Pharmacology_Katzung

Pharmacology_Katzung. Camille E. Beauduy, PharmD, & Lisa G. Winston, MD motion tenderness is present. A first-catch urine specimen is obtained for chlamydia and gonorrhea nucleic acid amplifi-cation testing. A urine pregnancy test is also ordered as the patient reports she “missed her last period.” Pending these results, the decision is made to treat her presumptively for chlamydial cervicitis. What are two potential treatment options for her possible chlamydial infection? How does her potential pregnancy affect the treatment decision? A 22-year-old woman presents to her college medical clinic complaining of a 2-week history of vaginal discharge. She denies any fever or abdominal pain but does report vaginal bleeding after sexual intercourse. When questioned about her sexual activity, she reports having vaginal intercourse, at times unprotected, with two men in the last 6 months. A pelvic examination is performed and is positive for muco-purulent discharge from the endocervical canal. No cervical


Pharmacology_Katzung

Pharmacology_Katzung. The drugs described in this chapter inhibit bacterial protein synthesis by binding to and interfering with ribosomes. Most are bacteriostatic, but a few are bactericidal against certain organisms. Tetracycline and macrolide resistance is common. Except for tigecycline and the streptogramins, these antibiotics may be administered orally. All of the tetracyclines have the basic structure shown at right: *There is no OH at position 6 on methacycline and doxycycline. Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acidic and fairly stable. Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity. Tigecycline is a glycylcycline and a semisynthetic derivative of minocycline. Mechanism of Action & Antimicrobial Activity


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action & Antimicrobial Activity Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible organisms concentrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex (Figure 44–1). This prevents addition of amino acids to the growing peptide.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines are active against many Gram-positive and Gram-negative bacteria, including certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas. For susceptible organisms, differences in clinical efficacy may be attributable to features of absorption, distribution, and excretion of individual drugs. Tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline, all of which are poor substrates for the efflux pump, if that is the mechanism of resistance. Three mechanisms of resistance to tetracycline analogs have been described: (1) impaired influx or increased efflux by an active transport protein pump; (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; and (3) enzymatic inactivation. The most important of these are production of an efflux pump and ribosomal protection. Tet(AE) efflux pump-expressing Gram-negative species are resistant to the older tetracyclines,


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 44–1 Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid 6 (peptide bond formation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit (step 1).


Pharmacology_Katzung

Pharmacology_Katzung. doxycycline, and minocycline. They are susceptible, however, to tigecycline, which is not a substrate of these pumps. Similarly, a different pump [Tet(K)] of staphylococci confers resistance to tetracycline, but not to doxycycline, minocycline, or tigecycline, none of which are pump substrates. The Tet(M) ribosomal protection protein expressed by Gram-positives produces resistance to tetracycline, doxycycline, and minocycline, but not to tigecycline, which, because of its bulky t-butylglycylamido substituent, has a steric hindrance effect on Tet(M) binding to the ribosome. Tigecycline is a substrate of the chromosomally encoded multidrug efflux pumps of Proteus sp and Pseudomonas aeruginosa, accounting for their intrinsic resistance to all tetracyclines including tigecycline.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines differ in their absorption after oral administration and in their elimination. Absorption after oral administration is approximately 60–70% for tetracycline and demeclocycline (not typically used as an antibiotic; see below); and 95–100% for doxycycline and minocycline. Tigecycline is poorly absorbed orally and must be administered intravenously. A portion of an orally administered dose of tetracycline remains in the gut lumen, alters intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which contain multivalent cations; and by alkaline pH. Tetracycline and demeclocycline should be administered on an empty stomach, while doxycycline and minocycline absorption is not impaired by food. Specially buffered doxycycline and minocycline solutions are formulated for intravenous administration.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines are 40–80% bound by serum proteins. Oral dosages of 500 mg every 6 hours of tetracycline hydrochloride produce peak blood levels of 4–6 mcg/mL. Peak levels of 2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or minocycline. Steady-state peak serum concentrations of tigecycline are 0.6 mcg/mL at the standard dosage. Tetracyclines are distributed widely to tissues and body fluids except for cerebrospinal fluid, where concentrations are 10–25% of those in serum. Tetracyclines cross the placenta and are also excreted in breast milk. As a result of chelation with calcium, tetracyclines bind to—and damage—growing bones and teeth. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of tetracycline and doxycycline by 50% due to induction of hepatic enzymes that metabolize the drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines are excreted mainly in bile and urine. Concentrations in bile exceed those in serum tenfold. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels. Ten to fifty percent of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to forty percent of the drug is excreted in feces. Doxycycline and tigecycline, in contrast to other tetracyclines, are eliminated by nonrenal mechanisms and do not accumulate significantly in renal failure, requiring no dosage adjustment.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines are classified as short-acting (tetracycline, as well as the agricultural agents chlortetracycline and oxytetracycline), intermediate-acting (demeclocycline), or long-acting (doxycycline and minocycline) based on serum half-lives of 6–8 hours, 12 hours, and 16–18 hours, respectively. Tigecycline has a half-life of 36 hours. The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing for certain indications, but, by convention, these two drugs are usually dosed twice daily.


