text: View Full Chapter Figures Only Tables Only Videos Only Print Share Email Send Email Your Name (required) Example: John Doe Email Address (required) Please enter a valid sender email address. Example: email@example.com CC Me Recipient Email Address (required) Separate multiple email address with semi-colons (up to 5). Subject Subject for your email. Message (Maximum characters: 1,000) Send Cancel Copyright Paragraph Text Copyright Line Text Get Citation Citation AMA Citation Guglielmo B. Guglielmo B Guglielmo, B. Joseph.Chapter e1. Anti-Infective Chemotherapeutic & Antibiotic Agents. In: Papadakis MA, McPhee SJ, Rabow MW. Papadakis M.A., McPhee S.J., Rabow M.W. Eds. Maxine A. Papadakis, et al.eds. CURRENT Medical Diagnosis & Treatment 2014. New York, NY: McGraw-Hill; 2014. http://accessmedicine.mhmedical.com/content.aspx?bookid=330&Sectionid=44291033. Accessed May 30, 2016. APA Citation Guglielmo B. Guglielmo B Guglielmo, B. Joseph.(2014). Chapter e1. Anti-Infective Chemotherapeutic & Antibiotic Agents. In Papadakis MA, McPhee SJ, Rabow MW. Papadakis M.A., McPhee S.J., Rabow M.W. Eds. Maxine A. Papadakis, et al. (Eds), CURRENT Medical Diagnosis & Treatment 2014. Retrieved May 30, 2016 from http://accessmedicine.mhmedical.com/content.aspx?bookid=330&Sectionid=44291033. MLA Citation Guglielmo B. Guglielmo B Guglielmo, B. Joseph. "Chapter e1. Anti-Infective Chemotherapeutic & Antibiotic Agents." CURRENT Medical Diagnosis & Treatment 2014. Papadakis MA, McPhee SJ, Rabow MW. Papadakis M.A., McPhee S.J., Rabow M.W. Eds. Maxine A. Papadakis, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessMedicine. Web. May 30, 2016. <http://accessmedicine.mhmedical.com/content.aspx?bookid=330&Sectionid=44291033>. Download citation file: RIS (Zotero) EndNote BibTex Medlars ProCite RefWorks Reference Manager © Copyright Tools Search Book Top Return Clip Chapter e1. Anti-Infective Chemotherapeutic & Antibiotic Agents B. Joseph Guglielmo, PharmD + Penicillins ++ The penicillins share a common chemical nucleus (6-aminopenicillanic acid) that contains a beta-lactam ring essential to their biologic activity. ++ Antimicrobial Action & Resistance ++ The initial step in penicillin action is the binding of the drug to receptors—penicillin-binding proteins. The proteins of different organisms vary in number and in affinity for a given drug. After penicillins have attached to receptors, peptidoglycan synthesis is inhibited due to blockage of transpeptidation. The final bactericidal action is the removal of an inhibitor of the autolytic enzymes in the cell wall, which activates the enzymes and results in cell lysis. Organisms that produce beta-lactamases (penicillinases) are resistant to some penicillins because the beta-lactam ring is broken and the drug is inactivated. Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are susceptible to beta-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are not susceptible. ++ Microbial resistance to penicillins is caused by four factors: (1) Production of beta-lactamases, eg, by staphylococci, gonococci, Haemophilus species, and coliform organisms, including extended-spectrum beta-lactamase–producing bacteria; (2) lack of penicillin-binding proteins or decreased affinity of penicillin-binding protein for beta-lactam antibiotic receptors (eg, resistant pneumococci, methicillin-resistant staphylococci, enterococci) or impermeability of cell envelope; (3) failure of activation of autolytic enzymes in the cell wall—"tolerance," eg, in staphylococci, group B streptococci; and (4) cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans. ++ Natural Penicillins ++ The natural penicillins include penicillin G for parenteral administration (aqueous crystalline or benzathine penicillin G) or for oral administration (penicillin G and phenoxymethyl penicillin [penicillin V]). They are most active against gram-positive organisms and are susceptible to hydrolysis by beta-lactamases. They are used (1) for infections caused by susceptible and moderately susceptible pneumococci, depending on the site of infection; (2) other streptococci (including anaerobic streptococci); (3) meningococci; (4) non–beta-lactamase-producing staphylococci; (5) Treponema pallidum and other spirochetes; (6) Propionibacterium acnes and other gram-positive anaerobic bacilli; (7) non-difficile clostridia; and (8) actinomyces. See Table 30–4. ++ Pharmacokinetics & Administration ++ Penicillin has wide extracellular distribution after parenteral administration. Lower levels are present in the eye, prostate, and central nervous system. However, with inflammation of the meninges and with appropriate dosing, adequate penetration into the cerebrospinal fluid takes place. ++ Because benzathine penicillin allows for extended release of penicillin, continuous blood and tissue levels are achieved, allowing for the treatment of syphilis. ++ Phenoxymethyl penicillin (penicillin V) is the oral penicillin of choice because of its superior bioavailability. Penicillin is primarily renally eliminated by glomerular filtration and active tubular secretion. ++ Clinical Uses ++ Most infections due to susceptible organisms respond to aqueous penicillin G in daily doses of 1–2 million units administered intravenously every 4–6 hours. For life-threatening infections (meningitis, endocarditis), increased doses (3–4 million units intravenously every 4 hours) are required. ++ Penicillin V is the drug of choice in the treatment of streptococcal pharyngitis and cellulitis. Syphilis requires weekly injections of benzathine penicillin, 2.4 million units intramuscularly for 1–3 weeks, depending on the stage of the disease (see Table 30–6). ++ Extended-Spectrum Penicillins ++ The extended-spectrum group of penicillins includes the aminopenicillins: ampicillin and amoxicillin and the ureidopenicillin piperacillin (available only in combination with the beta-lactamase inhibitor tazobactam). These drugs are susceptible to destruction by staphylococcal (and other) beta-lactamases. This group of penicillins is similar to the natural penicillins in its activity against gram-positive bacteria; however, these agents offer modest aerobic gram-negative coverage as well. ++ Antimicrobial Activity ++ Ampicillin and amoxicillin are active against most strains of Proteus mirabilis, Listeria, and non–beta-lactamase-producing strains of Haemophilus influenzae but are inactive against most gram-negative pathogens. Both drugs are effective against penicillin-susceptible pneumococcus and Enterococcus faecalis; however, ampicillin-resistant E faecalis has emerged. Enterococcus faecium is likely to be resistant to ampicillin and piperacillin. ++ Ticarcillin and piperacillin are no longer marketed. However, considering that piperacillin-tazobactam and ticarcillin-clavulanate are commercially available, knowledge of the spectrum of activity of piperacillin and ticarcillin is important. Piperacillin is active against Pseudomonas aeruginosa and Klebsiella. Similar to ampicillin, piperacillin is active against E faecalis and pneumococci. The extended-spectrum penicillins inhibit many but not all anaerobes. Ampicillin and amoxicillin are not active against beta-lactamase–producing strains of Bacteroides fragilis—in contrast to piperacillin, which is active against many of these isolates. ++ Pharmacokinetics & Administration ++ Ampicillin can be given orally or parenterally. Amoxicillin is preferable to ampicillin in the oral treatment of infection because of its improved oral bioavailability and less frequent dosage frequency. An extended-release amoxicillin tablet (Moxatag) is approved for once-daily use for streptococcal pharyngitis in children < 12 years. ++ Piperacillin (in combination with tazobactam) is given intravenously and increased doses (200–300 mg/kg/d) are required for treatment of infections due to P aeruginosa. ++ See eTable 30–6.1 for a summary of dosage adjustments that are required in kidney disease. ++ Clinical Uses ++ Amoxicillin is given orally for minor infections such as acute sinusitis or acute otitis media. Ampicillin is administered intravenously for pneumonia, meningitis, bacteremia, or endocarditis. ++ Amoxicillin is also used as prophylaxis for endocarditis. Because of the increased serum and respiratory secretion levels with amoxicillin when compared with penicillin, this agent is effective in the treatment of susceptible and moderately penicillin-susceptible pneumococcus. In general, if amoxicillin levels remain above the minimum inhibitory concentration (MIC) of intermediately susceptible pneumococcus for more than 40% of the dosing interval (which can be achieved with a dose of 40 mg/kg/d in adults), bacteriologic cure rates are optimal. An ambulatory 3-day course of amoxicillin, 80–90 mg/kg/d in two doses, has been found to be equivalent to parenteral antibacterials in the treatment of outpatient-treated community-acquired pneumonia. ++ Penicillins Combined with Beta-Lactamase Inhibitors ++ The addition of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents inactivation of the parent penicillin by some, but not all, bacterial beta-lactamases. Marketed products include Augmentin (amoxicillin, 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid); Augmentin XR (amoxicillin 1 g plus 62.5 mg of clavulanic acid); Unasyn (ampicillin 1 g plus sulbactam 0.5 g, and ampicillin 3 g plus sulbactam 1 g); Timentin (3 g ticarcillin plus 100 mg clavulanate); and Zosyn (piperacillin 3 g plus tazobactam 0.375 g, and piperacillin 4 g plus tazobactam 0.5 g). Augmentin is given orally and the others, intravenously. In general, the beta-lactamase inhibitors effectively inactivate beta-lactamases produced by Staphylococcus aureus, H influenzae, Moraxella catarrhalis, and B fragilis. In contrast, the beta-lactamase inhibitors are variably and unpredictably effective against beta-lactamases produced by certain aerobic gram-negative bacilli, such as Enterobacter. Of the available parenteral drugs, Zosyn has the broadest spectrum of activity. Like Unasyn, Zosyn is active against ampicillin-susceptible enterococci. It has greater in vitro activity against P aeruginosa, Serratia, and Klebsiella species when compared with Augmentin, Timentin or Unasyn. While Zosyn and Timentin are active in vitro, their efficacy is less clear in the treatment of extended-spectrum beta-lactamase–producing organisms. ++ Augmentin is generally used only for the treatment of refractory cases of otitis media and for prophylaxis of infections resulting from animal and human bites because of its gastrointestinal side effects and increased cost compared to amoxicillin. However, the Infectious Diseases Society of America (IDSA) considers Augmentin to be the drug of choice in the treatment of acute bacterial rhinosinusitis. The roles of Unasyn, Timentin, and Zosyn include the treatment of polymicrobial infections such as peritonitis from a ruptured viscus, osteomyelitis in a diabetic patient, or traumatic osteomyelitis. ++ As discussed previously, when Zosyn or Timentin is used to treat Pseudomonas infections, increased dosages (200–300 mg/kg/d of the piperacillin [or ticarcillin] component) should be used. ++ Piperacillin-tazobactam treatment of pseudomonal isolates with reduced piperacillin-tazobactam susceptibility may be associated with increased mortality. Nonpseudomonal infection can be treated with lower doses (100–200 mg/kg/d). Continuous infusions of piperacillin-tazobactam may be superior to intermittent bolus dosing in the treatment of serious bacterial infection. ++ Antistaphylococcal Penicillins ++ Oxacillin, cloxacillin, dicloxacillin, and nafcillin are resistant to degradation by beta-lactamases produced by staphylococci. They are less active than natural penicillins against nonstaphylococcal gram-positive bacteria; however, they are still effective in the treatment of certain streptococcal infections, including skin and soft tissue infections due to group A streptococci. ++ The primary route of clearance of the above agents is nonrenal—thus, no dosage adjustment is needed in chronic kidney disease. ++ Toxicity & Adverse Events ++ All penicillins are associated with allergic reactions, ranging from serious IgE-mediated reactions, including anaphylaxis and bronchospasm, to non–IgE-mediated reactions, such as macular papular rash. Only a small minority of patients who claim allergy to penicillin will have a reaction with subsequent exposure to penicillins. All penicillins in excessive doses, particularly with decreased renal function, have been associated with seizures. ++ Of the oral penicillins, amoxicillin-clavulanate is more commonly associated with diarrhea. Nafcillin administered at high doses is associated with a modest leukopenia, and oxacillin has been linked with a higher incidence of liver toxicity than other agents in this class. High doses of penicillins, particularly piperacillin (with tazobactam), inhibit platelet aggregation and produce hypokalemia due to binding of potassium and subsequent elimination by the kidney. ++Garbutt JM et al. Amoxicillin for acute rhinosinusitis. A randomized controlled trial. JAMA. 2012 Feb 15;307(7):685–92. [PubMed: 22337680] ++Kardos N et al. Penicillin: the medicine with the greatest impact on therapeutic outcomes. Appl Microbiol Biotechnol. 2011 Nov;92(4):677–87. [PubMed: 21964640] ++Rodríguez-Baño J et al. Beta-lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012 Jan 15;54(2):167–74. [PubMed: 22057701] ++Wessels MR. Clinical Practice. Streptococcal pharyngitis. N Engl J Med. 2011 Feb 17; 364(7): 648–55. [PubMed: 21323542] + Cephalosporins ++ The cephalosporins, structurally related to the penicillins, consist of a beta-lactam ring attached to a dihydrothiazoline ring. Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial activities. Cross reactions between penicillins and cephalosporins are thought to be related primarily to similarities in the molecular structure of side chains; for example, penicillin and cefoxitin have similar side chains, as do ampicillin and cephalexin. ++ The mechanism of action of cephalosporins is analogous to that of the penicillins: (1) binding to specific penicillin-binding proteins, (2) inhibition of cell wall synthesis, and (3) activation of autolytic enzymes in the cell wall. Resistance to cephalosporins may be due to poor permeability of the drug into bacteria, lack of penicillin-binding proteins, or degradation by beta-lactamases. ++ Cephalosporins have been divided into five major groups or "generations" (see eTable 30–4.1) based on their antibacterial activity: First-generation cephalosporins have good activity against aerobic gram-positive organisms and some community-acquired gram-negative organisms (P mirabilis, Escherichia coli, Klebsiella species); second-generation drugs have a slightly extended spectrum against gram-negative bacteria, and some are active against gram-negative anaerobes; and third-generation cephalosporins are active against many gram-negative bacteria. Not all cephalosporins fit neatly into this grouping, and there are exceptions to the general characterization of the drugs in the individual classes; however, the generational classification of cephalosporins is useful for discussion purposes. Cefepime is considered a fourth-generation agent because it is more stable against plasmid-mediated beta-lactamase and has little or no beta-lactamase-inducing capacity. Cefepime compares favorably with ceftazidime with respect to its gram-negative activity; however, its stability versus plasmid-mediated beta-lactamase results in improved coverage against Enterobacter and Citrobacter species. The gram-positive coverage of cefepime approaches that of cefotaxime or ceftriaxone. None of the currently available agents are active against the enterococcus. A fifth-generation cephalosporin, ceftaroline, is uniquely active against methicillin-resistant S aureus and has comparable gram-negative spectrum activity as third-generation agents. ++ First-Generation Cephalosporins ++ Antimicrobial Activity ++ In vitro activity includes coverage of gram-positive cocci, including viridans streptococci, group A hemolytic streptococci, and S aureus. As with all cephalosporins, they are inactive against enterococci and methicillin-resistant staphylococci. Activity against H influenzae is poor, and penicillin-resistant streptococci (both intermediately and highly resistant) are resistant to first-generation cephalosporins. Among gram-negative bacteria, E coli, Klebsiella pneumoniae, and P mirabilis are the most likely susceptible. Anaerobic gram-positive cocci are usually susceptible, but B fragilis is not. ++ Pharmacokinetics & Administration ++ Oral ++ Cephalexin, cephradine, and cefadroxil are generally well absorbed. Cefadroxil, because of its longer half-life, can be given twice daily instead of four times daily. ++ Intravenous ++ Cefazolin is preferred because its longer half-life allows for less frequent dosing. In kidney disease, it requires dosage adjustment. ++ Intramuscular ++ Cefazolin can be given intramuscularly; however, the intravenous route is preferred because of the every 8-hour dosing schedule. ++ Clinical Uses ++ Oral drugs are used for treatment of urinary tract infections, and they can be used for minor skin and soft tissue infections (eg, cellulitis, soft tissue abscess). However, the increase in the incidence of community-associated methicillin-resistant S aureus has limited the use of these agents in some instances. ++ Intravenous first-generation cephalosporins are the antibacterial agents of choice for prophylaxis of infection of most clean surgical procedures; however, those institutions with high rates of postoperative surgical site infection due to methicillin-resistant staphylococci should consider the use of alternative agents, such as vancomycin. The second-generation cephalosporins cefoxitin and cefotetan have expanded anaerobic activity and are superior to first-generation agents for prophylaxis of infection following elective colorectal surgery or hysterectomy. ++ First-generation cephalosporins do not adequately penetrate into cerebrospinal fluid and are less potent than second- and third-generation agents; thus, they cannot be used in the treatment of meningitis. ++ Second-Generation Cephalosporins ++ Second-generation cephalosporins are a heterogeneous group with marked individual differences in activity and pharmacokinetics. In general, they are active against gram-negative organisms inhibited by first-generation cephalosporins, however, with additional aerobic gram-negative activity. Indole-positive Proteus and Klebsiella (including first-generation cephalosporin-resistant strains) as well as M catarrhalis and Neisseria species are usually sensitive to the