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Antibiotics are largely classified by their chemical structures and subsequent mechanisms of action. Four major groups exist:
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Those that inhibit formation of bacterial cell walls, for example, the β-lactams (penicillins, cephalosporins, and carbapenems) and vancomycin; these are generally bacteriocidal.
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.
Those that interfere with bacterial nucleic acid synthesis, for example, rifampin (inhibits RNA polymerase), and quinolones (inhibit bacterial topoisomerase). These agents are typically bacteriocidal.
Those that interfere with key enzymes in folate metabolism, for example, trimethoprim and sulfonamides.
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Bacteriocidal versus Bacteriostatic Agents
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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.
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Susceptibility Testing
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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.
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Resistance Mechanisms
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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.
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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.
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Pharmacokinetics and Pharmacodynamics
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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.
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Adjustments for Renal Insufficiency
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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:
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C
CR = ideal weight (kg) × (140 - age)
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72 × serum creatinine (mg/dL)
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This formula applies to men; for women, multiply by 0.85. Some antibiotics are removed by hemodialysis and require additional dosing.
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Pregnancy and Lactation
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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.
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Prophylaxis and Perioperative Use
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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.
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The American Heart Association (AHA) published its most recent guidelines regarding infective endocarditis (IE) prophylaxis in 2007. Compared to earlier recommendations, the latest guidelines recommend prophylaxis only for those patients with a high risk of a poor outcome from IE, rather than a high lifetime risk of IE alone. Prophylaxis has further been restricted to dental procedures, and those involving the respiratory tract (nasal and oral mucosa included) or infected tissue elsewhere. Conditions that warrant prophylaxis include prosthetic valve, certain congenital cardiac anomalies, valve disease in cardiac transplant patients, and a prior history of IE.
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Several studies have demonstrated that bacteremia rates for routine dermatologic surgery procedures involving properly cleansed and noninflamed skin are near 3%. In comparison, tooth brushing produces bacteremia rates between 24% and 40%. Therefore, antibiotic use for prophylaxis against endocarditis is not indicated for routine surgical procedures on noninflamed and surgically prepared skin. The data for procedures involving inflamed skin, sites associated with a higher rate of bacteremia (such as mucosa, genitalia, and ear), and prolonged procedures such as Mohs micrographic surgery are less clear. Prophylaxis for high- and moderate-risk patients in these situations varies by institution and practitioner. Procedures that must be performed on infected tissue probably warrant antibiotic prophylaxis in the high- and moderate- risk group due to higher rates of bacteremia.
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Data concerning the risk of infection of total joint arthroplasty following dermatologic procedures is sparse. Most infections of involving joint replacements occur in the immediate postoperative period. Prophylaxis for low-risk patients whose joint replacement is greater than 2 years old is not recommended. Procedures in high-risk patients, patients having joint prostheses less than 2 years old, and procedures on patients with vascular grafts or neurologic shunts present situations with no current recommendation guidelines.
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While wound classification correlates well with infection rate, most routine dermatologic procedures are difficult to categorize and are probably best classified between clean (class I) and clean-contaminated (class II) wounds. These wounds are at low risk of infection, and prophylactic antibiotics to prevent surgical site infection are not warranted. This generally includes most Mohs micrographic surgical procedures, which have reported infection rates of 2%-3%. However, the risk of infection increases when Mohs procedures involve mucosal sites, the ear, or involve delayed closures. In these cases, prophylactic antibiotics may be warranted, though dedicated studies to address this question are lacking. There is much debate regarding the use of antibiotic prophylaxis following medium to deep facial laser resurfacing or chemical peels. Reported infection rates of these clean-contaminated wounds are less than 10%. Furthermore, some studies have demonstrated selection of pathogenic organisms and higher infection rates following prophylaxis in this setting. As such, antibiotic prophylaxis for these procedures is probably not warranted.
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If the decision to administer antibiotic prophylaxis has been made, it is important to choose an antibiotic that will achieve proper wound coagulum concentrations at the time of surgery and have an adequate spectrum of activity against the most common likely pathogens at that site. The AHA recommends administration of antibiotic 30–60 minutes prior to surgery to ensure proper concentrations in the wound coagulum. However, according to the latest AHA guidelines, the antibiotic can be given up to 2 hours after the procedure if the preoperative dose is not given. The most likely organisms to cause infection following dermatologic procedures are staphylococcal and streptococcal species. It is important to consider Gram-negative organisms in sites near the waist, involving the ear, or in diabetic patients.
Viridans group
Streptococci and
Peptostreptococci are the leading pathogens following procedures involving the mouth. For surgery involving glabrous skin, a cephalosporin or
dicloxacillin is used.
Clindamycin or macrolides are considerations for penicillin-allergic patients.
Amoxicillin is the agent of choice for oral mucosal procedures.