Pharmacology_Katzung

Pharmacology_Katzung. A tetracycline is the drug of choice in the treatment of most infections caused by rickettsiae and Borrelia sp, including Rocky Mountain spotted fever and Lyme disease. Tetracyclines are used preferentially to treat Anaplasma phagocytophilum and Ehrlichia sp. Tetracyclines are also excellent drugs for the treatment of Mycoplasma pneumoniae, chlamydiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. They may be used in various Gram-positive and Gram-negative bacterial infections, including vibrio infections, provided the organism is not resistant. In cholera, tetracyclines rapidly stop the shedding of vibrios, but tetracycline resistance is an increasing problem. Tetracyclines remain effective in most chlamydial infections, including sexually transmitted infections. Doxycycline is also an alternative agent recommended by the Centers for Disease Control and Prevention for primary and secondary


Pharmacology_Katzung

Pharmacology_Katzung. most chlamydial infections, including sexually transmitted infections. Doxycycline is also an alternative agent recommended by the Centers for Disease Control and Prevention for primary and secondary syphilis in patients with penicillin allergy. A tetracycline—in combination with other antibiotics—is indicated for plague, tularemia, and brucellosis. Tetracyclines are sometimes used in the treatment or prophylaxis of protozoal infections, eg, those due to Plasmodium falciparum (see Chapter 52). Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, leptospirosis, and some nontuberculous mycobacterial infections (eg, Mycobacterium marinum). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis and urinary tract infections. However, many strains of bacteria causing these infections are now resistant, and other agents have largely supplanted tetracyclines.


Pharmacology_Katzung

Pharmacology_Katzung. Minocycline, 100 mg orally twice daily for 5 days, can eradicate the meningococcal carrier state, but because of side effects and resistance of many meningococcal strains, ciprofloxacin or rifampin is preferred. Demeclocycline is rarely used as an antibacterial, but it has been used off-label in the treatment of inappropriate secretion of antidiuretic hormone because of its inhibition of antidiuretic hormone in the renal tubule (see Chapter 15).


Pharmacology_Katzung

Pharmacology_Katzung. Tigecycline, the first glycylcycline to reach clinical practice, has several unique features that warrant its consideration apart from the older tetracyclines. Its spectrum is very broad, and many tetracycline-resistant strains are susceptible to tigecycline because it is not affected by the common resistance determinants. Susceptible organisms include coagulase-negative staphylococci and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant strains; streptococci, penicillin-susceptible and resistant; enterococci, including vancomycin-resistant strains; Gram-positive rods; Enterobacteriaceae; multidrug-resistant strains of Acinetobacter sp; anaerobes, both Gram-positive and Gram-negative; rickettsiae, Chlamydia sp, and Legionella pneumophila; and rapidly growing mycobacteria. Proteus and Providencia sp and P aeruginosa, however, are intrinsically resistant.