parenteral second-generation agents. Cefuroxime is active against H influenzae, including beta-lactamase-producing strains, but has little activity against B fragilis. In contrast, cefoxitin and cefotetan are active against many strains of B fragilis. Against gram-positive organisms, second-generation agents are generally less active than the first-generation cephalosporins (cefuroxime is an exception). Second-generation agents have no activity against P aeruginosa. ++ Pharmacokinetics & Administration ++ Oral ++ Only cefaclor, cefuroxime axetil, and cefprozil can be given orally. Cefuroxime axetil is deesterified to cefuroxime after absorption. Its longer half-life permits twice-daily dosing, and absorption is enhanced when it is taken with food (as is not the case with many other oral antibiotics). ++ Intravenous and Intramuscular ++ Because of differences in drug half-life and protein binding, peak serum levels achieved and dosing intervals vary greatly for this group of drugs (see eTable 30–4.2). Drugs with shorter half-lives (cefoxitin) require more frequent dosing than drugs with longer half-lives (eg, cefuroxime). Dosage adjustment is required with kidney disease. ++ Clinical Uses ++ Because of their activity against beta-lactamase–producing H influenzae and M catarrhalis, cefprozil and cefuroxime axetil have a role in the treatment of sinusitis and otitis media in those patients unresponsive to amoxicillin. ++ Because of their activity against B fragilis, cefoxitin and cefotetan can be used to treat mixed anaerobic infections, eg, peritonitis and diverticulitis, as well as prophylaxis following colorectal surgery, vaginal or abdominal hysterectomy, and appendectomy. However, since many B fragilis and enteric gram-negative organisms are resistant, alternative agents are preferred for serious intra-abdominal infections. ++ Third-, Fourth-, & Fifth-Generation Cephalosporins ++ Antimicrobial Activity ++ Most of these drugs are active against staphylococci (not methicillin-resistant strains) but less so than first-generation cephalosporins. Ceftazidime, however, has notably weak activity against S aureus and pneumococci. While inactive against enterococci, most third- and fourth-generation cephalosporins inhibit most streptococci (ceftazidime is an exception to this rule). Ceftriaxone and cefotaxime offer the most reliable antipneumococcal coverage. A major advantage of third-, fourth-, and fifth- generation cephalosporins is their expanded gram-negative coverage. In addition to organisms inhibited by other cephalosporins, they are more active against Serratia marcescens, Providencia, Haemophilus, and Neisseria, including beta-lactamase–producing strains. Ceftazidime is unique among all third-generation agents because it is active against P aeruginosa. Acinetobacter, Citrobacter, Enterobacter, and nonaeruginosa strains of Pseudomonas are variably sensitive to third-generation cephalosporins, and Listeria is uniformly resistant. Activity against B fragilis is variable. In contrast to the third-generation agents, cefepime—the only currently available fourth-generation cephalosporin—is more active against Enterobacter and Citrobacter, has activity comparable to that of ceftazidime against P aeruginosa, and has gram-positive activity similar to that of ceftriaxone. ++ Cefpodoxime proxetil, cefdinir, cefditoren pivoxil, cefixime, and ceftibuten (the only oral agents in this group) are more active than cefuroxime axetil against gram-negative pathogens. However, none of these oral agents are equal to the parenteral third-generation cephalosporins against these pathogens. All third- and fourth-generation cephalosporins are uniformly active against Streptococcus pyogenes (group A Streptococcus). Cefpodoxime proxetil, cefditoren pivoxil, and cefdinir are active against methicillin-sensitive S aureus, whereas ceftibuten has little activity (none are active against methicillin-resistant strains). Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are active against penicillin-sensitive strains of Streptococcus pneumoniae (the pneumococcus), but ceftibuten has marginal activity. None of the oral cephalosporins are reliable against intermediately susceptible or penicillin-resistant S pneumoniae. Similar to other members of this class, these drugs are ineffective against enterococci and Listeria monocytogenes. The one available fifth-generation cephalosporin, ceftaroline, is unique in that it represents the only beta-lactam with in vitro activity against methicillin-resistant S aureus. Unlike other beta-lactams, ceftaroline binds PBP2a, a penicillin binding protein encoded by the mecA gene in methicillin-resistant S aureus. The gram-negative spectrum of activity approximates that of ceftriaxone, thus it is inactive against P aeruginosa, Acinetobacter spp, and B fragilis. ++ Pharmacokinetics & Administration ++ The intravenous third- and fourth-generation agents distribute into extracellular fluid and reach levels in the cerebrospinal fluid exceeding those needed to inhibit susceptible pathogens, particularly in the presence of inflamed meninges. At the present time, the cerebrospinal fluid penetration of ceftaroline is unknown and the drug has not been studied in the treatment of meningitis. The half-lives of these drugs are variable, resulting in differing dosage needs (see eTable 30–4.2). Ceftriaxone is eliminated primarily by biliary excretion, and no dosage adjustment is required in kidney disease. The other drugs are eliminated primarily by the kidney and thus require dosage adjustment in kidney disease. ++ Clinical Uses ++ Because of their penetration into the cerebrospinal fluid and potent in vitro activity, intravenous third-generation cephalosporins are effective in the treatment of meningitis due to susceptible pneumococci, meningococci, H influenzae, and enteric gram-negative rods. In meningitis in older patients, third-generation cephalosporins should be combined with ampicillin or trimethoprim-sulfamethoxazole until L monocytogenes has been excluded. Ceftazidime has been used to treat meningitis due to Pseudomonas. The dosage for meningitis should be at the upper limits of the recommended range, because cerebrospinal fluid levels of these drugs are only 10–20% of serum levels. Ceftazidime or cefepime is frequently administered empirically in the febrile neutropenic patient. Ceftriaxone is indicated for gonorrhea, chancroid, and more serious forms of Lyme disease. Because of its long half-life and once-daily dosing requirement, ceftriaxone is an attractive option for the outpatient parenteral therapy of infections due to susceptible organisms. ++ Cefepime is useful for third-generation cephalosporin–resistant isolates such as Enterobacter and Citrobacter. While cefepime has an extended spectrum of activity compared with third-generation agents, a meta-analysis revealed increased all-cause mortality with this agent when compared with other beta-lactams. Additional analyses have refuted this finding, and cefepime appears no different than any other beta-lactam with respect to mortality risk. Considering its spectrum of activity, including methicillin-resistant S aureus, ceftaroline is useful in the treatment of skin and soft tissue infection due to this pathogen, particularly if gram-negative pathogens are coinfecting. ++ Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are the best third-generation oral agents against pneumococci and S aureus. Cefixime is available in an oral suspension and 400-mg tablets. However, cefixime is no longer considered a drug of choice in the treatment of gonorrhea because of the increased rate cefixime-resistant cases. ++ Adverse Effects of Cephalosporins ++ Allergy ++ Cephalosporins, like penicillins, are sensitizing, and a variety of hypersensitivity reactions occur, including anaphylaxis, fever, skin rashes, nephritis, and hemolytic anemia. The frequency of IgE cross-allergy between cephalosporins and penicillins approximates 5–10%. However, the risk of cross-reactivity is dependent on the specific cephalosporin. Cross reactivity between penicillin and cephalosporins is more common with first-generation agents, when compared with later generations. Persons with a history of anaphylaxis to penicillins should not receive cephalosporins. The likelihood of non–IgE-mediated cross-reactivity between penicillins and cephalosporins is unknown but likely very low. Allergies to a given agent may or may not extend to the entire cephalosporin class. ++ Toxicity ++ Ceftriaxone has been associated with a dose-dependent biliary sludging syndrome and cholelithiasis due to precipitation of drug when its solubility in bile is exceeded. Long-term administration of 2 g/d or more is a risk factor for this complication. Cefepime may be associated with an increased rate of neurotoxicity, particularly with large doses and concomitant kidney disease. ++Ceftaroline fosamil (Teflaro)—a new IV cephalosporin. Med Lett Drugs Ther. 2011 Jan 24;53(1356):5–6. [PubMed: 21252841] [[XSLOpenURL/ 21252841]]++Cephalosporins for patients with penicillin allergy. Med Lett Drugs Ther. 2012 Dec 24:54(1406):101. [PubMed: 23282790] + Other beta-Lactam Drugs ++ Monobactams ++ Aztreonam is the sole marketed monobactam, so named due its monocyclic beta-lactam ring resistant to many beta-lactamases. Aztreonam is active against gram-negative organisms (including Pseudomonas) but has no activity against gram-positive organisms or anaerobes. Aztreonam resembles ceftazidime in its gram-negative activity. Thus, it is generally strong against E coli, Klebsiella, Proteus, and Pseudomonas spp, but unpredictable against Acinetobacter, Enterobacter, and Citrobacter spp. Clinical uses of aztreonam are limited because of the availability of third-generation cephalosporins with a broader spectrum of activity and minimal toxicity. Despite the structural similarity of aztreonam to penicillin, IgE cross-reactivity does not exist, and it can therefore be used in patients with IgE-mediated penicillin allergy. ++ Carbapenems ++ This class of drugs is structurally related to beta-lactam antibiotics. Imipenem, the first drug of this type, has a wide spectrum of activity that includes most gram-negative rods (including P aeruginosa) and gram-positive organisms and anaerobes, with the exception of Burkholderia cepacia, Stenotrophomonas maltophilia, E faecium, and methicillin-resistant S aureus and Staphylococcus epidermidis. The half-life of imipenem is 1 hour. Dosage adjustment is required in renal insufficiency. ++ Meropenem and doripenem are similar to imipenem in spectrum of activity and pharmacology. Of particular importance, the carbapenems are the most reliable agents in the treatment of infection secondary to extended-spectrum beta-lactamase-producing E coli and Klebsiella spp. Meropenem and doripenem are less likely to cause seizures than imipenem, although the risk of seizures is low with imipenem if dosage is appropriately adjusted for renal insufficiency. Meropenem and doripenem are associated with less nausea and vomiting than imipenem, a feature of importance when high doses must be used, as in the treatment of Pseudomonas infection in patients with cystic fibrosis. The usual dose for meropenem is 1–2 g intravenously every 8 hours. Dosage adjustment in renal insufficiency is required. Doripenem (500 mg-1 g intravenously every 8 hours) is used in the treatment of intra-abdominal infection and pyelonephritis. Unlike meropenem, doripenem is not approved for the treatment of other serious hospital-acquired infections. In the treatment of ventilator-associated pneumonia, doripenem (administered for 7 days) was associated with higher mortality than imipenem (administered for 10 days). ++ Ertapenem is similar to the other carbapenems in its activity against aerobic gram-positive and anaerobic organisms but is inactive against Pseudomonas and Acinetobacter. Because of its long half-life (4 hours), it can be administered once daily. The usual dose is 1 g intravenously every 24 hours and adjustments are needed for renal insufficiency. ++ The carbapenems should not be routinely used as first-line therapy unless the pathogen is multidrug-resistant and is known to be susceptible to these agents. In patients hospitalized for a prolonged period with presumed infection with a multidrug-resistant organism, empiric use of carbapenems is reasonable. (Ertapenem should not be used if Pseudomonas and Acinetobacter are expected.) Pseudomonas may rapidly develop resistance to carbapenems. The use of imipenem or meropenem alone appears to be as effective as combination therapy in the febrile neutropenic patient, and the carbapenems are as effective as combination therapy in certain polymicrobial infections such as peritonitis and pelvic infections. ++ The most common adverse effects of carbapenems are diarrhea, reactions at the infusion site, and skin rashes. Seizures, nausea, and vomiting are more commonly observed with imipenem. Patients allergic to penicillins may be allergic to imipenem and meropenem as well. While earlier studies suggested up to 50% cross-reactivity between penicillin and imipenem in patients with confirmed IgE-mediated reactions to penicillin, more recent data strongly suggest the cross-reactivity is < 5%. ++Gazin M et al. Current trends in culture-based and molecular detection of extended-spectrum-beta-lactamase-harboring and carbapenem-resistant Enterbacteriaceae. J Clin Microbiol. 2012 Apr;50(4):1140–6. [PubMed: 22259207] ++Kollef MH et al. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia. Crit Care. 2012 Nov 13;16(6):R218. [PubMed: 23148736] + Erythromycin Group (Macrolides) ++ The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring with various sugars attached. ++ Antimicrobial Activity ++ Erythromycins inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes. While they are generally bacteriostatic, they can sometimes be bactericidal for certain organisms. Similar to penicillin, the rate of macrolide-resistant S pneumoniae has increased (25–35%), and increased regional resistance in group A streptococci has been reported. Erythromycin-resistant pneumococci are resistant to azithromycin and clarithromycin as well. Chlamydia, Mycoplasma, Legionella, and Campylobacter organisms are susceptible. ++ Pharmacokinetics & Administration ++ Preparations for oral use include erythromycin base, erythromycin stearate, estolate, and ethyl succinate. Erythromycins are excreted primarily nonrenally; no adjustment is therefore required in renal insufficiency. Azithromycin is available for oral and intravenous use. ++ Azithromycin is available for oral and intravenous use; the latter is particularly useful in the treatment of Legionnaire disease. ++ Clinical Uses ++ Macrolides are effective in the treatment of infection due to Legionella, Mycoplasma, Ureaplasma, Corynebacterium (including diphtheria), Chlamydia and Chlamydophila (including ocular and respiratory infections) organisms. They are useful alternatives in the treatment of streptococcal and pneumococcal disease in patients with serious penicillin allergy, such as anaphylaxis. When administered early, erythromycin may shorten the course of Campylobacter enteritis. Erythromycins are effective against certain Bartonella species (bacillary angiomatosis) and Rhodococcus species. In vitro data suggest that macrolides have a direct effect on neutrophil function and the production of cytokines associated with inflammation. Thus, these agents are sometimes used for their anti-inflammatory action. The most well-documented non-antibacterial benefit associated with the macrolides (azithromycin) is in the prevention of cystic fibrosis exacerbation. A potential link between chlamydial infection and coronary disease has been suggested, and it was hypothesized that the benefit of macrolides was due to the antichlamydial activity of these agents. However, large subsequent trials have refuted this benefit. ++ Adverse Effects ++ Nausea, vomiting, and diarrhea may occur after oral or intravenous intake. Erythromycins—particularly the estolate—can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Hepatitis recurs if the drug is readministered. Reversible auditory impairment occurs with large prolonged dosing, particularly in patients with impaired kidney or liver function. Clarithromycin and erythromycin have been associated with prolongation of the QT interval and torsades de pointes—more commonly in women. Erythromycins (and clarithromycin) can increase the effects of oral anticoagulants, digoxin, theophylline, calcium channel blockers, and cyclosporine by inhibiting cytochrome P450. An increased risk of cardiac-associated death has been reported with erythromycin, particularly in patients receiving concomitant inhibitors of cytochrome P450 3A4. ++ Azalides ++ Antimicrobial Activity ++ Azalides (azithromycin, clarithromycin, and others) are closely related structurally to the macrolides. They are similar to erythromycin in activity against most organisms and are slightly more active in vitro than erythromycin against H influenzae (azithromycin > clarithromycin > erythromycin). They are also active against Chlamydia trachomatis, Ureaplasma urealyticum, and Haemophilus ducreyi. In addition, these drugs have in vitro activity against a number of unusual pathogens, including atypical mycobacteria (Mycobacterium avium-intracellulare, Mycobacterium chelonei, Mycobacterium fortuitum, Mycobacterium marinum), Toxoplasma gondii, Campylobacter jejuni, Helicobacter pylori, and Borrelia burgdorferi. ++ Pharmacokinetics & Administration ++ Azithromycin and clarithromycin are more acid-stable than erythromycin, concentrate intracellularly and in tissues, and have a long terminal half-life, with high tissue concentrations that persist for days. The elevated tissue levels associated with azithromycin and clarithromycin has been proposed to overcome the high incidence of in vitro resistance seen with pneumococci (30%), but clinical observations have confirmed that in vitro resistance is associated with clinical failure. ++ Clinical Uses ++ Azithromycin and clarithromycin are approved for treatment of streptococcal pharyngitis, uncomplicated skin infections, and acute bacterial exacerbations of chronic bronchitis. When prescribing these agents in the treatment of pharyngitis in young adults, caution should be used due to the increased risk for Fusobacterium necrophorum, the etiologic agent in Lemierre syndrome. Morbidity and mortality in this patient population has been estimated to be substantially greater than that associated with infectious complications associated with S pyogenes. While penicillins and cephalosporins are active against F necrophorum, macrolides are predictably inactive. Because