Chapter 230. Antibiotics

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

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

Susceptibility Testing

Resistance Mechanisms

Pharmacokinetics and Pharmacodynamics

Adjustments for Renal Insufficiency

Pregnancy and Lactation

Prophylaxis and Perioperative Use

Mechanism of Action

One of the oldest and largest groups of antibiotics, penicillins are members of the β-lactam family.6 All penicillins have a nucleus composed of a thiazolidine ring and β-lactam ring, which is required for antibiotic activity. Different side chains alter activity and resistance to degradation, but all β-lactams share a similar bacteriocidal mechanism of action. They bind to specific penicillin binding proteins (PNBs), inhibit cell-wall peptidoglycan synthesis, and inactivate an inhibitor of autolytic enzymes present on bacterial cell walls.

There are several groups of penicillins, largely separated by their chemical structure and resistance to bacterial degradation. The natural penicillins exhibit the narrowest spectrum of activity and are susceptible to enzymatic degradation by β-lactamases. Penicillin G is the most useful drug in this group. Administered parenterally, it is active against Streptococcus, Neisseria meningitidis, Clostridium sp., spirochetes, Pasteurella multocida, Eikenella corrodens, Erysipelothrix rhusiopathiae and non-β-lactamase producing Staphylococci. Penicillin G is the treatment of choice for Treponema pallidum infection in all forms. Penicillin V is the oral form of the drug and is generally less potent than Penicillin G because of lower achievable blood levels.

Aminopenicillins (ampicillin, amoxicillin), carboxypenicillins (carbenicillin, ticarcillin), and ureidopenicillins (piperacillin) provide a broader spectrum of activity. All of these semisynthetic agents are susceptible to β-lactamase. Aminopenicillins are oral agents and have limited activity against Staphylococci and enteric organisms. They are routinely used for infections of the upper airway, head, and neck (bronchitis, sinusitis, otitis), and have no activity against Pseudomonas sp. Carboxypenicillins have some activity against Pseudomonas sp. and Proteus sp., and are often administered with aminoglycosides for the treatment of serious pseudomonal infections. The ureidopenicillins have a similar Gram-positive profile. Derived from ampicillin, they have greater activity against Gram-negative bacteria than the carboxypenicillins. Amoxicillin, ticarcillin, and piperacillin are often coupled with β-lactamase inhibitors to enhance activity against S. aureus. β-Lactamase inhibitors include tazobactam, clavulanic acid, and sulbactam, and work best against β-lactamases encoded on plasmids.

The final group of penicillins (oxacillin, dicloxacillin, and nafcillin) are inherently β-lactamase resistant and exhibit excellent activity against S. aureus; they have no activity against Enterococci or enteric Gram-negative organisms. β-lactamase-resistant penicillins remain an excellent choice for empiric therapy of uncomplicated SSTIs such as folliculitis, impetigo, furunculosis, and cellulitis where community-acquired MRSA is not suspected.

Pharmacokinetics

Absorption of oral penicillins is variable and depends on each compound's acid stability and amount bound to food. Most oral penicillins should be taken at least 1 hour before or 1 hour after meals. Absorption of amoxicillin is unaffected by food. Unabsorbed penicillin is degraded by gastrointestinal flora. Penicillin G, nafcillin, carbenicillin, ticarcillin, and piperacillin are poorly absorbed and unstable at low pH; as such, they are administered parenterally. Penicillins are widely distributed in body fluids and tissues, but areas of poor availability include the cerebrospinal fluid, prostate, and intraocular fluid. These drugs do not typically cross the blood-brain barrier, but can reach effective levels in patients with meningitis due to increased meningeal permeability. Natural penicillins can interact with amines (such as procaine and benzathine) to form salts with relatively low solubility; administered intramuscularly, penicillin is released more slowly, prolonging drug delivery. Most free penicillin is excreted renally. Penicillins are excreted in breast milk in low quantity, and are considered safe to use during breastfeeding. Indications are listed in Box 230-1.

