antibiotics are soluble compounds produced by an organism that inhibit bacterial growth; the term also includes synthetic compounds such as fluoroquinolones. The majority of skin and soft-tissue infections (SSTI) are caused by Gram-positive organisms, most of which are susceptible to well-known agents with a relatively narrow spectrum of antimicrobial activity. In these cases, β-lactams, macrolides, and fluoroquinolones have been the mainstays of therapy.1 Increased use and misuse of these antibiotics has led to selection and propagation of resistant bacteria. Community-acquired resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), have recently emerged as causes of SSTIs such as cellulitis, folliculitis, furunculosis, impetigo, erysipelas, and abscesses. More ominous is the emergence of complicated SSTIs with resistant pathogens, for example, MRSA and vancomycin-resistant Enterococci (VRE). Complicated cutaneous infections include those involving deeper tissues, those requiring surgical intervention, or those coincidental with underlying diseases that may complicate therapy. Combination therapy with well-established antimicrobials has been effective in many cases, and new antibiotics have broadened treatment options. However, given the relative paucity of new antimicrobials on the horizon, dermatologists are likely to be faced with growing treatment challenges. Understanding the pharmacologic properties of antibiotics ensures the most judicious use of these agents, and familiarity with antibiotic dosing schedules and adverse events will lead to therapeutic choices that achieve the highest degree of patient compliance.

Mechanisms of Action

 Antibiotics are largely classified by their chemical structures and subsequent mechanisms of action. Four major groups exist:

1. 
   

    Those that inhibit formation of bacterial cell walls, for example, the β-lactams (penicillins, cephalosporins, and carbapenems) and vancomycin; these are generally bacteriocidal.

   
   
2. 
   

    Those that interfere with protein synthesis by binding to either the 50S or 30S bacterial ribosomal subunit may be bacteriostatic or bacteriocidal. Reversible binding (tetracyclines, macrolides, lincosamides, and linezolid) usually halts microbial growth, resulting in a bacteriostatic effect. Irreversible bacteriocidal binding occurs with aminoglycosides.

   
   
3. 
   

    Those that interfere with bacterial nucleic acid synthesis, for example, rifampin (inhibits RNA polymerase), and quinolones (inhibit bacterial topoisomerase). These agents are typically bacteriocidal.

   
   
4. 
   

    Those that interfere with key enzymes in folate metabolism, for example, trimethoprim and sulfonamides.

Bacteriocidal versus Bacteriostatic Agents

 While antibiotics may be considered bactericidal (producing cell death) or bacteriostatic (halting cell growth or division), the distinction is based on in vitro assays. In an immunocompetent host, both modes of action can eliminate pathogens. Other considerations such as absorption, tissue distribution, and drug metabolism/elimination often play a more important role in eradication of infection. Additionally, some antibiotics are variably bacteriotoxic and bacteriostatic depending on the infective organism. There are few situations where the distinction may be clinically relevant: bacterial meningitis, infective endocarditis, osteomyelitis, and infections occurring in neutropenic patients. Finally, host factors such as immunocompromising disease or therapy, and ability to debulk infections by debridement or drainage, may also overshadow in vitro susceptibility in treating infection.

Susceptibility Testing

 Susceptibility testing, following isolation and identification of an organism from an appropriate clinical specimen, helps to direct therapy. A standard concentration of the bacteria is grown at several concentrations of antibiotic. The minimum inhibitory concentration (MIC) is defined as the lowest concentration at which growth is inhibited. An isolate is considered susceptible if the MIC is below the maximum concentration normally achieved in patients’ serum following accepted dosing schedules. Susceptibility determinations are somewhat relative and should be interpreted with caution. The laboratory breakpoints may not recognize variation in tissue antibiotic concentration or antibiotic activity (low pH, anaerobic environment, and protein concentration) at the site of infection. In-vitro determinations of MIC may fail to detect inducible resistance among certain pathogens (e.g., inducible clindamycin resistance among Staphylococci). However, susceptibility testing for most dermatologic infections is reliable.