Pharmacology_Katzung

Pharmacology_Katzung. Tigecycline, formulated for intravenous administration only, is given as a 100-mg loading dose, then 50 mg every 12 hours. As with all tetracyclines, tissue and intracellular penetration is excellent; consequently, the volume of distribution is quite large and peak serum concentrations are low. Elimination is primarily biliary, and no dosage adjustment is needed for patients with renal insufficiency. In addition to the tetracycline class effects, the chief adverse effect of tigecycline is nausea, which occurs in up to one third of patients, and occasionally vomiting. Neither nausea nor vomiting usually requires discontinuation of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Tigecycline is approved for treatment of skin and skin-structure infection, intra-abdominal infections, and community-acquired pneumonia. However, in a meta-analysis of clinical trials, tigecycline was associated with a small but significant increase in the risk of death compared with other antibiotics used to treat these infections. The increased risk was most apparent in hospital-acquired and ventilator-associated pneumonia but was also seen in other infections. This has led the U.S. Food and Drug Administration (FDA) to issue a black box warning that tigecycline should be reserved for situations where alternative treatments are not suitable. Because active drug concentrations in the urine and serum are relatively low, tigecycline may not be effective for urinary tract infections or primary bacteremia. Tigecycline has in vitro activity against a wide variety of multidrug-resistant pathogens (eg, methicillin-resistant S aureus, extended-spectrum β-lactamaseproducing Gram-negatives,


Pharmacology_Katzung

Pharmacology_Katzung. bacteremia. Tigecycline has in vitro activity against a wide variety of multidrug-resistant pathogens (eg, methicillin-resistant S aureus, extended-spectrum β-lactamaseproducing Gram-negatives, and Acinetobacter sp); however, its clinical efficacy in infections with multidrug-resistant organisms, compared with other agents, is unproven.


Pharmacology_Katzung

Pharmacology_Katzung. A. Oral Dosage The oral dosage for rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride, is 0.25–0.5 g four times daily for adults and 25–50 mg/kg/d for children (8 years of age and older). For severe systemic infections, the higher dosage is indicated, at least for the first few days. The dosage for doxycycline is 100 mg once or twice daily; the minocycline dose is 100 mg twice daily. Doxycycline is the oral tetracycline of choice for most indications because it is generally well tolerated, it can be given twice daily, and its absorption is not significantly affected by food. All tetracyclines chelate with metals, and none should be orally administered with milk, antacids, or ferrous sulfate. To avoid deposition in growing bones or teeth, tetracyclines should be avoided in pregnant women and children younger than 8 years. B. Parenteral Dosage


Pharmacology_Katzung

Pharmacology_Katzung. B. Parenteral Dosage Doxycycline and minocycline are available for intravenous injection at the same doses as the oral formulations. Intramuscular injection is not recommended because of pain and inflammation at the injection site. Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most adverse effects are due to direct toxicity of the drug or to alteration of microbial flora. A. Gastrointestinal Adverse Effects Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracyclines. These effects are attributable to direct local irritation of the intestinal tract. Oral tetracyclines can rarely cause esophageal ulceration, so patients should be instructed to take them with 8 ounces of water and remain upright for at least 30 minutes after each dose.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines alter the normal gastrointestinal flora, with suppression of susceptible coliform organisms and overgrowth of Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia, and Candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or Clostridium difficile– associated colitis. However, the risk of C difficile colitis may be lower with tetracyclines than with other antibiotics. B. Bony Structures and Teeth Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia. It can also be deposited in bone, where it may cause deformity or growth inhibition. Because of these effects, tetracyclines are generally avoided in pregnancy. If the drug is given for long periods to children younger than 8 years, similar changes can result.


Pharmacology_Katzung

C. Other Toxicities

Pharmacology_Katzung. C. Other Toxicities


Pharmacology_Katzung

Pharmacology_Katzung. Tetracyclines can impair hepatic function, especially during pregnancy, in patients with preexisting liver disease, and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. Renal tubular acidosis and Fanconi syndrome have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may cause nephrotoxicity. Tetracycline and minocycline may accumulate to toxic levels in patients with impaired kidney function. Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided. Systemically administered tetracyclines commonly induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons. Dizziness, vertigo, and tinnitus have been noted, particularly with high doses or prolonged administration of minocycline. These symptoms may also occur with higher doses of doxycycline.


Pharmacology_Katzung

Pharmacology_Katzung. The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus, now called Saccharopolyspora erythraea. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. Erythromycin (R1 = CH3, R2 = H) Clarithromycin (R1, R2 = CH3) The general structure of erythromycin is shown with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various esters and salts. Mechanism of Action & Antimicrobial Activity


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action & Antimicrobial Activity The antibacterial action of erythromycin and other macrolides may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. The binding site is near the peptidyltransferase center, and peptide chain elongation (ie, transpeptidation) is prevented by blocking of the polypeptide exit tunnel. As a result, peptidyl-tRNA is dissociated from the ribosome. Erythromycin also inhibits the formation of the 50S ribosomal subunit (Figure 44–1).