Dosing Regimen

(See Table 230-1)

Dosing adjustment for patients with renal insufficiency is necessary.

Risks and Precautions

(See Box 230-2)

Complications

(Table 230-2)

Hypersensitivity reactions are the most common adverse events reported with penicillins.7 Reported incidence varies from 0.7%–10%, and manifestations range from mild to severe (Table 230-2). Penicillin hypersensitivity is probably overreported by patients, but 2%–4% of true allergic reactions are life threatening. For true penicillin-allergic patients, treatment warrants use of another class of antibiotic. If penicillin allergy is uncertain and if penicillin treatment is required, skin prick testing may be performed to detect type I hypersensitivity, followed by intradermal testing if negative. Negative testing may be followed by a challenge dose of oral penicillin under observation. Approximately 10%–20% of patients with a history of “penicillin allergy” have a positive skin test, and approximately 3% of those with a negative skin test and a history of allergy have an allergic response after a challenge dose of penicillin. These reactions tend to be mild. Patients with positive skin tests can undergo desensitization therapy when a β-lactam must be given.

Mechanism of Action

Cephalosporins are β-lactams with the same mechanism of action as penicillins, i.e., they inhibit bacterial cell-wall synthesis by blocking peptidoglycan incorporation.8 Cephalosporins differ structurally from penicillins by their dihydrothiazine ring versus the thiazolidine ring of penicillins. Most cephalosporins have some activity against both Gram-positive (excluding Enterococci) and Gram-negative organisms, though the spectrum of activity varies widely among the group. The cephalosporins are comprised of four “generations” based on spectrum of activity and evolution of development. The first generation includes cephalexin, cefadroxil, and the parenteral agents cefazolin and cephalothin, all of which have good activity against methicillin-sensitive S. aureus and Streptococcus sp. and limited activity against Gram-negative organisms; for example, Escherichia coli and Klebsiella sp. The second generation includes cefprozil, cefaclor, cefuroxime axetil, and the parenteral agents cefotetan, cefoxitin, and cefuroxime, offering expanded Gram-negative activity over the first generation agents, specifically against Hemophilus influenzae and Moraxella catarrhalis. Third generation agents include cefdinir, cefditoren, and the parenteral agents cefotaxime, ceftriaxone, ceftazidime, and cefoperazone. They exhibit an expanded spectrum of activity against Gram-negative pathogens, but are less effective against Gram-positive organisms. As such, they are extremely helpful for Gram-negative nosocomial infections. Cefotaxime and ceftriaxone cross the blood-brain barrier and are effective treatment for meningitis caused by H. influenzae, N. meningitidis, and penicillin-sensitive S. pneumoniae. Ceftazidime and cefoperazone are active against Pseudomonas aeruginosa, and cefdinir and cefditoren are useful in the treatment of SSTIs due to their activity against S. aureus as well as Streptococcus sp. The only “fourth generation” cephalosporin available in the United States is cefepime, a parenteral agent with good activity against a broad spectrum of Gram-positive and Gram-negative organisms, including P. aeruginosa.

Pharmacokinetics

Cephalosporins are a chemically diverse class of antibiotics with unique pharmacokinetic and pharmacodynamic properties. Most orally administered cephalosporins can be taken without food. The esterified cephalosporins (cefuroxime and cefpodoxime) should be taken with food to prolong mucosal contact time since they require enzymatic cleavage in the intestinal tract. Agents that lower the gastric pH may also reduce absorption of these two drugs. Cefaclor is an extended release formulation and should similarly be given with food. Most cephalosporins are renally excreted. Cephalosporins are excreted in breast milk to varying degrees. First, second, and third generation cephalosporins are compatible with breastfeeding, and excretion in breast milk occurs in varying degrees.