of the long half-life, outpatient oral treatment with azithromycin is with once-daily dosing for a total of 5 days (500 mg on day 1 and then 250 mg on days 2–5). Clarithromycin is usually administered in a dosage of 250–500 mg orally twice daily, although an extended-release formulation that is given as a single daily 1000-mg dose is approved for acute sinusitis and acute exacerbation of chronic bronchitis. The azalides are more expensive than erythromycin; however, the less frequent dosing and improved tolerability make them preferable choices in most patients. ++ Azithromycin is used as single-dose therapy (1 g) for chlamydial genital infections. While more expensive than 7 days of treatment with doxycycline, the assurance of adequate supervised therapy makes azithromycin preferred therapy in most patients. Azithromycin can also be used as single-dose therapy (1 g) for chancroid, and a single dose of 1 g is as efficacious as 7 days of doxycycline for nongonococcal urethritis in men and incubating syphilis. A single dose of azithromycin (20 mg/kg, maximum dose of 1 g) is effective in treating trachoma and substantially reduces disease burden in endemic areas. A 1-g dose of azithromycin is also effective therapy for severe cholera. The spectrum of activity of the macrolides—particularly their atypical coverage—results in their usefulness in mild to moderate cases of community-acquired pneumonia; however, penicillin-resistant strains are often resistant to these agents as well. Azithromycin taken daily for 1 year has been found to decrease the frequency of exacerbations and improved quality of life; however, cochlear toxicity and isolation of azithromycin-resistant bacterial isolates also has been observed. Weekly 1200-mg doses of azithromycin are effective in preventing Mycobacterium avium complex infections in HIV-positive patients, and doses of 500 mg daily are useful in M avium complex pulmonary infections in non–HIV-positive patients. Azithromycin is effective in the treatment of dysentery caused by multidrug-resistant Shigella and Campylobacter organisms. Used as prophylaxis, azithromycin (500 mg weekly) is as effective as benzathine penicillin in preventing streptococcal infections in military recruits, and at a dose of 250 mg daily it is adequate as prophylaxis for malaria (although inferior to doxycycline for multidrug-resistant Plasmodium falciparum). Clarithromycin has been used for the therapy of M avium complex infections, usually in combination with other drugs (eg, rifabutin and ethambutol), and can be given daily (500 mg twice daily) or three times weekly (1000 mg) as intermittent therapy. Oral clarithromycin (500 mg twice daily for 6 months), in combination with other agents, is effective therapy for disseminated M chelonei infections. Clarithromycin has also been used in combination regimens for the therapy of H pylori infections. When clarithromycin is given with omeprazole and amoxicillin, cure rates in excess of 80–90% have been achieved. The broad use of the macrolides has resulted in increased bacterial resistance. A prospective, randomized trial of healthy volunteers treated with azithromycin or clarithromycin revealed rapid increases in macrolide-resistant streptococci, which continue up to 6 months after the course of therapy. Furthermore, clarithromycin, but not azithromycin, was found to increase the proportion of the more resistant macrolide-lincosamide-streptogramin phenotype resistance. ++ Adverse Effects ++ Adverse effects of azithromycin and clarithromycin are similar to those of erythromycin, but upper gastrointestinal upset, the major side effect, occurs less often with the azalides. Hepatic enzyme elevations and reversible cochlear toxicity have been reported. Clarithromycin is similar to erythromycin in its effect on the cytochrome P450 system. Azithromycin is associated with minimal to no drug interactions. Macrolides prolong QT in patients at risk (patients receiving concomitant agents known to prolong QT, history of prolonged QT). ++ Fidaxomycin ++ Fidaxomycin is a nonabsorbed macrolide approved for the treatment of Clostridium difficile infection. At a dose of 200 mg twice daily for 10 days, fidaxomycin is equal to vancomycin in the treatment of this disease. An advantage of fidaxomycin compared to oral vancomycin is that the macrolide is associated with fewer recurrences as measured by 25 days after treatment conclusion. While the drug offers an important advance in the treatment of C difficile infection, its considerable acquisition cost is a barrier to its use in most patients with this disease. The most common adverse events reported in clinical trials include nausea and vomiting. ++Albert RK et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011 Aug 25;365(8):689–98. [PubMed: 21864166] ++Ray WA et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881–90. [PubMed: 22591294] ++Venugopal AA et al. Fidaxomycin: a novel macrocyclic antibiotic approved for the treatment of Clostridium difficile infection. Clin Infect Dis. 2012 Feb;54(4):568–74. [PubMed: 22156854] + Ketolides ++ Telithromycin, the one available ketolide, is similar in structure to macrolides but has a broader spectrum of activity. Telithromycin offers activity against both penicillin-resistant and macrolide-resistant pneumococci and is equal to azithromycin against atypical pathogens and H influenzae. The dose is 800 mg/d orally, and no adjustment is needed for kidney disease or liver insufficiency. Upon telithromycin's approval, upper gastrointestinal toxicity and visual disturbances (occurring more frequently in women than men) were the most commonly observed adverse events. However, telithromycin has since been associated with severe hepatotoxicity resulting in liver transplant and death. Telithromycin also has been found to exacerbate myasthenia gravis. Cytochrome P450 inhibition with telithromycin approximates that of erythromycin, and increased serum levels of warfarin and other agents would be expected with concomitant administration of telithromycin. The serious hepatotoxicity of telithromycin significantly limits its use in the treatment of outpatient respiratory tract infection. There is no clear indication for this agent. + Tetracycline Group ++ The tetracyclines are a group of drugs with common basic chemical structures, antimicrobial activity, and pharmacologic properties. ++ Antimicrobial Activity ++ Tetracyclines are inhibitors of protein synthesis and are bacteriostatic for many gram-positive and gram-negative bacteria. They are strongly inhibitory for the growth of mycoplasmas, rickettsiae, chlamydiae, spirochetes, and some protozoa (eg, amebas). Their antipneumococcal activity approaches that of the macrolides; almost all H influenzae are inhibited. Tetracyclines also have some activity against some vancomycin-resistant enterococci. Doxycycline and minocycline are potential options for therapy of staphylococcal infections, including infections with many methicillin-resistant strains. There are marked in vitro differences between tetracyclines with respect to staphylococci. Tetracycline-resistant staphylococci often retain susceptibility to doxycycline and minocycline and doxycycline-resistant S aureus can still be susceptible to minocycline. Tetracyclines have little utility in the treatment of gram-negative aerobic infection. However, minocycline is reliable in its activity against S maltophilia. Receipt of doxycycline in combination with ceftriaxone in the treatment of community-acquired pneumonia has been associated with a reduction in the rate of associated antibacterial C difficile disease. The antibacterial activity of doxycycline against C difficile is likely the mechanism of action for this finding. ++ Pharmacokinetics & Administration ++ Oral bioavailability varies depending on the drug. Absorption is impaired by dairy products, aluminum hydroxide gels (antacids), and chelation with divalent cations, eg, Ca2+ or Fe2+. Chelation is less problematic with doxycycline and minocycline when compared with tetracycline. Consequently, doses of tetracyclines should be staggered at least 2 hours before or after receipt of multivalent cations. Oral bioavailability is moderate with tetracycline and highest with doxycycline and minocycline (95% or more). Lipid solubility of minocycline and doxycycline accounts for their penetration into the cerebrospinal fluid, prostate, tears, and saliva. ++ Tetracyclines are primarily metabolized in the liver and excreted in bile. Doxycycline requires no dosage adjustment in kidney disease; in contrast, other tetracyclines should be avoided or given in reduced dosage. ++ For patients unable to take oral medication, some tetracyclines (doxycycline, minocycline) are formulated for parenteral administration in doses similar to the oral ones. ++ Clinical Uses ++ Tetracyclines are drugs of choice for infections with Chlamydia, Chlamydophila, Mycoplasma, Rickettsia, Ehrlichia, and Vibrio organisms and for some spirochetal infections. Sexually transmitted diseases in which chlamydiae often play a role—endocervicitis, urethritis, proctitis, and epididymitis—should be treated with doxycycline for 7–14 days. Pelvic inflammatory disease is often treated with doxycycline plus cefoxitin or cefotetan. Other chlamydial infections (psittacosis, lymphogranuloma venereum, trachoma) and sexually transmitted diseases (granuloma inguinale) also respond to doxycycline. Other uses include treatment of acne, respiratory infections, Lyme disease and relapsing fever, brucellosis, glanders, tularemia (often in combination with streptomycin), cholera, mycoplasmal pneumonia, actinomycosis, nocardiosis, malaria, infections caused by M marinum and Pasteurella species (typically after an animal bite), and as malaria prophylaxis (including multidrug-resistant P falciparum). They also have been used in combination with other drugs for amebiasis, falciparum malaria, and recurrent ulcers due to H pylori. With its modest activity against pneumococci (same or better than macrolides) and reliable coverage of H influenzae, Chlamydophila, Legionella, and Mycoplasma organisms, doxycycline should be considered as a potential empiric therapy for mild to moderate outpatient pneumonia. Doxycycline and minocycline are options in the treatment of community-onset skin and soft tissue infection due to methicillin-resistant S aureus. As discussed previously, minocycline and doxycycline are superior to tetracycline in the treatment of methicillin-resistant S aureus; doxycycline-resistant isolates are often still inhibited by minocycline. Minocycline is equally as efficacious as doxycycline for the therapy of nongonococcal urethritis and cervicitis. ++ Adverse Effects ++ Allergy ++ Hypersensitivity reactions with fever or skin rashes are uncommon. ++ Gastrointestinal Side Effects ++ Diarrhea, nausea, and anorexia are common. Tetracycline administration, particularly doxycycline and minocycline, should be avoided at bedtime due to the risk of esophageal erosion. ++ Bones and Teeth ++ Tetracyclines are bound to calcium deposited in growing bones and teeth, causing fluorescence, discoloration, enamel dysplasia, deformity, or growth inhibition. Therefore, tetracyclines should not be given to pregnant women, nursing women, or children under 8 years of age. ++ Liver Damage ++ Tetracyclines can impair hepatic function or even cause liver necrosis, particularly in the presence of preexisting liver disease. ++ Kidney Effects ++ Demeclocycline can cause nephrogenic diabetes insipidus and has been used therapeutically to treat inappropriate antidiuretic hormone secretion. Tetracyclines, particularly tetracycline, may increase blood urea nitrogen (BUN) due to their antianabolic activity. ++ Other ++ Tetracyclines—principally demeclocycline—may induce photosensitization, especially in fair-skinned individuals. Minocycline induces vestibular reactions (dizziness, vertigo, nausea, vomiting), with a frequency of 35–70% after doses of 200 mg daily and has also been implicated as a cause of hypersensitivity pneumonitis. + Glycylcyclines ++ Tigecycline, a tetracycline derivative, is available as a parenteral antibacterial for the treatment of nosocomial infection. It is active against most gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci and many multidrug resistant aerobic gram-negative bacilli, including Acinetobacter, Enterobacter, Citrobacter, and extended-spectrum beta-lactamase–producing E coli and Klebsiella. However, tigecycline has little to no activity against Pseudomonas and only modest activity versus Proteus spp. In addition, tigecycline demonstrates excellent anaerobic activity against B fragilis and gram-positive anaerobes. A loading dose of 100 mg is administered intravenously with maintenance at 50 mg every 12 hours. The drug distributes into deep compartments with a large volume of distribution and low serum levels. Considering the low achievable serum levels associated with tigecycline, this agent should be used cautiously in bacteremic patients. The drug is primarily eliminated via biliary/fecal excretion with a half-life of 30–40 hours. Dose adjustment to 25 mg every 12 hours is recommended in Child-Turcotte-Pugh C liver disease. Tigecycline has similar adverse events as the tetracyclines; upper gastrointestinal side effects are particularly common. While approved for complicated skin and soft-tissue infection and intra-abdominal infection, the spectrum of activity of tigecycline has resulted in its use in the treatment of certain resistant gram-negative pathogens, including extended-spectrum beta-lactamase–producing organisms. However, considering the low associated serum levels, tigecycline should not be used in septic patients. Tigecycline has been associated with increased mortality in ventilator-associated pneumonia when compared with imipenem. Consequently, its use in sepsis and ventilator-associated pneumonia is not recommended. ++Doernberg SB et al. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis. 2012 Sep;55(5):615–20. [PubMed: 22563022] ++Tasina E et al. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect Dis. 2011 Nov;11(11):834–44. [PubMed: 21784708] + Chloramphenicol ++ Antimicrobial Activity ++ Chloramphenicol binds to the 50S subunit of ribosomes and inhibits protein synthesis. While active against S pneumoniae, H influenzae, and Neisseria meningitidis, it is used minimally because of its toxicity and the availability of alternative agents. Chloramphenicol is active against certain rickettsiae. ++ Pharmacokinetics & Administration ++ Chloramphenicol is widely distributed in tissues, including the eye and cerebrospinal fluid. Chloramphenicol is metabolized in the liver, and < 10% is excreted unchanged in the urine. Thus, no dosage adjustment is needed in kidney disease. Patients with liver disease may accumulate the drug, and levels should be monitored. ++ Clinical Uses ++ Chloramphenicol is an occasional alternative to more standard therapy for (1) meningococcal, H influenzae, or pneumococcal infections of the central nervous system; (2) anaerobic or mixed infections in the central nervous system, eg, brain abscess; (3) as an alternative to tetracyclines in rickettsial infections, especially in pregnant women, in whom tetracycline is contraindicated. ++ Adverse Effects ++ Chloramphenicol in excess of 50 mg/kg/d regularly causes reversible disturbances in red cell maturation within 1–2 weeks. In contrast, it is also associated with an irreversible aplastic anemia in 1:40,000–1:25,000 courses of chloramphenicol treatment. + Aminoglycosides ++ Aminoglycosides are a group of bactericidal drugs sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. At present, the group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, paromomycin, and spectinomycin. All these agents inhibit protein synthesis in bacteria by inhibiting the function of the 30S subunit of the bacterial ribosome. Resistance is based on (1) a deficiency of the ribosomal receptor (chromosomal mutant); (2) the enzymatic destruction of the drug (plasmid-mediated transmissible resistance of clinical importance) by acetylation, phosphorylation, or adenylylation; or (3) a lack of permeability to the drug molecule or failure of active transport across cell membranes. Resistance can be chromosomal (eg, streptococci are relatively impermeable to aminoglycosides) or plasmid-mediated (eg, in gram-negative enteric bacteria). Anaerobic bacteria are resistant to aminoglycosides because transport across the cell membrane is an oxygen-dependent energy-requiring process. ++ All aminoglycosides are potentially ototoxic (cochlear and vestibular) and nephrotoxic, although to different degrees. All can accumulate in kidney disease; therefore, dosage adjustments must be made in patients with kidney dysfunction (see eTable 30–4.3). ++ Because of their considerable toxicity and the availability of less toxic agents, (eg, cephalosporins, quinolones, carbapenems, beta-lactamase inhibitor combinations), aminoglycosides have been used less often in recent years. They are most commonly used to treat resistant gram-negative organisms that are sensitive only to aminoglycosides, or in low doses in combination with beta-lactam drugs or vancomycin for their synergistic effect (eg, enterococci, penicillin-resistant viridans streptococci, right-sided S aureus endocarditis, S aureus and S epidermidis prosthetic valve infection). Although aminoglycosides demonstrate in vitro activity against many gram-positive bacteria, they should never be used alone to treat infections caused by these organisms—both because there is minimal clinical experience with such infections and because less toxic alternatives are available. Aminoglycosides are inferior to beta-lactams as monotherapy in the treatment of Pseudomonas infections, particularly in febrile neutropenic patients. ++ General Properties of Aminoglycosides ++ Because of the similarities of the aminoglycosides, a summary of properties is presented briefly. ++ Absorption, Distribution, Metabolism, and Excretion ++ Aminoglycosides are not absorbed from the gastrointestinal tract. They diffuse poorly into the eye, prostate, bile, central nervous system, and spinal fluid after parenteral injection. ++ The serum half-life is 2–3 hours in patients with normal kidney function. Excretion is almost entirely by glomerular filtration. Aminoglycosides are removed effectively by hemodialysis or continuous hemofiltration. ++ Dosage and Effect of Impaired Kidney Function ++ In persons with normal kidney function who have gram-negative infections, the dosage of amikacin is 15 mg/kg/d in a single daily dose; that for gentamicin, tobramycin, or netilmicin is 5–7 mg/kg injected once daily. A single large daily