Resistance Mechanisms

 Since the advent of antibiotics, microbes have become increasingly resistant to available therapies. Approximately 70% of all infective bacteria encountered in the hospital setting have developed resistance to at least one of the antibiotics initially used to treat them. In order for an antibiotic to be effective, it must reach its target in an active form, bind to the target, and inhibit the organism’s growth. Bacteria can evade the intended action if: (1) the drug cannot reach its target, for example, efflux pumps in the bacterial cell membrane can remove antibiotics from the cell. Numerous antibiotics (β-lactams, tetracyclines, fluoroquinolones, and macrolides) are eliminated in this fashion. (2) The drug is inactivated, as exemplified by resistance to β-lactams by organisms able to produce β-lactamase. (3) The drug can no longer bind its target. Numerous permutations of this mechanism are known. One such example is natural mutation of bacterial topoisomerases resulting in fluoroquinolone resistance.

 There are many ways in which bacteria can acquire resistance genes. Spontaneous mutations may be preferentially selected and passed to progeny. More common is the intraspecies or interspecies horizontal transfer of genetic material encoding resistance determinants. Horizontal transfer mechanisms (plasmids, transposons, transformation, conjugation, viral transduction) typically result in higher levels of resistance than spontaneous mutation, leading to incremental changes in bacterial resistance patterns. There are now many bacterial strains that have incorporated resistance determinants for multiple antibiotics, making treatment daunting. Multidrug resistance typically occurs in areas of intensive antibiotic use. Exact resistance rates for uncomplicated SSTIs are unknown, but growing resistance patterns have been reported with macrolide-resistant group A Streptococcus isolates, community-acquired MRSA isolates, and fluoroquinolone-resistant staphylococcal and streptococcal isolates. As resistance patterns emerge, appropriate culture and susceptibility testing become more important.

Pharmacokinetics and Pharmacodynamics

 Pharmacokinetics refers to the absorption, distribution, and elimination of a drug.2 Peak and trough serum concentrations after antimicrobial dosing are examples of pharmacokinetic parameters. Pharmacodynamics describes the relationship between pharmacokinetic measurements (drug concentrations) and antimicrobial effect (dose > MIC). For some antibiotics, treatment efficacy is determined predominantly by the amount of time between doses during which tissue concentration of drug is above the MIC, irrespective of the peak tissue level of antibiotic. This is referred to as time-dependent growth inhibition, and is true for most β-lactam antibiotics. Conversely, peak tissue levels of drug following each dose typically predict eradication of infection. Aminoglycosides and fluoroquinolones exhibit such concentration-dependent growth inhibition. Such activity may also vary depending on the organism and site of infection. Use of a drug at an inappropriately low dose or wide dosing interval can encourage the development of resistance.

Adjustments for Renal Insufficiency

 Many antibiotics excreted by the kidneys require dosing adjustments for patients with renal insufficiency to ensure adequate dosing and avoid drug toxicity (Table 230-1). Adjustments to either the amount of drug or frequency of its administration are based on creatinine clearance, which is most easily approximated using the following calculation:

 CCR = ideal weight (kg) × (140 – age)

 72 × serum creatinine (mg/dL)

 This formula applies to men; for women, multiply by 0.85. Some antibiotics are removed by hemodialysis and require additional dosing.

Pregnancy and Lactation

 Ideally, systemic antibiotics should be avoided during pregnancy. However, for uncomplicated SSTIs, penicillins, cephalosporins, and erythromycin, as class B medications, are considered the safest candidates for use. As class D medications, tetracyclines, fluoroquinolones, and trimethoprim-sulfamethoxazole are contraindicated during pregnancy (Table 230-2). Most antibiotics are considered safe for lactating (breastfeeding) women, but fluoroquinolones should be avoided due to possible development of arthropathies and cartilage defects.3 Infrequently used systemically in dermatologic practice, metronidazole has carcinogenic and mutagenic risk. If used, current guidelines recommend discontinuation of breastfeeding for 12–24 hours to allow for excretion of the drug.

Prophylaxis and Perioperative Use

 The prophylactic use of antibiotics in dermatology and dermatologic surgery is controversial.4,5 Published guidelines and existing studies inadequately address dermatologic procedures (such as prolonged procedures and involvement of mucosal sites), and a consensus does not exist. It is likely that antibiotics are currently overused in this arena, and several recent publications have proposed guidelines relevant to dermatology. Prophylactic antibiotic use may be considered for two purposes: (1) prevention of endocarditis and/or prosthesis infection, and (2) prevention of surgical site infection.