Indications

(See Box 230-3)

Dosing Regimen

(Table 230-1)

Risks and Precautions

(See Box 230-4)

Complications

(Table 230-2)

Cephalosporins cross-react with penicillin in up to 20% of penicillin allergic patients, with most reactions occurring between penicillins and first- or second-generation cephalosporins.9 The common β-lactam ring is responsible for the shared mechanism of action and some antigenic cross-reactivity, and the respective side chains for hypersensitivity reactions. Cephalosporins and penicillins with similar side chains are more likely to produce a cross-reactive hypersensitivity reaction in penicillin allergic patients. Cefoxitin, cefamandone, cefaloram, cephalothin, and cephaloridine have side chains structurally similar to penicillin, while cefaclor, cephalexin, cefprozil, cephradine, and cefadroxil have side chains similar to amoxicillin or ampicillin. Some oral agents that lack side chain similarity to penicillin, ampicillin, or amoxicillin include cefdinir, cefpodoxime, cefditoren, and cefuroxime, and these agents may be safer for use in patients reporting a penicillin class allergy. Patients reporting a penicillin allergy with a negative penicillin allergy skin test have no greater risk of an allergic reaction to β-lactams than the general population. Cephalosporins, due to their greater variety of metabolite structures than other β-lactams, are able to elicit cephalosporin-specific allergic responses.

Mechanism of Action

Tetracyclines inhibit bacterial protein synthesis by binding to the 30s ribosomal subunit and blocking transfer RNA binding to the mRNA-ribosome complex.10 Doxycycline and minocycline are semisynthetic second-generation tetracyclines most commonly used in dermatology. More lipophilic, they generally exhibit greater activity than tetracycline, especially versus S. aureus and community-acquired strains of MRSA.11 As a class, tetracyclines have a broad spectrum of activity, including many Gram-positive and Gram-negative bacteria, spirochetes, Mycoplasma, Rickettsia, Chlamydia, and some protozoa. Doxycycline is preferred therapy for the treatment of infections due to Borrelia sp., Brucella sp., Chlamydia sp., Ehrlichia sp. (monocytic and granulocytic ehrlichiosis), Calymmatobacterium granulomatis (granuloma inguinale), Coxiella burnetii (Q fever), Leptospira sp., Mycoplasma sp., Rickettsia sp., and Francisella tularensis. It is also treatment for infections caused by Actinomyces sp., Bacillus anthracis, Mycobacterium marinum, and Vibrio vulnificus. In patients allergic to penicillins, doxycycline is commonly used to treat animal bites and syphilis. Tetracyclines can be helpful for the treatment of acne, rosacea, perioral dermatitis, autoimmune blistering disease (bullous pemphigoid, linear IgA bullous dermatosis, and dermatitis herpetiformis), and confluent and reticulated papillomatosis (Gougerot-Cartaud), probably because of their anti-inflammatory properties.

Pharmacokinetics

Tetracycline is incompletely absorbed primarily in the stomach and small intestine, necessitating its ingestion on an empty stomach. Doxycycline and minocycline are unaffected by the presence or absence of food and have longer half-lives than tetracycline, requiring less frequent dosing. They also have much greater lipid solubility than tetracycline, allowing for excellent tissue penetration, with rapid availability in secretions of the prostate, respiratory tract, female reproductive tract, and bile. Nonetheless, patients should avoid concurrent ingestion of iron preparations, aluminum hydroxide gels, calcium and magnesium salts, or milk products, as these significantly lower absorption of the entire class. Tetracycline is excreted primarily by the kidneys, and patients with renal failure require dosing adjustment. Doxycycline is excreted in the feces and no adjustments for renal or hepatic failure are necessary. Minocycline is largely metabolized before excretion, but does not accumulate in patients with hepatic failure. Tetracyclines cross the placenta and appear in high concentrations in breast milk. Because of their ability to accumulate in developing bone and teeth, their use during pregnancy, while nursing, and throughout childhood should be avoided.