dose of gentamicin, tobramycin, netilmicin, or amikacin is as efficacious as—and no more nephrotoxic than—traditional dosing every 8–12 hours. When a single large daily dose is given, peak levels are not required. Trough aminoglycoside levels should be undetectable in patients with normal body composition and kidney function receiving once-daily dosing. Some clinicians recommend serum level monitoring 12–18 hours after the dose and extending the interval to every 48–72 hours for patients with elevated aminoglycoside levels. Others have suggested maintaining the dosage interval but decreasing the dose. Patients with kidney disease, volume overload, or obesity have altered antibiotic clearance or volume of distribution. In patients with abnormal kidney function or body composition, once-daily dosing is not recommended and aminoglycoside levels are recommended to guide dosing. For more traditional dosing, peak levels > 6 mcg/mL are desirable in the treatment of serious gram-negative infection, including pneumonia. Trough levels of more than 2 mcg/mL have been associated with an increased incidence of nephrotoxicity. In patients with normal body composition, once-daily dosing regimens as set forth in eTable 30–4.3 should be followed. Reduced gentamicin doses (1 mg/kg every 8 hours) are recommended when used synergistically with beta-lactams or vancomycin in the treatment of serious gram-positive infection (eg, enterococcal endocarditis). Bacterial isolates with "susceptible" MICs of 1–4 mcg/mL treated with aminoglycosides lead to unacceptably low probability of good clinical outcome. Increasing the dose of aminoglycosides to improve chances for improved outcome is likely to be associated with an increased risk of ototoxicity and nephrotoxicity. ++ Adverse Effects ++ All aminoglycosides can cause ototoxicity and nephrotoxicity. Ototoxicity can be irreversible and is cumulative, presenting as hearing loss (cochlear damage), noted first with high-frequency tones, or as vestibular damage, manifested by vertigo and ataxia. Amikacin is likely more cochlear-toxic than gentamicin, tobramycin, or netilmicin. Nephrotoxicity is usually reversible and occurs with similar frequency with gentamicin, tobramycin, amikacin, and netilmicin. ++ In very high doses, usually associated with irrigation of an inflamed peritoneum, aminoglycosides can be neurotoxic, producing a curare-like effect with neuromuscular blockade that results in respiratory paralysis. ++ Streptomycin ++ The usual dosage of streptomycin is 15–25 mg/kg/d (about 1 g/d) injected in one or two divided doses intramuscularly. If administered over 30–60 minutes, it can also be given intravenously. Streptomycin exhibits all the adverse effects typically associated with the aminoglycosides; however, it has greater vestibular toxicity and probably less nephrotoxicity when compared with gentamicin. ++ Resistance emerges so rapidly and has become so widespread that only a few specific indications for this drug remain: plague and tularemia; endocarditis caused by E faecalis or viridans streptococci (use in conjunction with penicillin or vancomycin) in strains that are susceptible to high levels of streptomycin (ie, ≤ 2000 mcg/mL)—gentamicin may be substituted for streptomycin in this setting; active tuberculosis when other less toxic drugs cannot be used; and acute brucellosis (in combination with tetracycline). ++ Neomycin, Kanamycin, & Paromomycin ++ These aminoglycosides are closely related, with similar activity and complete cross-resistance. Systemic use has been abandoned because of ototoxicity and nephrotoxicity. ++ Neomycin, often combined with bacitracin and polymyxin, is a component of several over-the-counter topical ointments and creams. While the drug mixture covers most likely encountered staphylococci, streptococci, and gram-negative bacteria, the efficacy of topical application is questionable. ++ Neomycin or kanamycin can give rise to allergic reactions when applied topically to skin or eye. ++ Paromomycin, closely related to neomycin and kanamycin, is poorly absorbed after oral administration and has been used mainly to treat asymptomatic intestinal amebiasis and in doses of 25–30 mg/kg/d in three divided doses for 7 days to treat giardiasis in pregnancy. A dosage of 500 mg orally three or four times daily is marginally effective for cryptosporidiosis in HIV/AIDS. ++ Amikacin ++ Amikacin is a semisynthetic derivative of kanamycin. It is relatively resistant to enzymes that inactivate gentamicin and tobramycin. Many gram-negative enteric bacteria—including many gentamicin-resistant strains of Proteus, Enterobacter, and Serratia organisms are inhibited. After injection of 15 mg/kg/d of amikacin divided every 12 hours, peak levels in serum are 20–30 mcg/mL. In addition to therapy for serious gram-negative infections, amikacin is sometimes included with other drugs for therapy of M avium complex and M fortuitum complex. ++ Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Drug levels should be monitored in patients with chronic kidney disease. ++ Gentamicin ++ With doses of 5 mg/kg/d of this aminoglycoside, serum levels are sufficient for bactericidal effect against most gram-negative organisms. Enterococci generally are resistant; however, the addition of gentamicin to cell wall active agents, such as penicillin or vancomycin, is associated with increased bactericidal activity against this pathogen. ++ Indications, Dosages, & Routes of Administration ++ Gentamicin is used in serious infections caused by gram-negative bacteria. The usual dosage is 5 mg/kg/d intravenously administered once daily. In endocarditis due to viridans streptococci or E faecalis, gentamicin in lower synergistic doses (3 mg/kg/d) is combined with penicillin or ampicillin. A single daily dose of 3 mg/kg is just as effective as divided daily doses in the synergistic treatment of endocarditis due to viridans streptococci. In kidney disease, the dose should be adjusted as noted above. ++ Tobramycin ++ Tobramycin closely resembles gentamicin in antibacterial activity, toxicity, and pharmacologic properties and exhibits partial cross-resistance. It is more active than gentamicin against P aeruginosa but much less active than gentamicin when used synergistically with penicillin for enterococcal endocarditis. Dosing is the same as for gentamicin. Tobramycin is also given by aerosol (300 mg twice daily) to patients with cystic fibrosis. This improves pulmonary function and decreases colonization with Pseudomonas without toxicity and with minimal selection for resistant strains. ++ Netilmicin shares many characteristics with gentamicin and tobramycin and can be given in a similar dosage. It may be less ototoxic and less nephrotoxic than the other aminoglycosides. ++Banerjee S et al. Monitoring aminoglycoside level. BMJ. 2012 Sep 27;345:e6354. [PubMed: 23044986] ++Smyth AR et al. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 2012 Feb 15;2:CD002009. [PubMed: 22336782] + Polymyxins ++ The polymyxins (colistin and polymyxin B) are basic polypeptides that are bactericidal for certain gram-negative aerobic rods, including Pseudomonas. Because of poor distribution into tissues and substantial toxicity (primarily nephrotoxicity and neurotoxicity), systemic use of these agents has been limited to infections caused by multidrug-resistant gram-negative organisms that are sensitive only to the polymyxins. Colistin has been used with increasing frequency in the treatment of pan-resistant Acinetobacter baumanii and P aeruginosa. In the treatment of cancer patients with multidrug-resistant P aeruginosa, colistin has been found to be more effective than other antibacterial options. The more recent experience suggests colistin to be associated with less nephrotoxicity and neurotoxicity than previously described. Dosage adjustments are required with decreased renal function. ++Florescu DF et al. What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression. Clin Infect Dis. 2012 Mar 1;54(5):670–80. [PubMed: 22322268] ++Yahav D et al. Colistin: new lessons on an old antibiotic. Clin Microbiol Infect. 2012 Jan;18(1):18–29. [PubMed: 22168320] + Antituberculous Drugs ++ Singular problems exist in the treatment of tuberculosis and other mycobacterial infections. The organisms are intracellular, have long periods of metabolic inactivity, and tend to develop resistance to any one drug. Therefore, combined drug therapy is used to delay the emergence of this resistance. First-line drugs, increasingly used together in all tuberculosis, are isoniazid, ethambutol, rifampin, and pyrazinamide. ++ See Chapter 9: Pulmonary Disorders for a discussion of these medications. + Alternative Drugs in Tuberculosis Treatment ++ The drugs listed alphabetically below are usually considered only in cases of drug resistance (clinical or laboratory) to first-line drugs. ++ Capreomycin is an injectable agent given intramuscularly in doses of 15–30 mg/kg/d (maximal dose 1 g). Major toxicities include ototoxicity (both vestibular and cochlear) and nephrotoxicity. If the drug must be used in older patients, the dose should not exceed 750 mg. ++ Clofazimine is a phenazine dye used in the treatment of leprosy and is active in vitro against M avium complex and Mycobacterium tuberculosis. It is given orally as a single daily dose of 100 mg for treatment of M avium complex disease. Its clinical efficacy for the therapy of tuberculosis has not been established. Adverse effects include nausea, vomiting, abdominal pain, and skin discoloration. ++ Cycloserine, a bacteriostatic agent, is given in doses of 15–20 mg/kg (not to exceed 1 g) orally and has been used in re-treatment regimens and for primary therapy of highly resistant M tuberculosis. It can induce a variety of central nervous system dysfunctions and psychotic reactions. ++ Ethionamide, like cycloserine, is bacteriostatic and is given orally in a dose of 15–20 mg/kg (maximal dose 1 g). It has been used in combination therapy but is poorly tolerated with marked gastric irritation. ++ The fluoroquinolones ofloxacin, levofloxacin, ciprofloxacin, and moxifloxacin are active in vitro against M tuberculosis, with MICs of 0.25–2 mcg/mL. These drugs have been demonstrated to be efficacious in treating tuberculosis in patients unable to take isoniazid, rifampin, and pyrazinamide; however, rapid emergence of resistance has been described in some series. Doses include ciprofloxacin, 750 mg orally twice daily; ofloxacin, 400 mg orally twice daily; and levofloxacin, 750 mg orally once daily. Linezolid is effective in achieving culture conversion in patients with treatment-refractory, highly resistant pulmonary tuberculosis. However, the long-term use of this agent for tuberculosis is associated with significant side effects, particularly the 600 mg daily dose. ++Lee M et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012 Oct 18;367(16):1508–18. [PubMed: 23075177] + Rifamycins ++ In addition to its use as a primary agent in the treatment of tuberculosis, rifampin is used as an adjunct in the treatment of S aureus infections. When used as monotherapy, rifampin is associated with rapid emergence of resistance in staphylococci. However, when added to other primary antistaphylococcal agents, rifampin improves outcomes in the treatment of infected prosthetic hardware. Rifaximin, a derivative of rifamycin, is nonabsorbable, reaches very high levels in the stool, and has a broad spectrum of antibacterial activity, including aerobic and anaerobic gram-positive and gram-negative organisms. It is approved for use in nonpregnant women and for persons aged 12 years and older to treat noninvasive traveler's diarrhea (200 mg three times daily for 3 days) and should not be used if fever or bloody diarrhea is present. Rifamycins consistently display potent in vitro activity against C difficile, and small studies suggest rifaximin is useful, particularly in the treatment of patients with recurrent disease. Other potential uses include prophylaxis of traveler's diarrhea (200 mg/d) and therapy of hepatic encephalopathy (400 mg twice daily). Recent trials suggest rifaximin to be useful in the treatment of irritable bowel syndrome in certain patients. It is well tolerated and safe. Rifapentine, a long-acting rifamycin, in combination with isoniazid, can be administered once-weekly for 12 weeks in the treatment of latent tuberculosis. Considering the gold standard for latent tuberculosis has been isoniazid monotherapy for 9 months, it is likely that this new regimen may result in improved patient adherence. ++Pimentel M et al; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan 6;364(1):22–32. [PubMed: 21208106] ++Sterling TR et al; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155–66. [PubMed: 22150035] + Sulfonamides & Antifolate Drugs ++ Antimicrobial Activity ++ Sulfonamides are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. Organisms that utilize PABA in the synthesis of folates and pyrimidines are inhibited. Animal cells and some resistant microorganisms (eg, enterococci) use exogenous folate and thus are not affected by sulfonamides. ++ Trimethoprim and pyrimethamine are compounds that inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid by blocking the enzyme dihydrofolate reductase. These two agents are generally used in combination with other drugs (usually sulfonamides) to prevent or treat a number of bacterial and parasitic infections. At high doses, all can inhibit mammalian dihydrofolate reductase, but clinically this is a problem only with pyrimethamine. Folinic acid (leucovorin) is given concurrently with pyrimethamine to reduce the risk of bone marrow suppression. ++ Sulfonamides alone are rarely used in the treatment of bacterial infection. When used in combination with other drugs, sulfonamides are useful in the treatment of toxoplasmosis and pneumocystosis. ++ The combination of trimethoprim (one part) plus sulfamethoxazole (five parts) is bactericidal for E coli, Klebsiella, Enterobacter, Salmonella, and Shigella, though substantial resistance has emerged with all these organisms. It is also active against many strains of Serratia, Providencia, S maltophilia, B cepacia (formerly Pseudomonas cepacia), and Burkholderia pseudomallei, but not against P aeruginosa. It is inactive against anaerobes and enterococci but inhibits most Nocardia and S aureus (including methicillin-resistant S aureus) and about 50% of S epidermidis isolates. M catarrhalis, H influenzae, H ducreyi, L monocytogenes. ++ Pharmacokinetics & Administration ++ Trimethoprim-sulfamethoxazole is well absorbed from the gastrointestinal tract and widely distributed in tissues and fluids, including cerebrospinal fluid, achieving similar serum levels with either intravenous or oral administration. Dosage adjustment is required for renal insufficiency (creatinine clearance ≤ 50 mL/min). ++ Clinical Uses ++ Present indications for sulfonamides are outlined below. ++ Urinary Tract Infections ++ Coliform bacteria, the most common cause of urinary tract infections, are moderately inhibited by sulfonamides, and the IDSA recommends trimethoprim-sulfamethoxazole as a first-line agent in the treatment of uncomplicated disease. However, resistance of E coli has emerged and IDSA cautions against using in communities with high (ie, > 20%) rates of resistance. Since trimethoprim is concentrated in the prostate, trimethoprim-sulfamethoxazole, one double-strength tablet twice daily for 14–21 days, is effective in acute prostatitis. In chronic prostatitis, treatment for 6–12 weeks is indicated. Considering the increased observation of community-acquired methicillin-resistant S aureus (caMRSA), trimethoprim-sulfamethoxazole is a drug of choice in the outpatient treatment of this organism. Epidemiologic evaluations demonstrate that antibacterials have only a moderate role in the treatment of skin and soft-tissue infection due to caMRSA. Nonetheless, trimethoprim-sulfamethoxazole retains excellent coverage of this pathogen and is commonly used in the treatment of these community infections. ++ Parasitic Infections ++ Trimethoprim-sulfamethoxazole is effective for prophylaxis and treatment of Pneumocystis pneumonia, Cyclospora infection, and Isospora belli infection. For therapy of Pneumocystis pneumonia, 15 mg/kg/d of trimethoprim (with the associated 75 mg/kg/d of sulfamethoxazole) in three or four divided doses is administered intravenously or orally—depending on the severity of disease—for 3 weeks. The dose for prophylaxis is 160 mg trimethoprim + 800 mg sulfamethoxazole daily or three times per week. (When given daily, it is also effective prophylaxis against toxoplasmal encephalitis.) I belli infection in HIV/AIDS has been successfully treated with 160 mg trimethoprim + 800 mg sulfamethoxazole orally four times daily for 10 days followed by twice-daily administration for 3 weeks. Cyclosporiasis is successfully treated with 160 mg trimethoprim and 800 mg sulfamethoxazole twice daily for 7–10 days. Sulfadiazine with pyrimethamine is also used to treat and prevent recurrence of toxoplasmosis. ++ Other Bacterial Infections ++ Sulfonamides are the drugs of choice for Nocardia infections. Trimethoprim-sulfamethoxazole is widely distributed in tissues, penetrates into the cerebrospinal fluid, and has been used to treat meningitis caused by gram-negative rods, though third-generation cephalosporins have greater clinical experience and are preferred. ++ Trimethoprim-sulfamethoxazole is effective also for infections with Enterobacter, B pseudomallei (melioidosis), S maltophilia, or B cepacia; in combination with rifampin, for eradication of nasopharyngeal carriage of staphylococci; for prophylaxis against meningococcal disease when susceptible strains predominate; for Pneumocystis prophylaxis in organ transplant recipients; and for treatment of L monocytogenes meningitis. ++ Leprosy ++ Certain sulfones are widely used (see below). ++ Adverse Effects ++ Adverse reactions to sulfonamides occur in 10–15% of non-HIV/AIDS patients (usually a minor rash or gastrointestinal disturbance) and in up to 50% of patients with HIV/AIDS (predominantly rash, fever, neutropenia, and thrombocytopenia, often severe enough to require discontinuation of therapy). Adverse events are multifactorial in origin, including hypersensitivity, toxicity, and idiosynchratic. ++ Systemic Side Effects ++ Fever, skin rashes, urticaria; nausea, vomiting, or diarrhea; stomatitis, conjunctivitis, arthritis, aseptic meningitis, exfoliative dermatitis; bone marrow depression, thrombocytopenia, hemolytic anemia (in G6PD deficiency) or aplastic anemia, granulocytopenia, leukemoid reactions; hepatitis, polyarteritis nodosa, vasculitis, Stevens-Johnson syndrome; reversible