Indications

(See Box 230-5)

Dosing Regimen

(Table 230-1)

Risks and Precautions

(See Box 230-6)

Complications

(See Table 230-2)

Mechanism of Action

Clindamycin is a lincosamide antibiotic derived through chemical modification of lincomycin.12 Its absorption and spectrum of activity are better than its predecessor, which is now obsolete. Clindamycin binds to the bacterial 50s ribosomal subunit and inhibits protein synthesis through blockade of peptide chain initiation. The binding site overlaps the sites of other antibiotics that bind the 50s subunit such as macrolides (erythromycin), accounting for the antagonism noted between the drugs. Clindamycin facilitates opsonization and phagocytosis and decreases bacterial adhesion (to host cells) and production of staphylococcal exotoxin. Persistent binding at the 50s subunit leads to prolonged antibiotic effect in some organisms. Drug resistance by mutation at the 50S ribosomal binding site.

Clindamycin is effective against most Gram-positive cocci, anaerobes, and some protozoa. In dermatologic practice, it is active against most Streptococcus species (including S. viridans), methicillin-sensitive S. aureus, and S. epidermidis. Its anaerobic spectrum of activity includes Peptococci, Peptostreptococci, propionibacteria, Clostridium perfringens, and fusobacteria. Toxoplasma gondii is often effectively treated with combinations including clindamycin. It is ineffective against strains of Enterococcus and JK group corynebacteria.

Pharmacokinetics

Clindamycin is not inhibited by food intake and reaches therapeutic levels in most tissue except cerebrospinal fluid. The drug preferentially accumulates in polymorphonuclear leukocytes, which may explain its benefit as treatment for abscesses. Clindamycin is primarily metabolized by the liver and excreted in the bile, though 10% is excreted in the urine. Dosing adjustments are necessary for patients with hepatic failure or combined hepatic and renal failure. It is not removed by dialysis.

Indications

(See Box 230-7)

Dosing Regimen

(Table 230-1)

Risks and Precautions

(See Box 230-8)

Complications

(Table 231-2)

Clindamycin frequently causes gastrointestinal upset and diarrhea (2%–20% of patients), and may occasionally cause pseudomembranous colitis attributed to Clostridium difficile, a life-threatening complication reported in 0.1%–10% of patients. Despite its classic association with clindamycin, pseudomembranous colitis may occur following administration of virtually any antibiotic. Treatment includes discontinuation of the drug and administration of metronidazole.

Mechanism of Action

Erythromycin is the prototypical macrolide antibiotic; derivatives include dirithromycin, clarithromycin, and azithromycin. All are bacteriostatic and inhibit bacterial protein synthesis by reversibly binding the 50s ribosomal subunit. Structural modifications of clarithromycin and azithromycin confer increased acid stability, tissue penetration, and spectrum of activity.13 The macrolides have good but varied activity against Gram-positive pathogens: clarithromycin > erythromycin > azithromycin. Streptococcal resistance to macrolides is fairly common (up to 40% of group A isolates), and S. aureus may be variably susceptible to erythromycin. Streptococcal resistance to macrolides is class-wide rather than drug specific. Erythromycin has poor activity against most Gram-negative pathogens, but azithromycin and clarithromycin have good activity against H. influenzae, N. gonorrhoeae, M. catarrhalis, Chlamydia, Mycoplasma pneumoniae, H. pylori, Toxoplasma gondii, Treponema pallidum, Borrellia burgdorferi, and nontuberculous mycobacteria. Azithromycin has good activity against Pasteurella multocida and Eikenella corrodens, making it a useful alternative in the treatment of infected bites. Clarithromycin is the most active macrolide against M. leprae and is widely used for skin infections with several other nontuberculous mycobacteria, notably M. chelonae, M. abscessus, and M. fortuitum.

Pharmacokinetics

Macrolides accumulate intracellularly in polymorphonuclear leukocytes and macrophages, and in part account for their activity against intracellular pathogens. Erythromycin base is absorbed in the small intestine and inactivated by gastric acidity, hence its availability as enteric-coated tablets or capsules. (Food lowers gastric pH and may delay absorption.) Erythromycin esters (erythromycin estolate, stearate, and ethylsuccinate) are less acid labile than the base form. Except its extended-release formulation, which should be given with food, clarithromycin may be given with or without food. Tissue concentrations of macrolides typically exceed plasma levels. Concentrations of erythromycin in breast milk are approximately 50% of maternal serum levels. Erythromycin can cross the placenta, but except clarithromycin (pregnancy category C), the macrolides are category B. Clarithromycin and azithromycin have longer half-lives, allowing for less frequent dosing (Table 230-1). Azithromycin remains in tissue longer and accumulates at high levels intracellularly (tissue fibroblasts) allowing for daily short-term dosing after a loading dose. Clarithromycin is metabolized by the liver and excreted by the kidneys. Patients with renal failure require dosing adjustments. Adjustments are not necessary for erythromycin, azithromycin, or dirithromycin, which primarily undergo hepatic metabolism. Erythromycin and clarithromycin interact with the cytochrome P-450 system, which can prompt numerous potential drug interactions (see Risks and Precautions). Erythromycin and clarithromycin inhibit CYP 3A4, and erythromycin also inhibits CYP 1A2.

Indications

(See Box 230-9)

Dosing Regimen

(Table 230-1)

Risks and Precautions

(See Box 230-10)

Complications

(See Table 230-2)

Mechanism of Action

Fluoroquinolones are fluorinated derivatives of the first quinolone, nalidixic acid.14 They act by inhibiting the action of bacterial topoisomerases II (DNA gyrase) and IV, leading to impaired DNA replication, transcription, and repair. In Gram-positive organisms, the primary target is topoisomerase IV; in Gram-negative bacteria the target is topoisomerase II. Agents available in the United States are ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and gemifloxacin.15,16 Fluoroquinolones have a broad spectrum of activity, with appreciable bacteriocidal activity against a variety of Gram-negative organisms including Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria. Ciprofloxacin is most active against Pseudomonas aeruginosa. As a class, the fluoroquinolones have limited anaerobic activity, but the newer agents gemifloxacin and moxifloxacin exhibit lower MICs against these organisms. These newer fluoroquinolones have better activity against Gram-positive organisms. Moxifloxacin, in particular, has been approved for the treatment of uncomplicated SSTIs. Some of the newer fluoroquinolones (levofloxacin, moxifloxacin) exhibit good activity against Streptococcus, but often develop resistance to S. aureus rapidly. They should not be first line therapy for uncomplicated SSTIs, but they should be instrumental in the treatment of complicated, polymicrobial, and/or Gram-negative infections such as diabetic ulcers or deep tissue infections. Ciprofloxacin and levofloxacin are effective agents for gonorrhea, chlamydia, erysipeloid, granuloma inguinale, and chancroid (see Indications). Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin are effective against some Mycobacterium species including M. tuberculosis, M. chelonae, M. fortuitum, and M. kansasii, though available data are limited.

Pharmacokinetics

Fluoroquinolones are rapidly absorbed after oral ingestion with a large volume of distribution. Food does not inhibit absorption. Unlike β-lactams, fluoroquinolones act in a concentration-dependent manner and can be administered twice daily. Most are excreted by the kidneys, and adjustments for renal failure are usually necessary. Moxifloxacin is eliminated in the liver by conjugation with glucuronide and sulfate. None of the fluoroquinolones are removed by dialysis. Most are excreted in breast milk in small and almost negligible quantities, but rare side effects have occurred in breastfeeding infants. Ciprofloxacin has been associated with phototoxicity, pseudomembranous colitis, and green teeth upon eruption. Norfloxacin is not found in the breast milk of mothers taking the drug, while ofloxacin and levofloxacin are excreted in smaller quantities than ciprofloxacin. Ciprofloxacin and ofloxacin are compatible with breastfeeding according to American Academy of Pediatrics guidelines.