hyperkalemia; and many others have been reported. Because of the risk of Stevens-Johnson syndrome, patients with a previous rash after trimethoprim-sulfamethoxazole should not receive the drug again. ++ HIV-positive patients intolerant to trimethoprim-sulfamethoxazole can often be desensitized. While a number of desensitization protocols exist, a 70% success rate has been reported after giving 0.004 mg trimethoprim/0.02 mg sulfamethoxazole as oral suspension and increasing the dose tenfold each hour to achieve a final dose of 160 mg trimethoprim/500 mg sulfamethoxazole. ++ Urinary Tract Disturbances ++ Older sulfonamides were relatively insoluble and would precipitate in urine. The most commonly used sulfonamides presently (sulfamethoxazole) are quite soluble, and the old admonition to force fluids is no longer warranted. Sulfonamides have been implicated in interstitial nephritis. Patients with toxoplasmosis receiving high-dose sulfadiazine therapy are predisposed to crystalluria. ++Gupta K et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar;52(5):e103–20. [PubMed: 21292654] ++Sibanda EL et al. Does trimethoprim-sulfamethoxazole prophylaxis for HIV induce bacterial resistance to other antibiotic classes? Results of a systematic review. Clin Infect Dis. 2011 May;52(9):1184–94. [PubMed: 21467024] + Sulfones Used in the Treatment of Leprosy ++ A number of drugs closely related to the sulfonamides (eg, dapsone) have been used effectively in the long-term treatment of leprosy. The clinical manifestations of both lepromatous and tuberculoid leprosy can often be suppressed by treatment extending over several years. At least 5–30% of Mycobacterium leprae organisms are resistant to dapsone, so initial combined treatment with rifampin is advocated. Dapsone, 100 mg daily, is effective therapy for mild to moderate Pneumocystis pneumonia in AIDS when combined with trimethoprim, 20 mg/kg/d in four divided doses. At a dose of 50–100 mg daily or 100 mg two or three times a week, it is effective prophylaxis for Pneumocystis jiroveci infection and, when combined with pyrimethamine, 50 mg per week, also prevents Toxoplasma encephalitis in HIV-infected patients. ++ Absorption, Metabolism, & Excretion ++ All sulfones are well absorbed from the intestinal tract, are distributed widely in all tissues, and tend to be retained in skin, muscle, liver, and kidney. Leprous skin contains ten times more drug than normal skin. Sulfones are excreted into the bile and reabsorbed by the intestine, prolonging therapeutic blood levels. Excretion into the urine is variable, and the drug occurs in urine mostly as a glucuronic acid conjugate. ++ Dosages & Routes of Administration ++ See Leprosy, in Chapter 33: Bacterial & Chlamydial Infections, for recommendations. ++ Adverse Effects ++ The sulfones may cause any of the side effects listed above for sulfonamides. Considering that sulfones can be cross-reactive with sulfonamides, they should not be used in those patients experiencing significant sulfonamide adverse events. Anorexia, nausea, and vomiting are common. Hemolysis, methemoglobinemia, or agranulocytosis may occur. G6PD status should always be determined prior to initiation of dapsone therapy. If sulfones are not tolerated, clofazimine can be substituted. + Specialized Drugs Used Against Bacteria ++ Bacitracin ++ This polypeptide is selectively active against gram-positive bacteria. Because of severe nephrotoxicity associated with systemic administration, its use has been limited to topical application on surface lesions, usually in combination with polymyxin or neomycin. ++ Mupirocin ++ Mupirocin (formerly pseudomonic acid) is a naturally occurring antibiotic produced by Pseudomonas fluorescens active against most gram-positive cocci, including methicillin-sensitive and methicillin-resistant S aureus and most streptococci (but not enterococci). Used topically, it is somewhat effective in eliminating staphylococcal nasal carriage in the majority of patients for up to 3 months after application to the anterior nares twice daily for 5 days. However, recurrent colonization occurs (50% at the end of 1 year), and when mupirocin is used long-term over months, resistance can emerge. High rates of mupirocin resistance have been observed in methicillin-resistant S aureus isolates from surgical intensive care unit patients, despite minimal in-hospital mupirocin use. This finding suggests the benefit of mupirocin is limited. Monthly application for 5 days each month for up to a year decreases staphylococcal colonization, which in turn lowers the risk of recurrent staphylococcal skin infections. Studies demonstrate an associated reduction in postoperative staphylococcal lung infections in colonized patients treated with mupirocin. Whether it is more effective than trimethoprim-sulfamethoxazole or dicloxacillin plus rifampin for eradication of staphylococcal nasal carriage is unknown. The IDSA recommends the use of mupirocin with chlorhexidine preferentially over oral antibacterials for methicillin-resistant S aureus decolonization. Mupirocin appears to be equal to oral beta-lactams in the treatment of mild impetigo. ++ Clindamycin ++ Clindamycin is active against gram-positive organisms including S pneumoniae, viridans streptococci, group A streptococci, and S aureus, though resistance has been described in all of these organisms. Pneumococci or staphylococci with an efflux-based mechanism of resistance can be effectively treated with clindamycin. However, isolates with ribosomal methylase resistance are also resistant to clindamycin. Enterococci and most S epidermidis also are resistant. However, at the present time, most caMRSA isolates are often susceptible to clindamycin. In those instances in which caMRSA isolates demonstrate resistance to macrolides but susceptibility to clindamycin, additional microbiologic testing ("D" test) is advised to confirm the effectiveness of clindamycin. A dosage of 0.15–0.3 g every 6 hours is generally given when the oral route is used for bacterial infection. It is widely distributed in tissues but not in cerebrospinal fluid. Excretion is primarily nonrenal. Clindamycin is currently recommended as an alternative drug for prophylaxis against endocarditis following certain dental procedures in patients allergic to amoxicillin. Clindamycin, 300 mg orally twice daily for 7 days, can be used as an alternative to metronidazole for the therapy of bacterial vaginosis. Topical application of a 2% vaginal cream once or twice daily for 7 days is also effective. Clindamycin is active against most anaerobes, including Prevotella, Clostridium, Peptococcus, Peptostreptococcus, and Fusobacterium organisms. However, up to 25% of Bacteroides isolates are resistant, and alternative agents should be considered for serious infections due to these organisms. It is frequently used to treat less severe infections in which anaerobes are significant pathogens (eg, aspiration pneumonia, pelvic and abdominal infections), often in combination with other drugs (aminoglycosides, cephalosporins, fluoroquinolones). Patients with hospital-acquired infection should be given clindamycin, 600–900 mg intravenously every 8 hours. Clindamycin is effective in the treatment of staphylococcal osteomyelitis, particularly in children. Because tissue models document that clindamycin significantly decreases toxin production, the addition of clindamycin to penicillin for therapy of group A streptococcus toxic shock syndrome is often used. Clindamycin in combination with primaquine is effective in Pneumocystis pneumonia, and clindamycin with quinine is of value for falciparum malaria. While useful in brain abscess, clindamycin is ineffective in meningitis. ++ Common side effects are diarrhea, nausea, and skin rashes. Antibiotic-associated colitis has been associated with the administration of clindamycin and other antibiotics and is due to a necrotizing toxin produced by C difficile. Interestingly, antecedant use of clindamycin is not a risk factor for the more recent hypervirulent strain of C difficile. Rather, prior receipt of fluoroquinolones is a significant risk factor. C difficile is usually susceptible to—and can be treated with—metronidazole or vancomycin given orally (see below). ++ Metronidazole & Tinidazole ++ Metronidazole is an antiprotozoal drug (see Chapter 35: Protozoal & Helminthic Infections) also active against most anaerobic gram-negative bacilli (ie, Bacteroides, Prevotella, Fusobacterium) as well as Clostridium species but has minimal activity against many anaerobic gram-positive and microaerophilic organisms. It is well absorbed after oral administration and is widely distributed in tissues. It penetrates well into the cerebrospinal fluid, yielding levels similar to those in serum. The drug is metabolized in the liver, and dosage reduction is required in severe hepatic insufficiency or biliary dysfunction. Tinidazole is identical in spectrum of activity to metronidazole. ++ Metronidazole is used to treat amebiasis and giardiasis (see Chapter 35: Protozoal & Helminthic Infections) and in the following circumstances: ++ 1. Vaginitis caused by Trichomonas vaginalis can be treated with a single dose of either metronidazole or tinidazole (2 g) or 500 mg orally three times daily for 7 days. Bacterial vaginosis is treated with metronidazole 500 mg twice daily for 7 days. Metronidazole vaginal cream (0.75%) applied twice daily for 5 days is also effective.2. In anaerobic infections, metronidazole can be given orally or intravenously, 500 mg three times daily. In contrast to clindamycin or cefoxitin and cefotetan, metronidazole is active against virtually all B fragilis isolates. 3. Metronidazole is less expensive and equally as efficacious as oral vancomycin for the therapy of C difficile colitis and is the drug of choice for mild to moderate disease. A dosage of 500 mg orally three times daily is recommended. If oral medication cannot be administered in the treatment of C difficile colitis, intravenous metronidazole can be tried at the same dose; however, the efficacy associated with this route is unproven. Because of the emergence of vancomycin-resistant enterococci as a major pathogen and the role of oral vancomycin in selecting for these resistant organisms, metronidazole should be used as first-line therapy for mild to moderate C difficile disease. While metronidazole and vancomycin are equally effective in the treatment of mild to moderate C difficile disease, oral vancomycin is superior to metronidazole in the treatment of severe disease. 4. Preparation of the colon before bowel surgery. 5. Therapy of brain abscess, often in combination with penicillin or a third-generation cephalosporin. 6. In combination with clarithromycin and omeprazole for therapy of H pylori infections. ++ Adverse effects include stomatitis, nausea, and diarrhea. Ingestion of alcohol while taking metronidazole occasionally results in a disulfiram reaction. With prolonged use at high doses, reversible peripheral neuropathy can develop. Metronidazole can decrease the metabolism of warfarin, necessitating dosage adjustment of warfarin. Metronidazole is carcinogenic in certain animal models and mutagenic for certain bacteria, but these effects have not resulted in an increased risk of cancer in humans. ++Cohen SH et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010. Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of American (IDSA). Infect Control Hosp Epidemiol. 2010 May; 31(5): 431–55. [PubMed: 20307191] ++ Vancomycin ++ Vancomycin is bactericidal for most gram-positive organisms, particularly staphylococci and streptococci; it is, however, bacteriostatic for most enterococci. While active against staphylococci, vancomycin kills more slowly when compared with nafcillin. Although vancomycin has retained activity against staphylococci and streptococci, vancomycin-resistant strains of enterococci (particularly E faecium) have emerged. S aureus both intermediately sensitive and highly vancomycin-resistant has been observed in patients receiving long-term vancomycin therapy. Vancomycin is not absorbed from the gastrointestinal tract and thus useful orally only for the treatment of antibiotic-associated enterocolitis. For systemic effect, the drug must be administered intravenously (30 mg/kg/d in two or three divided doses). Vancomycin is excreted mainly via the kidneys. In end-stage kidney disease, the half-life may extend to 8 days. Vancomycin is cleared via high-flux hemodialysis and continuous arteriovenous hemofiltration (CAVH), resulting in the need for increased dosing. In patients with impaired kidney function, the dosing interval is determined by measuring trough serum levels. When trough serum levels decline to 10–15 mcg/mL, repeat dosing is required, primarily in the treatment of severe infection. As an example, more aggressive dosing with associated troughs of > 15 mcg/mL has been recommended in the treatment of methicillin-resistant S aureus ventilator-associated pneumonia. However, the association of attainment of these elevated trough levels and efficacy has not been proven. Large doses (≥ 4 g daily) have been associated with mild reversible nephrotoxicity. Vancomycin efficacy is closely correlated with pharmacokinetics/pharmacodynamics. Specifically, area-under-the-curve divided by the minimum inhibitory concentration (MIC) of > 400 has been associated with favorable outcomes in serious infection due to S aureus. Considering this relationship, the MIC is critical toward the decision to use vancomycin; in those instances in which the MIC is ≥ 2 mcg/mL (or ≥ 1.5 mcg/mL by E-test), alternatives to vancomycin should be used. These include daptomycin, linezolid, televancin, and other agents, depending on the site of infection. ++ Indications for parenteral vancomycin include the following: (1) Severe staphylococcal infections in penicillin-allergic patients; for methicillin-resistant S aureus and S epidermidis infections and for serious infections (pneumonia, meningitis) due to resistant S pneumoniae. (2) Severe enterococcal infections in the penicillin-allergic patient or if the enterococcus is penicillin-resistant. (3) Other gram-positive infections in penicillin-allergic patients, eg, viridans streptococcal endocarditis. (4) Surgical prophylaxis in penicillin-allergic patients. (5) For gram-positive infections due to organisms that are multidrug-resistant, ie, Corynebacterium jeikeium. (6) Endocarditis prophylaxis in the penicillin-allergic patient. In antibiotic-associated enterocolitis, vancomycin, 0.125 g, is given orally four times daily. Oral vancomycin is preferred over oral metronidazole in the treatment of severe C difficile disease. ++ Thrombophlebitis sometimes follows intravenous injection. The drug is infrequently ototoxic when given concomitantly with aminoglycosides or high-dose intravenous erythromycins; it is potentially nephrotoxic when administered with aminoglycosides. Some studies suggest larger vancomycin doses or elevated trough levels or both to be associated with an increased incidence of mild nephrotoxicity. Rapid infusion or high doses (1 g or more) may induce diffuse hyperemia ("red man syndrome") and can be avoided by extending infusions over 1–2 hours, by reducing the dose, or by pretreating with a histamine antagonist such as hydroxyzine. ++Liu C et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011 Feb;52(3):e18–55. [PubMed: 21208910] [[XSLOpenURL/ 21208910]]++Rybak MJ et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009 Aug 1;49(3):325–7. [PubMed: 19569969] ++van Hal SJ et al. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis. 2012 Mar;54(6):755–71. [PubMed: 22302374] + Streptogramins ++ Synercid, the one approved streptogramin, is a combination of two synthetic derivatives of pristinamycin—quinupristin and dalfopristin—in a 30:70 ratio that is administered intravenously. It is bactericidal and inhibits protein synthesis by binding to bacterial ribosomes. Its major clinical use is in the therapy of gram-positive infections, particularly methicillin-resistant S aureus and S epidermidis and enterococci, including vancomycin-resistant E faecium. The combination is not reliably active against E faecalis. The recommended dose is 7.5 mg/kg/dose intravenously every 8 hours. In addition to phlebitis with peripheral administration, the major adverse effect is arthralgias and myalgias, which resolve with discontinuation of the drug. It is primarily cleared via the liver; streptogramins inhibit the cytochrome P450 system, resulting in increased levels of cyclosporine and other agents. With the availability of linezolid and daptomycin, the indications for this agent are extremely limited. + Oxazolidinediones ++ Oxazolidinediones represent a class of antibacterials of which linezolid is the one available agent. Linezolid is primarily active against aerobic gram-positive pathogens, including penicillin-resistant pneumococci, methicillin-resistant staphylococci and enterococci (both E faecalis and vancomycin-sensitive and vancomycin-resistant E faecium) and mycobacteria. Linezolid is bacteriostatic against all of these pathogens. Linezolid-resistant and vancomycin-resistant enterococci and linezolid-resistant S aureus and S epidermidis have been isolated. The oral bioavailability of linezolid is complete, with serum levels approaching those observed with intravenous administration. The drug is eliminated primarily by nonrenal mechanisms. The primary toxicity is bone marrow suppression with long-term therapy, particularly the platelet and white blood cell lines. Other adverse effects include neuropathy and mitochondrial toxicity with long-term use. Linezolid is a mild monoamine oxidase inhibitor and while concomitant use of selective serotonin reuptake inhibitors may result in a serotonin syndrome, most patients can safely receive both agents together. In the treatment of methicillin-resistant S aureus pneumonia, linezolid is superior to vancomycin. While linezolid is modestly superior to vancomycin in confirmed methicillin-resistant S aureus pneumonia, it offers little to no advantage in the empiric treatment of hospital-acquired or ventilator-associated pneumonia. Of particular concern are the increasing reports of linezolid-resistant Enterococcus and staphylococci, which reinforce that this agent should be used judiciously. + Daptomycin ++ Daptomycin is a bactericidal lipopeptide with a spectrum of activity similar to that of linezolid or quinupristin-dalfopristin. This spectrum includes methicillin-resistant staphylococci and vancomycin-resistant enterococci; however, MICs are much lower for the former than the latter. Daptomycin has poor oral bioavailability, thus is only available as a parenteral product. Its long pharmacologic half-life allows for once-daily dosing (4 mg/kg every 24 hours in skin and soft tissue infection and 6 mg/kg every 24 hours in the treatment of bacteremia and right-sided endocarditis); dosage adjustment is necessary in the presence of kidney disease. Up to 10 mg/kg daily has been used to treat serious infection, particularly that associated with enterococcus. The primary adverse event associated with daptomycin is a reversible, dose-dependent myopathy observed with > 7 days of therapy. Daptomycin cannot be used in the treatment of respiratory tract infection because pulmonary surfactant binds daptomycin, resulting in minimal free drug concentrations in pulmonary secretions. ++Campbell ML et al. Treatment of methicillin-resistant Staphylococcus aureus infections with a minimum inhibitory concentration of 2 mcg/mL to vancomycin: old (trimethoprim/sulfamethoxazole) versus new (daptomycin or linezolid) agents. Ann Pharmacother. 