Indications

(See Box 230-11)

Dosing Regimen

(Table 230-1)

Risks and Precautions

(See Box 230-12)

Complications

(See Table 230-2)

Mechanism of Action

Trimethoprim/sulfamethoxazole (cotrimoxazole) is a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) in a 1:5 ratio. Both compounds inhibit nucleic acid synthesis by inhibiting two enzymes in the bacterial tetrahydrofolic acid synthesis pathway. Together, these compounds exhibit synergistic action that is relatively specific to bacterial cells.

TMP/SMX is a broad-spectrum antibiotic with good activity against many aerobic Gram-positive cocci including S. aureus, S. pyogenes, and S. viridans; it is often effective in the treatment for community-acquired MRSA.11 Other susceptible pathogens include: H. influenzae, E. coli, Proteus mirabilis, Klebsiella pneumoniae, Shigella, Yersinia, and Brucella. While Pseudomonas aeruginosa is resistant, other Pseudomonas species and Stenotrophomonas maltophilia are generally sensitive. TMP/SMX can be effective therapy for infections with Nocardia and atypical mycobacteria. The drug has no activity against anaerobes.

Pharmacokinetics

TMP and SMX are well absorbed but achieve different serum concentrations following administration of equal quantities of drug. A serum ratio of 1:20 (TMP:SMX) is necessary for optimal synergy against the largest variety of pathogens, which can be achieved by administration of the drug in a fixed 1:5 ratio. Both compounds are rapidly distributed to tissues, including the CSF and sputum. Excretion is via the kidneys.

Indications

(See Box 230-13)

Dosing Regimen

(Table 230-1)

Risks and Precautions

(See Box 230-14)

Complications

(Table 230-2)

While the aforementioned compounds comprise the vast majority of antibiotics used in dermatologic practice, several new or infrequently used medications bear mentioning for the treatment of complicated SSTIs or systemic infections due to resistant pathogens.17 In many hospitals, these drugs have restricted use, predicated on approval by an infectious disease specialist.

Vancomycin

Vancomycin (Vancocin) is a glycopeptide antibiotic effective against Gram-positive bacteria only; specifically Gram-positive infections resistant to β-lactams or when their use is contraindicated.18 In dermatology, vancomycin has been a first-line therapy for complicated and/or severe SSTIs due to hospital-acquired MRSA. In recent years, vancomycin-resistant isolates of S. aureus and Enterococcus faecium have been isolated. Vancomycin inhibits bacterial-cell-wall peptidoglycan synthesis. Dosing is determined by the patient's weight (15–20 mg/kg), and frequency of administration by the patient's creatinine clearance. As such, renal function requires monitoring during therapy. Potential adverse reactions include nephrotoxicity, ototoxicity, phlebitis at the injection site, hypersensitivity reactions, and leukopenia. “Red man syndrome,” secondary to histamine release, is an uncommon reaction, thought to be due to drug impurities. More refined preparations and slower infusions minimize this reaction. Drug-induced linear IgA disease is a rare cutaneous side effect. Two new glycopeptides, dalbavancin and oritavancin, are currently in clinical trials for the treatment of SSTIs.

Linezolid

Currently the only available oxazolidinone, linezolid (Zyvox) is currently approved by the FDA for the treatment of complicated SSTIs due to MRSA, as well as other drug-resistant Gram-positive infections including vancomycin-resistant Enterococcus faecium (VRE) and vancomycin-resistant S. aureus (VRSA).19 Its spectrum of activity includes Gram-positive organisms (including anaerobes), as well as nontuberculous mycobacteria such as M. chelonae and M. fortuitum. Largely bacteriostatic, linezolid inhibits the initiation of protein translation by binding to the 23S portion of the 50S ribosomal subunit, a unique mechanism of action which minimizes cross-resistance to other antibiotics. Nonetheless, linezolid-resistant enterococcal infections have occurred. Though renally excreted, dosing adjustments for renal failure are not necessary. Linezolid is generally well tolerated, but reversible thrombocytopenia and leucopenia occur in approximately 2% of patients, which seems to correlate with duration of therapy. This dictates monitoring of complete blood counts during therapy. Dosing for complicated infections is 600 mg twice daily, usually intravenously at first. The ability to convert to oral administration makes this drug an attractive option.

Quinupristin/Dalfopristin

Quinupristin/dalfopristin (Synercid) is a streptogram in antibiotic combination in a fixed 60:40 ratio.17 Both quinupristin and dalfopristin irreversibly inhibit bacterial protein translation by binding to different sites on the 50s ribosomal subunit. They exhibit synergistic, largely bacteriocidal activity against a variety of multidrug-resistant Gram-positive organisms including MRSA and VRE. Like linezolid, they have also been used in the treatment of VRSA infections. The recommended dose is 7.5 mg/kg intravenously twice daily for at least 7 days, with lower dosing for those patients with hepatic insufficiency. Patient tolerability can be a problem, especially phlebitis (75%), if administered peripherally; arthralgia; and myalgia. Quinupristin/dalfopristin is metabolized by the liver and excreted in the bile. Elevation of hepatic transaminases and bilirubin has been reported, and concomitant administration with drugs metabolized by the CYP3A4 system is contraindicated. Quinupristin/dalfopristin should be used with caution in patients taking cyclosporine or agents that prolong the QT interval.

Daptomycin

Daptomycin (Cubicin) is a cyclic lipopeptide; a new class of antibiotic derived from the fermentation of Streptomyces roseosporus.20 Daptomycin was recently approved in the United States for the treatment of complicated SSTIs caused by S. aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis and Enterococcus faecalis (vancomycin-susceptible strains only). Its mechanism of action is unclear, but it acts rapidly and is bacteriocidal against Gram-positive bacteria. Dosing is 4 mg/kg intravenously every 24 hours for 7–14 days. Daptomycin is excreted primarily by the kidneys (78%), requiring dosing adjustment for patients with renal impairment (CCr <30 mL/min). The drug is generally well tolerated, with headache and constipation being reported most commonly (4%). The primary serious adverse event is myopathy, which usually occurs at higher doses.

Ertapenem

Ertapenem (Invanz) is a long-acting carbapenem with a broad spectrum of antimicrobial activity similar to the older carbapenems, imipenem-cilastatin, and meropenem.17 Unlike imipenem, it has poor activity against Pseudomonas and Enterococci. In clinical trials, it was comparable to piperacillin/tazobactam in the treatment of complicated SSTIs. Active against both Gram-positive and Gram-negative aerobes and anaerobes, its use should be reserved for polymicrobial infections not otherwise sensitive to agents with more narrow spectra of activity. An extended half-life allows for once daily intravenous administration (1 g per day for 7–14 days), but it should be used cautiously in patients with renal impairment. CNS effects and hypersensitivity reactions have been noted.

Tigecycline

Tigecycline (Tygacil) is a glyclcycline antibiotic indicated for the treatment of complicated SSTI due to susceptible organisms, which include MRSA and VRE.21 A derivative of minocycline, tigecycline shares the same 30s ribosomal binding site and has a spectrum of activity similar to the classic tetracyclines. However, tigecycline demonstrates a greater volume of distribution, better activity against organisms with tetracycline resistance, and better activity against Streptococcus species. Tigecycline dosing is 50 mg intravenously twice daily following a 100-mg loading dose. Renal dosing is not required, but lower dosing is necessary for patients with severe hepatic disease. The same precautions taken with the tetracycline class of antibiotics should be observed with tigecycline.