2012 Dec;46(12):1587–97. [PubMed: 23212935] ++Wunderink RG et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012 Mar;54(5):621–9. [PubMed: 22247123] + Telavancin ++ Telavancin is the first approved lipoglycopeptide for the treatment of skin and soft-tissue infection due to resistant gram-positive bacterial pathogens. At the present time, skin and soft tissue infection is the only indication for this agent. Telavancin displays concentration-dependent bactericidal killing and a 7.5-h half-life and postantibiotic effect of 4-6 hours allowing for once-daily dosing. Taste disturbance, nausea, headache, foamy urine, and reversible kidney injury are the most commonly observed adverse events. Similar to daptomycin and linezolid, telavancin is useful in the treatment of resistant bacterial skin and soft-tissue infection and is an alternative for patients who are intolerant of vancomycin. ++Saravolatz LD et al. Telavancin: a novel lipoglycopeptide. Clin Infect Dis. 2009 Dec 15;49(12):1908–14. [PubMed: 19911938] + Quinolones ++ The quinolones are synthetic analogs of nalidixic acid with a broad spectrum of activity against many bacteria. The mode of action of all quinolones involves inhibition of bacterial DNA synthesis by blocking the enzyme DNA gyrase. ++ The earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not achieve systemic antibacterial levels after oral intake and thus were useful only as urinary antiseptics. The fluoroquinolone derivatives (ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin) have more potent antibacterial activity, achieve clinically useful levels in blood and tissues, and have low toxicity. ++ Antimicrobial Activity ++ A number of fluoroquinolones are in use. With a few exceptions, the spectrum of activity is similar among the available agents. In general, these drugs have moderate to excellent activity against Enterobacteriaceae but are also active against other gram-negative bacteria such as Haemophilus, Neisseria, Moraxella, Brucella, Legionella, Salmonella, Shigella, Campylobacter, Yersinia, Vibrio, and Aeromonas organisms. Resistance to E coli has significantly increased over the past decade, with some centers reporting up to 20–30% resistance. Ciprofloxacin and levofloxacin are the only agents with activity against P aeruginosa, but the increasing resistance of P aeruginosa to fluoroquinolones has limited their utility. None of these agents have reliable activity against S maltophilia or B cepacia or against certain genital tract pathogens, such as Mycoplasma hominis, U urealyticum, and Chlamydophila pneumoniae. M tuberculosis is sensitive to the quinolones, as is M fortuitum and Mycobacterium kansasii. ++ In general, the fluoroquinolones are less potent against gram-positive than against gram-negative organisms. Gemifloxacin, levofloxacin, and moxifloxacin have the best gram-positive activity, including against streptococci, pneumococci and S aureus and S epidermidis, including some methicillin-resistant strains. However, the emergence of resistant strains of staphylococci, particularly with monotherapy, has limited the use of these drugs in infections caused by these organisms. Use of fluoroquinolones to treat tuberculosis in South Africa has been associated with emergence of invasive disease due to levofloxacin non-susceptible S pneumoniae. T pallidum and Nocardia are resistant to all fluoroquinolones. ++ Moxifloxacin demonstrates modest activity against many of the significant anaerobic pathogens, including B fragilis and mouth anaerobes, and is approved for the treatment of intra-abdominal infection. Moxifloxacin also provides the most reliable coverage of M tuberculosis. ++ Pharmacokinetics & Administration ++ After oral administration, the fluoroquinolones are well-absorbed and widely distributed in body fluids and tissues and are concentrated intracellularly. Fluoroquinolones bind some heavy metals; thus, absorption is inhibited when administered concomitantly with iron, calcium, and other multivalent cations. Optimal oral bioavailability is achieved if fluoroquinolones are taken 1 hour before or 2 hours after meals. The serum half-life ranges from 4 hours (ciprofloxacin) to 12 hours (moxifloxacin). After ingestion of 500 mg, the peak serum level of ciprofloxacin is 2.5 mcg/mL, which is lower than that of the other quinolones (4–6 mcg/mL), but this is offset by ciprofloxacin's slightly greater in vitro potency against most gram-negative organisms. A number of the fluoroquinolones can be administered intravenously, resulting in peak serum levels ranging from 4 mcg/mL to 9 mcg/mL (see eTable 30–4.4). Most are eliminated via mixed renal and nonrenal pathways. As a result, only modest accumulation takes place in the presence of kidney disease. Exceptions are ofloxacin and levofloxacin, which are primarily dependent upon the kidney for elimination. ++ Clinical Uses ++ While fluoroquinolones previously were considered drugs of choice in the empiric treatment of uncomplicated urinary tract infection, the IDSA now recommends against using these agents as drugs of choice for the treatment of this infection in women. ++ Because quinolones have excellent penetration into prostatic secretions, they are effective in treating both acute and chronic bacterial prostatitis. ++ Quinolones are approved for treatment of certain sexually transmitted diseases. Ofloxacin, 300 mg orally twice daily for 7 days, is as effective as doxycycline, 100 mg orally twice daily for 7 days, for the therapy of C trachomatis cervicitis, urethritis, and proctitis. It is also effective for nongonococcal urethritis caused by U urealyticum. Ciprofloxacin is not effective for the therapy of chlamydial infections or nongonococcal urethritis. The increased prevalence of quinolone-resistant gonococci in the United States has resulted in the CDC no longer recommending these agents in the treatment of this disease. Intramuscular ceftriaxone is the one CDC-recommended primary therapeutic option for the treatment of Neisseria gonorrhoeae. ++ Pelvic inflammatory disease is usually caused by C trachomatis, N gonorrhoeae, Enterobacteriaceae, or anaerobes. Considering the high rate of fluoroquinolone-resistant N gonorrhoeae, regimens involving these agents are recommended as alternative regimens only in those patients unable to tolerate parenteral ceftriaxone, cefoxitin, or cefotetan. Oral outpatient treatment with ofloxacin, 400 mg twice daily (or levofloxacin 500 mg once daily) for 14 days with or without metronidazole, 500 mg orally twice daily for 14 days, can be used in select cases if the risk of gonorrhea is low. Epididymitis in young men (< 35 years of age) is caused most commonly by Chlamydia and the gonococcus. While intramuscular ceftriaxone plus oral doxycycline is the regimen of choice for acute epididymitis, levofloxacin, 500 mg orally once daily, (or ofloxacin, 300 mg orally twice daily) for 10 days, can be used. Fluoroquinolones have been used successfully to treat complicated skin and soft tissue infections and osteomyelitis caused by gram-negative organisms. Ciprofloxacin, 500–750 mg orally twice daily for at least 6 weeks, has been effective therapy for malignant otitis externa. ++ Quinolones are among the few oral agents active against Campylobacter; however, resistance has been steadily increasing and macrolides are significantly more active. In addition, they are active against the other major bacterial pathogens associated with diarrhea (Salmonella, Shigella, toxigenic E coli). Consequently, they have been used for the therapy of traveler's diarrhea as well as domestically acquired acute diarrhea. Norfloxacin, ciprofloxacin, and ofloxacin may be effective in eradicating the chronic carrier state of Salmonella when therapy is continued for 4–6 weeks. ++ Ciprofloxacin has been used to eradicate meningococci from the nasopharynx of carriers. ++ Fluoroquinolones are effective for prophylaxis against gram-negative infections in the neutropenic patient, and intravenous ciprofloxacin in combination with beta-lactam antibiotics has been used successfully to treat febrile neutropenia. ++ Gemifloxacin, levofloxacin, and moxifloxacin are sometimes referred to as "respiratory fluoroquinolones" due to their activity against the pneumococci, including penicillin-resistant strains as well as atypical respiratory bacteria. However, their broad aerobic gram-negative spectrum suggests that they should be reserved for the treatment of refractory infections or high-risk patients, including those with comorbidities or with recent receipt of beta-lactam antibacterials. One setting in which ciprofloxacin is indicated for the therapy of lower respiratory tract infections is in cystic fibrosis, in which P aeruginosa is the predominant pathogen. However, the increasing rate of resistance to ciprofloxacin and levofloxacin has diminished the use of these drugs for this indication. ++ Ciprofloxacin in combination with other agents has been used to treat M avium complex infections, and ciprofloxacin, levofloxacin, ofloxacin, and moxifloxacin may be efficacious in the therapy of multidrug-resistant tuberculosis. ++ Adverse Effects ++ The most prominent adverse effects of the quinolones are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, seizures, insomnia, impaired liver function, and skin rashes have been observed as well as more serious reactions such as acute kidney injury, hypoglycemia (especially with gatifloxacin, which has been removed from the US market), and anaphylaxis. Fluoroquinolones as a class prolong the QT interval; it is debated whether any one agent is implicated more than another. Quinolones should be used cautiously in patients receiving antiarrhythmics such as amiodarone or in persons with a history of prolonged QT. Prolongation of the prothrombin time and the international normalized ratio has been observed in some patients receiving stable doses of warfarin after ciprofloxacin has been given, but this interaction is unpredictable and modest if it exists at all. Tendinitis and tendon rupture have been reported with quinolone agents. The proposed mechanisms for this adverse event are not completely understood. It is known that fluoroquinolones decrease type I collagen, elastin, fibronectin, and beta1-integrin and inhibit cell proliferation and synthesis of matrix ground substance (fibroblast metabolism). However, the true mechanism for this complication is unclear at the present time. Nonetheless, risk factors are well known and include concomitant corticosteroid use and age > 60 years. The FDA has approved a black box warning for tendinopathy. Patients experiencing musculoskeletal symptoms while receiving fluoroquinolones should discontinue therapy. ++Han JH et al. Risk factors for efflux pump overexpression in fluoroquinolone-resistant Escherichia coli. J Infect Dis. 2012 Nov 15;206(10):1597–603. [PubMed: 22966123] ++Lapi F et al. Fluoroquinolones and the risk of serious arrhythmia: a population-based study. Clin Infect Dis. 2012 Dec;55(11):1457–65. [PubMed: 22865870] + Pentamidine & Atovaquone ++ Pentamidine and atovaquone are antiprotozoal agents that are primarily used to treat Pneumocystis pneumonia. Pentamidine is discussed in Chapter 31: HIV Infection & AIDS and Chapter 35: Protozoal & Helminthic Infections. Atovaquone inhibits mitochondrial electron transport and probably also folate metabolism. The solid dosage form is poorly absorbed and should be given with food to maximize bioavailability. The suspension is significantly better absorbed and preferred especially in high-risk patients (those with diarrhea, malabsorption). It has moderate activity against P jiroveci. In comparative trials with trimethoprim-sulfamethoxazole and pentamidine in the therapy of Pneumocystis pneumonia in AIDS, atovaquone, 750 mg orally three times daily for 3 weeks, is less effective than both agents but better tolerated. It has also been used as prophylaxis in AIDS patients at a dosage of 1500 mg daily. Major adverse effects include rash, nausea, vomiting, diarrhea, fever, and abnormal liver function tests. The use of atovaquone is limited to patients with mild to moderate Pneumocystis infections who have not responded to or cannot tolerate other therapies. + Urinary Antiseptics ++ These drugs exert antimicrobial activity in the urine but have little or no systemic antibacterial effect. Their usefulness is limited to therapy and prevention of urinary tract infections. ++ Nitrofurantoin ++ Nitrofurantoin is active against the common gram-positive urinary pathogens E faecalis and Staphylococcus saprophyticus, but the drug inhibits only about 50% of E faecium. It is also used against E coli and Citrobacter, but activity against Proteus, Serratia, and Pseudomonas is poor. Considering its reliable activity against E coli, nitrofurantoin is one of the primary options recommended by the IDSA for the treatment of urinary tract infection. Following oral administration, about 50% of the drug is absorbed, but serum concentrations are very low and tissue levels are undetectable. Levels in the urine reach concentrations of 200–400 mcg/mL, which are well above the MICs of susceptible organisms. However, in kidney disease, subtherapeutic urine levels are present and drug accumulation takes place in serum. Given low serum levels, poor tissue penetration, and renal elimination, the use of nitrofurantoin is limited to therapy or prophylaxis of cystitis in patients with normal kidney function. Nitrofurantoin cannot be used to treat pyelonephritis or prostatitis. ++ The average daily dose in urinary tract infections is 100 mg orally four times daily, taken with food. The macrocrystal preparation can be given at a dosage of 100 mg twice daily. A single daily dose of 50–100 mg can prevent recurrent urinary tract infections in women. ++ Oral nitrofurantoin often causes nausea and vomiting. The crystalline formulation is better tolerated than previous preparations. Hemolytic anemia may occur in G6PD deficiency. Other side effects are skin rashes and, uncommonly, peripheral neuropathy. Acute and chronic pulmonary hypersensitivity reactions may occur, and pulmonary fibrosis has occurred with prolonged use. ++ Fosfomycin ++ Fosfomycin tromethamine is a phosphonic acid derivative useful in the treatment of uncomplicated urinary tract infection. The spectrum of activity includes E coli, including extended-spectrum beta-lactamase–producing isolates, E faecalis, and other gram-negative aerobic urinary pathogens, but not P aeruginosa. Available as a 3-g sachet, fosfomycin may be useful for the single-dose treatment of the above organisms. Like nitrofurantoin, fosfomycin should not be used for systemic infection. However, the increased concentrations in urine allow for its use in uncomplicated bacteriuria. Considering the increased resistance associated with E coli in the treatment of urinary tract infection, fosfomycin has increased its utility in this disease state. In contrast, fosfomycin disodium is available in Europe for intravenous use and may be useful in the treatment of more serious infections. The most frequently reported adverse effects include diarrhea, headache, and nausea. ++Falagas ME et al. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis. 2010 Jan;10(1):43–50. [PubMed: 20129148] + Antifungal Drugs ++ Empiric antifungal therapy is rarely instituted except for febrile neutropenic and other high-risk patients. Therapy generally is reserved for situations in which yeast or mold is seen on KOH preparation or when isolated organisms are thought to be pathogenic. Antifungal standardized susceptibility testing is available for Candida spp, and predict clinical outcome. In contrast, susceptibility testing for most other fungi is not generally available; in vitro results for these pathogens is less predictive of patient outcomes. ++ Amphotericin B ++ Amphotericin B in vitro inhibits several organisms producing systemic mycotic disease in humans, including Aspergillus, Histoplasma, Cryptococcus, Coccidioides, Candida, Blastomyces, Sporothrix, and others. This drug can be used for treatment of these systemic fungal infections. Pseudallescheria boydii and Fusarium are often resistant to amphotericin B. ++ Lipid-based Amphotericin B ++ The nephrotoxicity of amphotericin has resulted in the development of lipid-based amphotericin B products. The most commonly used agents are amphotericin B lipid complex (ABLC; Abelcet) and liposomal amphotericin B (L-AmB; AmBisome). Complexing amphotericin B with lipid allows larger doses to be administered (3–6 mg/kg, depending on the preparation and the fungal species). Liposomal amphotericin 10 mg/kg/d is no better than 3 mg/kg/d in the treatment of invasive mold infection; however, the larger dose is associated with significantly increased nephrotoxicity. The lipid formulations are particularly effective for treatment of visceral leishmaniasis. Short courses (5–10 days) with low doses (2–4 mg/kg/d depending on which preparation is used) are very effective in eradicating the parasite, probably because of distribution of the drug to the reticuloendothelial system, the major site of parasite invasion. ++ These preparations are associated with less nephrotoxicity than conventional amphotericin B. Liposomal amphotericin is somewhat less nephrotoxic than ABLC. Infusion-related adverse effects are variable, with liposomal amphotericin the best tolerated. Liposomal amphotericin is equal to or better than that of conventional amphotericin B in febrile neutropenia, particularly in prevention of emergent Candida infections. ++ Conventional Amphotericin B ++ The availability of lipid-based amphotericin, echinocandins, and triazoles has resulted in a greatly reduced role for conventional amphotericin for the prevention and treatment of fungal infection. If conventional amphotericin B is used, the daily dose for most fungal infections varies from 0.3 mg/kg to 0.7 mg/kg, though infections caused by Aspergillus and Mucor are often treated with 1–1.5 mg/kg daily. ++ Combined treatment with flucytosine is beneficial in cryptococcal meningitis and possibly systemic candidiasis. In most patients with Foley catheter-related candiduria, antifungal therapy has no therapeutic benefit. ++ Neither kidney disease nor liver failure alters the pharmacokinetic disposition of amphotericin. The drug concentrates in the lung, liver, spleen, and kidney with minimal penetration into skin or adipose tissue. The drug is not removed by hemodialysis. ++ The intravenous administration of amphotericin B often produces chills, fever, vomiting, and headache. However, patients who experience infusion-related adverse effects may benefit from slowing the rate of administration. Tolerability may also be enhanced by temporary lowering of the dose or premedication with acetaminophen and diphenhydramine. Addition of 25 mg of hydrocortisone to the infusion decreases the incidence of rigors, and meperidine, 25–50 mg, is effective in arresting rigors once they start. Electrolyte disturbances (hypokalemia, hypomagnesemia, distal renal tubular acidosis) also commonly occur. Kidney injury can be reduced with sodium supplementation. As a result, administration of 0.5–1 L of 0.9% saline prior to infusion of amphotericin B is recommended. ++Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012 Jan;125(1 Suppl):S3–13. [PubMed: 22196207] ++Walsh TJ et al; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008 Feb 1;46(3):327–60. [PubMed: 18177225] [[XSLOpenURL/ 18177225]] ++ Nystatin ++ Nystatin has a wide spectrum of antifungal activity but is used almost exclusively to treat superficial candidal infections. It is too toxic for systemic administration, and the drug is not absorbed from mucous membranes or the gastrointestinal tract. Several preparations are available, including oral suspension (100,000 units/mL) and ointments, gels, and creams (100,000 units/g). For oral candidiasis, 500,000 units of suspension is used as a "swish and swallow" and repeated four times a day for at least 2 days after resolution of the infection. Infections of skin are treated with cream or ointment, 100,000 units applied to the affected area twice daily until resolution of the infection. ++ Flucytosine ++ Flucytosine inhibits some strains of Candida, Cryptococcus, and other fungi. Dosages of 3–8 g daily (75–150 mg/kg/d) orally produce therapeutic levels in serum, urine, and cerebrospinal fluid. When used as monotherapy, development of resistance is common; thus, flucytosine is not used as a single drug therapy except in candiduria. In kidney disease, flucytosine may accumulate to toxic levels, and dosage adjustment is needed. Because patients with HIV infection and normal kidney function do not tolerate the previously used doses of flucytosine (150 mg/kg/d in four divided doses), 75–100 mg/kg/d is recommended. The drug is effectively removed by hemodialysis. Toxic effects include bone marrow depression, abnormal liver function, and nausea. Bone marrow suppression is caused by conversion of flucytosine to fluorouracil. Combined use of flucytosine and amphotericin B in cryptococcal meningitis and possibly systemic candidiasis has been shown to be of value. ++ Natamycin ++ Natamycin is a polyene antifungal drug effective against many different fungi in vitro. When it is combined with appropriate surgical measures, topical application of 5% ophthalmic suspension may be beneficial in the treatment of keratitis caused by Fusarium, Acremonium (cephalosporium), or other fungi. The toxicity after topical application appears to be low. ++ Terbinafine ++ Terbinafine, an allylamine, inhibits fungal cell membrane function by blocking ergosterol synthesis. Terbinafine is available topically as well as in 250-mg tablets for oral administration. The recommended dosage is 250 mg daily for 12 weeks for toenail infections and 250 mg daily for 6 weeks for fingernail infections (success rate about 70%). Pulse therapy (1 week on and 3 weeks off) is as effective as continuous therapy for 6–12 weeks. The drug also is active against many strains of Candida and Aspergillus organisms and has been used in combination with other antifungals to treat severe infections with these pathogens. Most adverse effects are minor (diarrhea, dyspepsia) or transient (taste disturbance). Rare cases of severe hepatic injury have occurred. ++ Antifungal Imidazoles & Triazoles ++ These antifungal drugs inhibit synthesis of ergosterol, resulting in inhibition of membrane-associated enzyme activity, cell wall growth, and replication. ++ Clotrimazole, taken orally in the form of 10-mg troches five times daily, can prevent and treat oral candidiasis. Vaginal azole tablets inserted daily for 1–7 days are effective for vaginal candidiasis. Topical preparations for treatment of cutaneous dermatophytes are also available. ++ Fluconazole, a bis-triazole with activity similar to that of ketoconazole, is water-soluble and can be given both orally and intravenously. Absorption of the drug after oral administration is not pH-dependent. It penetrates well into the cerebrospinal fluid and eye. The drug has been shown to be effective primarily in the treatment of Candida, Cryptococcus, and Blastomyces infections. Candida albicans, C tropicalis, and C parapsilosus are usually sensitive to fluconazole, but many other species of Candida (C krusei, C glabrata, etc) are often resistant. Fluconazole-resistant strains of C albicans primarily have been observed in patients receiving antecedent fluconazole therapy. The drug is inactive against Aspergillus, Mucor, and Pseudallescheria. Fluconazole is effective in oropharyngeal candidiasis and candidal esophagitis. It is as effective or more effective than vaginal creams and suppositories in vaginal candidiasis; a single oral dose of fluconazole 150 mg is 80–90% effective. Fluconazole, 400 mg intravenously and orally daily, is as effective as amphotericin B, 0.5–0.6 mg/kg/d, for candidemia in both neutropenic and nonneutropenic patients. Most of these infections are intravenous line–related, and removal of the line is critical to successful therapy. Fluconazole (200 mg/d) is effective as long-term suppressive therapy of cryptococcal meningitis in patients with HIV/AIDS and is the drug of choice in this setting. In the treatment of cryptococcal meningitis, response rates and overall mortality rates are the same in patients treated with oral fluconazole and with amphotericin B. However, the mortality rate in the first 2 weeks is higher with fluconazole and sterilization of cerebrospinal fluid is slower with fluconazole. Consequently, induction generally takes place with amphotericin B for 2 weeks, followed by oral fluconazole. A dosage of 400 mg of fluconazole daily is effective therapy for coccidioidal meningitis (80% response), but improvement is slow, taking as long as 4–8 months. Increased doses (800–1200 mg/d) have been used; however, they have not been found to be superior to usual doses. Fluconazole, 400 mg daily, is effective prophylaxis against superficial and invasive fungal infections in bone marrow and liver transplant recipients, but concern has been raised about superinfection with resistant organisms (C krusei, C glabrata). Because the overall incidence of invasive fungal disease in HIV infection is low, universal prophylaxis to prevent disease is discouraged, especially with the advent of more potent antiretroviral therapy. Fluconazole is also effective for the therapy of cutaneous leishmaniasis due to Leishmania major in a dose of 200 mg/d for 6 weeks. ++ Fluconazole is well absorbed after oral administration (> 90% bioavailability), and serum levels approach those seen after administering the same dose intravenously. Thus, unless the patient cannot take medication by mouth or is hemodynamically unstable, the preferred route of administration is by mouth. While generally well tolerated, fluconazole is associated with dose-dependent nausea and vomiting. Altered liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and hepatitis have been reported. While less potent than other azoles (itraconazole, ketoconazole, posaconazole, voriconazole), fluconazole inhibits cytochrome P450 resulting in reduced elimination of certain agents. Rifampin and phenytoin increase metabolism of fluconazole necessitating increased fluconazole dosage. ++ Itraconazole is an oral triazole with variable bioavailability. It is moderately well absorbed from the gastrointestinal tract (food increases absorption from 30% to 60%; antacids and H2-receptor antagonists decrease absorption) and widely distributed in tissues with the notable exception of the central nervous system, where levels in spinal fluid are undetectable. Itraconazole solution is more predictably absorbed than the tablets. While the tablet formulation should be administered with food, the solution is best absorbed on an empty stomach. The drug is metabolized by the liver, and no dosage adjustment is needed in kidney disease. Itraconazole is very active against most strains of Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Sporotrichum schenkii, and various dermatophytes. It is also active against Aspergillus species but inactive against Fusarium and Zygomycetes. Itraconazole in doses of 200–400 mg/d is effective and approved therapy for localized or disseminated histoplasmosis. It is also effective in sporotrichosis, dermatophytic infections (including those of the nails), and oral and esophageal candidiasis. Itraconazole is at least as effective as fluconazole in the treatment of nonmeningeal coccidioidomycosis and may be superior in the management of skeletal disease. At doses of 200 mg twice daily, itraconazole increases exercise tolerance and decreases corticosteroid requirements in patients with allergic bronchopulmonary aspergillosis. Itraconazole pulse therapy with 200 mg twice daily for 1 week each month, repeated for 4 consecutive months, is effective in the treatment of onychomycosis. ++ Adverse effects are similar to those of fluconazole, with anorexia, nausea, vomiting, and abdominal pain occurring most commonly. Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur uncommonly. Drugs that increase hepatic drug-metabolizing enzymes (isoniazid, rifampin, phenytoin, phenobarbital) may increase itraconazole metabolism, and increased doses may be needed when these drugs are administered concurrently with itraconazole. Itraconazole decreases the metabolism of cyclosporine, digoxin, and warfarin. ++ The usual dosage is 200 mg once or twice daily with meals. ++ Voriconazole is a triazole antifungal with broad in vitro activity against most species of Candida and molds, Aspergillus, Fusarium, Pseudallescheria, and others. It is as efficacious as liposomal amphotericin in the therapy of documented and suspected fungal infections in febrile neutropenic patients, and it is superior to liposomal amphotericin in preventing breakthrough fungemias in this patient population. Voriconazole is superior to conventional amphotericin in the treatment of disseminated aspergillosis. Animal data also suggest voriconazole to be the most effective agent against Aspergillus, particularly in combination with caspofungin or another echinocandin. Voriconazole is the drug of choice in the treatment of Fusarium and Scedosporium infections. Voriconazole is widely used in the treatment of neutropenic patients with suspected or documented fungal infection. Voriconazole has limited activity against zygomycete pathogens, and some centers have reported increased rates of infection due to Rhizopus and Mucor in stem cell transplantation patients receiving voriconazole. Similar to fluconazole, oral administration leads to predictable absorption. The primary toxicity associated with voriconazole is infusion-related, transient visual disturbances, particularly during the first week of therapy. In addition, voriconazole is associated with photosensitivity reactions. Similar to itraconazole, voriconazole is associated with hepatotoxicity and numerous drug interactions. Enzyme inducers can decrease voriconazole plasma levels with possible reduction in efficacy. Pharmacogenomic differences in cytochrome P450 2C19 can result in large differences in voriconazole clearance; therapeutic trough levels should be 1–5 mcg/mL. Voriconazole also is an inhibitor of cytochrome P450 activity reducing the clearance of numerous substrates, including cyclosporine and tacrolimus. ++ Posaconazole is an antifungal derivative of itraconazole with similar spectrum of activity as voriconazole, including yeast and Aspergillus spp. Unique from voriconazole, posaconazole has activity against the zygomycete fungi approaching that of amphotericin. Salvage treatment studies demonstrate efficacy in the treatment of these pathogens. Posaconazole is superior to fluconazole as prophylaxis of neutropenia. The drug is only available as an oral formulation, which may limit its use in more acutely ill patients. Posaconazole should always be administered with food to ensure adequate oral bioavailability; the drug is primarily eliminated via nonrenal mechanisms. Similar to the other azole agents, posaconazole has primarily upper gastrointestinal adverse events and occasional liver function test abnormalities. While not as problematic as voriconazole, posaconazole is an inhibitor of cytochrome P450. ++ Ketoconazole, the first orally bioavailable azole, previously was used in the treatment of a variety of fungal infections. However, the improved spectrum of activity, reduced toxicity, and superior pharmacokinetics of newer azoles have reduced ketoconazole to a secondary role. ++Cleveland AA et al. Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008–2011. Clin Infect Dis. 2012 Nov 15;55(10):1352–61. [PubMed: 22893576] ++Dolton MJ et al. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother. 2012 Sep;56(9):4793–9. [PubMed: 22751544] ++ Echinocandins ++ The echinocandins (anidulafungin, caspofungin, micafungin) act by inhibiting fungal cell wall synthesis. They are active against Candida, including nonalbicans species, as well as Aspergillus species. They are not active against Cryptococcus or Fusarium. Their long pharmacologic half-life confers the advantage of once-daily dosing. No change in dose is necessary in patients with kidney disease; however, moderate to severe hepatic disease necessitates a reduction in dosage for caspofungin. Because dexamethasone, rifampin, and phenytoin significantly increase the metabolism of caspofungin, increased doses of the antifungal are necessary when these agents are given concomitantly. Animal data suggest that caspofungin is inferior to voriconazole in the treatment of Aspergillus; however, the addition of caspofungin to voriconazole has been associated with in vitro and in vivo additive or synergistic effects. Caspofungin is superior to conventional amphotericin B in the treatment of candidemia, primarily on the basis of greater patient tolerability. The echinocandins should be considered the drugs of choice in the treatment of infections due to C glabrata and C krusei. Micafungin has been found to be as effective and less toxic than liposomal amphotericin in the treatment of candidemia and invasive candidiasis. Anidulafungin is at least as effective as fluconazole in the treatment of invasive candidiasis. These agents are associated with minimal toxicity or adverse effects. Histamine release is common with basic polypeptide compounds, such as the echinocandins; thus infusion-related reactions have been reported. While increased liver function tests have been observed with the combination of caspofungin and cyclosporine, more recent analyses suggest that these two agents can be safely administered together. Considering the similarities in spectrum efficacy and safety between products, the choice of echinocandin likely will be based on cost differences. ++Chen J et al. Therapeutic drug monitoring of voriconazole in children. Ther Drug Monit. 2012 Feb;34(1):77–84. [PubMed: 22210097] ++Kontoyiannis DP. Invasive mycoses: strategies for effective management. Am J Med. 2012 Jan;125(1 Suppl):S25–38. [PubMed: 22196206] + Antiviral Chemotherapy ++ Several compounds can influence viral replication and the development of viral disease. ++ Amantadine is active against influenza A (but not influenza B) and previously has been effective both as prophylaxis and therapy. However, the high rate of emerged influenza resistance has resulted in amantadine (and rimantadine) no longer recommended in the treatment of influenza. Yearly immunization against influenza is the primary intervention for disease prevention. The usual adult dosage is 200 mg orally per day (in persons over 65 years of age, 100 mg). Worldwide rates of amantadine/rimantadine resistance have significantly increased over the years. Considering this predisposition for resistance, neuraminidase inhibitors such as zanamivir or oseltamivir are the drugs of choice for both treatment and prophylaxis. The most marked untoward effects of amantadine include insomnia, nightmares, and ataxia, especially in the elderly. Amantadine may accumulate and be more toxic in patients with kidney disease, and the dosage should be reduced. Rimantadine, an analog of amantadine, is as effective as amantadine and is associated with fewer central nervous system adverse effects. ++ Neuraminidase inhibitors, including zanamivir inhalation and oseltamivir tablets, are available for prevention and treatment of influenza A and B and are also active against the avian influenza virus. The majority of influenza A H1N1 viruses tested for drug resistance have been susceptible to oseltamivir and zanamivir but resistant to the adamantanes (amantadine, rimantadine). Thus, the choices center upon oseltamivir and zanamivir. To date, all oseltamivir-resistant isolates have been zanamivir-susceptible. As with amantadine and rimantadine, the neuraminidase inhibitors must be administered soon (within 48 hours) after the onset of symptoms to be effective. Zanamivir inhalers are difficult to use for some patients, especially those with asthma and chronic obstructive pulmonary disease, in whom bronchospasm has been reported. Gastrointestinal adverse events are the most commonly observed side effects with oseltamivir. In addition, while cause and effect are not well-established, neuropsychiatric disorders, including suicidal ideation, have been associated with oseltamivir. Both drugs are administered twice daily (oseltamavir, 75 mg orally; zanamivir 10 mg inhalation) for 5 days when used for therapy; however, up to 150 mg of oseltamivir twice daily has been recommended for more severe disease. Both agents reduce the duration of symptoms by only 1 day and viral shedding by 2 days. However, treatment of critically ill patients initiated within 5 days after symptom onset has been associated with decreased mortality. Both agents also effectively prevent disease in household contacts when administered prophylactically (oseltamavir 75 mg orally once daily, zanamavir 10 mg inhaled once daily) for 10 days. Critically ill patients, in most instances, are unable to receive antiviral agents via the oral or inhaled route of administration. Parenteral zanamivir and peramivir are potential options, however, only available investigationally at the present time. ++ Acyclovir is active against herpes simplex virus and varicella-zoster virus. In herpes-infected cells, it is selectively active against viral DNA polymerase and thus inhibits virus proliferation. Given intravenously (15 mg/kg/d in three divided doses), it is useful in the treatment of mucocutaneous herpes simplex in immunocompromised patients. It can reduce pain, accelerate healing, and prevent dissemination of herpes zoster and varicella in immunocompromised patients. The usual dosage for serious varicella-zoster infections is greater, ie, 30 mg/kg/d intravenously in three equal doses. The drug has no effect on establishment of latency, frequency of recurrence, or incidence of postherpetic neuralgia. Acyclovir (30 mg/kg/d intravenously in three equal doses) is the drug of choice for herpes encephalitis. Intravenous or oral acyclovir is effective prophylaxis against recurrent mucocutaneous and visceral herpes infections in transplant and other severely immunosuppressed patients. Prophylactic intravenous or oral acyclovir is effective in preventing cytomegalovirus (CMV) disease in some transplant settings (renal and perhaps bone marrow) but not in others (liver). ++ Oral acyclovir, 400 mg three times daily for 7–10 days, is effective in primary genital herpes simplex infections. Oral acyclovir at a dose of 800 mg three times a day for 2 days for recurrent genital herpes reduces viral shedding and symptoms. Suppressive therapy (400 mg twice daily) for 4–6 months reduces the frequency and severity of recurrent genital herpetic lesions. Acyclovir minimally affects symptoms or viral shedding in recurrent herpes labialis and is not generally used for this disease. However, in a dose of 400 mg twice daily, it is effective in preventing recurrent herpes labialis in those with frequent relapses and in preventing sun-induced relapses. ++ Other uses of oral acyclovir include (1) acceleration of healing of herpes zoster in immunocompetent patients if initiated within 48 hours after onset (800 mg five times daily for 7 days), (2) more rapid healing of rash and lessened clinical symptoms of primary varicella in adults and children if instituted within 24 hours after onset of rash and continued for 5–7 days, (3) prevention of herpes simplex and CMV infections in transplant recipients (in doses of 800 mg four or five times daily), and (4) prophylaxis against varicella in susceptible household contacts. ++ Topical 5% acyclovir ointment can shorten the period of pain and viral shedding in herpes simplex mucocutaneous oral lesions in immunosuppressed patients but not in patients with normal immunity. In contrast, acyclovir cream or penciclovir ointment (see famciclovir, below) appears to reduce the duration of pain and viral shedding by approximately 1 day in immunocompetent patients. Oral acyclovir is significantly more efficacious than topical therapy for this indication. ++ The absolute oral bioavailability of acyclovir is 10–30%. Famciclovir and valacyclovir (see below) can be significantly better absorbed than oral acyclovir and can be administered less frequently. Dosage reduction in kidney disease is required. Since hemodialysis reduces serum levels significantly, the daily dose should be given after hemodialysis. ++ Acyclovir is relatively nontoxic. Precipitation of drug in renal tubules has been described with intravenous acyclovir and can be avoided by maintaining adequate hydration and urine flow. Resistance has been described, usually in immunosuppressed patients who have received multiple courses of therapy. ++ Famciclovir is a prodrug of penciclovir. After oral administration, 75–80% is absorbed and deacetylated in the intestinal wall to the active drug, penciclovir. Penciclovir, like acyclovir, inhibits viral replication by interfering with viral DNA polymerase. Acyclovir-resistant strains of herpes simplex and varicella-zoster virus are also resistant to famciclovir. Famciclovir in a dose of 500 mg three times daily for 7 days accelerates healing of lesions in acute herpes zoster if started within 72 hours after the onset of rash. At a dose of 125 mg twice daily for 5 days, famciclovir is effective therapy of recurrent genital herpes; at a dose of 500 mg twice daily, it is effective as chronic suppressive therapy. ++ Valacyclovir is a prodrug of acyclovir that has significantly increased oral bioavailability when compared with acyclovir. After absorption, it is converted to acyclovir and serum levels are three to five times higher than those achieved with acyclovir. Valacyclovir at a dosage of 1 g three times daily for 7–10 days is effective therapy for herpes zoster when started within 72 hours after onset of rash and is slightly more effective than acyclovir in relieving zoster-associated pain. It shortens the course of initial episodes of genital herpes (1 g twice daily for 7–10 days), can be used to treat recurrent genital herpes (500 mg twice daily for three days), and is effective prophylaxis for recurrent genital herpes when given as a single 1-g daily dose. Valacyclovir prophylaxis (500 mg daily) reduces the rate of viral shedding and transmission of herpes in discordant monogamous couples. At doses of 2 g four times daily, valacyclovir is more effective than placebo in preventing CMV infections in seronegative recipients of a kidney from a seropositive donor. The adverse effect profile of valacyclovir is comparable to that of acyclovir. ++ Foscarnet (trisodium phosphonoformate) is a pyrophosphate analog that inhibits viral DNA polymerase of human herpesviruses (CMV, herpes simplex, varicella-zoster) and the reverse transcriptase of HIV. The drug is much less well tolerated than acyclovir and ganciclovir and more difficult to administer. Therefore, its use is limited to patients who do not respond to or cannot tolerate ganciclovir or acyclovir. Isolates of ganciclovir-resistant CMV and acyclovir-resistant herpes simplex and varicella-zoster usually are susceptible to foscarnet. Oral absorption is poor, and the drug must be given intravenously. The half-life is 3–5 hours, and this is prolonged with kidney disease. The usual induction dose is 60 mg/kg/dose every 8 hours, and the dose for maintenance therapy is 120 mg/kg once daily. Adjustments are required for even minimal impairment in kidney function (see package insert). ++ Foscarnet can cause severe phlebitis, thus central intravenous is generally used. Nephrotoxicity, which is dose-dependent and reversible, is the major toxicity. Prehydration with 2.5 L of 0.9% saline reduces nephrotoxicity. Foscarnet binds divalent cations, and hypocalcemia peripheral neuropathy, seizures and arrhythmias, hypomagnesemia, and hypophosphatemia can occur. Monitoring of electrolytes and kidney function is required during therapy. Anemia (20–50%) and nausea and vomiting (20–30%) are other common adverse effects. ++ Cidofovir is a nucleotide analog that is active against most all human herpesviruses and poxviruses. The drug has a prolonged pharmacokinetic intracellular half-life, allowing for administration every 1–2 weeks. Strains of CMV, herpes simplex virus, and herpes zoster virus that are resistant to ganciclovir or acyclovir often are susceptible to cidofovir. However, the least likely cross-resistance is between foscarnet and cidofovir. Cidofovir delays progression of CMV retinitis in newly diagnosed disease (5 mg/kg weekly for 2 weeks, followed by maintenance of 3–5 mg/kg every other week) and is effective therapy in relapsed disease or in patients who are intolerant of traditional therapy (5 mg/kg every other day). The drug is ineffective or only marginally effective in the treatment of AIDS-associated progressive multifocal leukoencephalopathy. Cidofovir is associated with a high incidence of nephrotoxicity, sometimes severe. To avoid this complication, probenecid, an inhibitor of active tubular secretion, and intravenous saline must be administered with each dose. Ocular toxicity, including uveitis and iritis, is another complication reported with cidofovir. ++ Ribavirin aerosol is used in the treatment of respiratory syncytial virus infections in bone marrow transplant patients. It is not known whether the addition of immune globulin provides additional benefit. Intravenous ribavirin (compassionate use availability only) can significantly lower the fatality rate of Lassa fever and has been used for hantavirus; however, the benefit is unclear. While used in some patients in the treatment of severe acute respiratory syndrome (SARS), its value and tolerability has been debated. During the SARS outbreak in Toronto, the use of high-dose ribavirin was associated with a high rate of anemia, hypomagnesemia, and bradycardia. The drug is teratogenic in animals, and pregnant women should not take care of patients receiving the aerosol. Oral ribavirin is used in combination with interferons to treat chronic hepatitis C infections (see Chapter 16: Liver, Biliary Tract, & Pancreas Disorders). The combination of oral ribavirin and interferon or peginterferon has been found to be superior to monotherapy with interferon. ++ Ganciclovir is an analog of acyclovir with similar antiviral activity, including activity against CMV. The drug is efficacious in the therapy of CMV retinitis in AIDS patients, but once therapy is stopped, the relapse rate is high, unless the patient is receiving highly active antiretroviral therapy (HAART) and has elevated CD4 lymphocyte counts. While yet to be evaluated in a prospective, controlled trial, the addition of intravenous immunoglobulin or CMV immune globulin to ganciclovir may improve outcomes associated with CMV pneumonitis in bone marrow transplant patients. Ganciclovir is frequently used in solid organ and stem cell transplant patients in the treatment and prevention of infection. However, there is no uniformity of opinion about the duration of therapy or the route of administration. Before the availability of oral valganciclovir (see below), which results in serum levels equivalent to those achieved with intravenous drug, ganciclovir was frequently administered intravenously and in the immediate posttransplant period for 1–2 weeks. Depending on the type of transplant (bone marrow transplant patients are at greater risk for developing CMV disease than solid organ transplant patients) and the serologic status of the donor and recipient (seronegative recipients who receive transplants from seropositive donors are at greatest risk for developing disease), various antiviral agents were used to prevent infection. Acyclovir, valacyclovir, ganciclovir, and valganciclovir have been used in the prevention of CMV in stem cell transplant patients. With the availability of oral valganciclovir, high-risk patients can benefit from prophylaxis without relying on the use of the intravenous route. In addition, because tests to detect early infection with CMV are very sensitive, the strategy for prevention has shifted from one of universal prophylaxis to one of preemptive therapy. At many institutions, high-risk patients are routinely screened for CMV DNA in blood by antigen detection or polymerase chain reaction. A positive test results in subsequent preemptive therapy with intravenous ganciclovir or oral valganciclovir. ++ The major adverse effect is neutropenia, which is reversible but may require the concomitant use of colony stimulating factors. Thrombocytopenia, nausea, rash, and phlebitis occur less commonly. ++ Oral ganciclovir is no longer marketed, and it has been replaced by valganciclovir, an esterification product of ganciclovir that is significantly better absorbed. Administration of 900 mg of valganciclovir orally results in serum ganciclovir levels equal to that achieved with an intravenous 5 mg/kg dose of ganciclovir. In CMV retinitis in AIDS patients, oral valganciclovir is as efficacious as intravenous ganciclovir therapy. ++ Lamivudine (3TC), a well-tolerated oral antiviral nucleoside analog used in treatment of HIV infection, is effective against hepatitis B. Once-daily therapy (100 mg) results in clinical, serologic, and histologic improvement in approximately 50% of patients. While lamivudine is useful, development of resistance is common with long-term therapy. Therapy post–liver transplantation is associated with a reduced risk of reinfection with hepatitis B. Unlike the combination of ribavirin and interferon, lamivudine does not improve the outcome seen with interferon monotherapy. ++ Adefovir is an antiviral agent with activity against hepatitis B. It is as effective against lamivudine-susceptible and lamivudine-resistant isolates. While previously used higher doses have been associated with substantial nephrotoxicity, this complication is rare with the lower doses (10 mg/d) used to treat hepatitis B. The antiretroviral tenofovir is at least as effective as adefovir and is particularly useful in the treatment of HIV- and hepatitis B–coinfected patients. Similar to adefovir, the primary toxicity associated with tenofovir is nephrotoxicity. ++ Entecavir is a nucleoside analog drug that has selective antihepatitis B virus (HBV) activity against both lamivudine-susceptible and lamivudine-resistant isolates. For patients with chronic hepatitis B who are beginning treatment for the first time (nucleoside-naïve patients), the recommended dosage of entecavir is a single 0.5-mg tablet taken once daily on an empty stomach; for those patients infected with lamivudine-resistant isolates, a single 1-mg tablet is taken once daily. While entecavir is useful for lamivudine-resistant isolates, cross-resistance has been observed among HBV nucleoside analogs. In cell-based assays, entecavir was associated with a 8- to 30-fold less inhibition of replication of HBV that contained lamivudine-resistant mutations than of wild-type virus. Adverse events are similar to those of other hepatitis B agents and include severe, acute exacerbation of hepatitis B after discontinuation as well as headache, abdominal pain, diarrhea, fatigue, and dizziness. ++ Telbivudine, the most recently approved agent, is also active against both lamivudine-susceptible and lamivudine-resistant isolates and comparative trials demonstrate clear superiority over lamivudine. The advantages over lamivudine include both viral suppression as well as normalization of ALT. Combination therapy with telbivudine and lamivudine does not offer any advantages over monotherapy with telbivudine. It is well absorbed by the oral route and food has no impact upon bioavailability. Telbivudine is administered once daily and patients with moderate to severe kidney disease require dosage adjustment. The adverse effect profile is comparable to that observed with other nucleoside analogs. ++ Boceprevir & Telaprevir ++ The serine protease inhibitors boceprevir and telaprevir represent a remarkable advancement in the treatment of hepatitis C. These agents, when administered concomitantly with the standard therapy (peginterferon and oral ribavirin), result in a significantly more sustained virologic response. Importantly, these antivirals are only indicated for HCV genotype 1 infection and should never be administered as monotherapy. Boceprevir is dosed at 800 mg three times daily and telaprevir at 750 mg three times daily. An additional consideration with telaprevir is that optimal oral bioavailability requires administration with at least 20 g of fat. While these agents are extremely effective in the treatment of this disease, they are associated with substantial toxicity and adverse events. In addition, they are associated with numerous important drug interactions. Approximately half of patients receiving boceprevir experience anemia, necessitating erythropoietin administration. In addition to anemia, dysgeusia, neutropenia, and thrombocytopenia are common with the use of boceprevir. Telaprevir is associated with substantial pruritus and other rash, observed in over 50% of patients. The rash is typically eczematous and maculopapular occurring within the first 2–3 weeks of therapy. A black box warning has been included in the prescribing information for telaprevir specific to these dermatologic toxicities. Similar to boceprevir, anemia is frequently observed in telaprevir-treated patients. Both agents are extensively metabolized, including the cytochrome P450 system, consequently enzyme inhibitors would be expected to reduce the metabolism of either drug, while inducers would increase clearance. In addition, telaprevir is a strong inhibitor of CYP3A4 and a substrate and inhibitor of P-glycoprotein. ++ Human interferons have been prepared from stimulated lymphocytes and by DNA recombinant technology. These agents have antiviral, antitumor, and immunoregulatory properties. The most common uses of these agents include therapy of chronic hepatitis due to hepatitis B, C, and D (see Chapter 16: Liver, Biliary Tract, & Pancreas Disorders). A long-acting preparation of interferon, peginterferon, in combination with oral ribavirin is superior to conventional interferon for therapy of hepatitis C. Relapse of the underlying disease after cessation of therapy is common but usually responds to reinstitution of drug. Adverse effects are common and include an influenza-like illness with fever, chills, nausea, vomiting, headache, arthralgia, and myalgias. Bone marrow suppression, especially with high-dose therapy, also occurs. Considering the poor tolerability of interferon, only a minority of patients infected with hepatitis C are actually candidates for therapy. ++Butt AA et al. Boceprevir and telaprevir in the management of hepatitis C virus-infected patients. Clin Infect Dis. 2012 Jan;54(1):96–104. [PubMed: 22156853] ++Chemaly RF et al. An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection. J Infect Dis. 2012 Nov;206(9):1367–71. [PubMed: 22927454] ++Sherman KE. Therapeutic approach to the treatment of the treatment-naïve patient with hepatitis C virus genotype 1 infection: a step-by-step approach. Clin Infect Dis. 2012 Nov;55(9):1236–41. [PubMed: 22843782]