Pharmacology_Katzung

Pharmacology_Katzung. Erythromycin is active against susceptible strains of Gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila pneumoniae, H pylori, Listeria monocytogenes, and certain mycobacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) also are susceptible. Gram-negative organisms such as Neisseria sp, Bordetella pertussis, Bartonella henselae, and Bartonella quintana as well as some Rickettsia species, Treponema pallidum, and Campylobacter species are susceptible. Haemophilus influenzae is somewhat less susceptible.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance to erythromycin is usually plasmid-encoded. Three general mechanisms have been identified: (1) reduced permeability of the cell membrane or active efflux; (2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase. Efflux and methylase production are the most important resistance mechanisms in Gram-positive organisms. Cross-resistance is complete between erythromycin and the other macrolides. Constitutive methylase production also confers resistance to structurally unrelated but mechanistically similar compounds such as clindamycin and streptogramin B (so-called macrolide-lincosamide-streptogramin, or MLS-type B, resistance), which share the same ribosomal binding site. Because nonmacrolides are poor inducers of the methylase, strains expressing an inducible methylase will appear susceptible in


Pharmacology_Katzung

Pharmacology_Katzung. or MLS-type B, resistance), which share the same ribosomal binding site. Because nonmacrolides are poor inducers of the methylase, strains expressing an inducible methylase will appear susceptible in vitro. However, constitutive mutants that are resistant can be selected out and emerge during therapy with clindamycin.


Pharmacology_Katzung

Pharmacology_Katzung. Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Food interferes with absorption. The stearate and ethylsuccinate formulations are fairly acid-resistant and somewhat better absorbed. A 500-mg intravenous dose of erythromycin lactobionate produces serum concentrations of 10 mcg/mL 1 hour after dosing. The serum half-life is approximately 1.5 hours normally and 5 hours in patients with anuria. Adjustment for renal failure is not necessary. Erythromycin is not removed by dialysis. Large amounts of an administered dose are excreted in the bile, and only 5% is excreted in the urine. Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus.


Pharmacology_Katzung

Pharmacology_Katzung. Erythromycin is a traditional drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma) and in respiratory, neonatal, ocular, or genital chlamydial infections. While it was used in treatment of community-acquired pneumonia because its spectrum of activity includes pneumococcus, M pneumoniae, and L pneumophila, newer macrolides are better tolerated and more commonly selected. Macrolide resistance is increasing in pneumococci and M pneumoniae. Erythromycin had also been useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci. Emergence of erythromycin resistance in staphylococci and in strains of group A streptococci has made macrolides less attractive as first-line agents for treatment of pharyngitis and skin and soft tissue infections. Erythromycin has been studied as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, but


Pharmacology_Katzung

Pharmacology_Katzung. of pharyngitis and skin and soft tissue infections. Erythromycin has been studied as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, but clindamycin, which is better tolerated, has largely replaced it.


Pharmacology_Katzung

Pharmacology_Katzung. The oral dosage of erythromycin base or stearate is 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage of erythromycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral erythromycin base (1 g) is sometimes combined with oral neomycin or kanamycin for preoperative preparation of the colon. The intravenous dosage of erythromycin lactobionate is 0.5–1.0 g every 6 hours for adults and 15–20 mg/kg/d divided every 6 hours for children. The higher dosage is recommended when treating pneumonia caused by L pneumophila. Anorexia, nausea, vomiting, and diarrhea are common. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most common reason for selecting an alternative to erythromycin. This side effect may actually be desirable in some circumstances, leading to the off-label use of erythromycin to treat patients with gastroparesis.


Pharmacology_Katzung

Pharmacology_Katzung. Erythromycins, particularly the older estolate formulation, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions include fever, eosinophilia, and rashes. Erythromycin metabolites inhibit cytochrome P450 enzymes and, thus increase the serum concentrations of numerous drugs, including theophylline, warfarin, cyclosporine, and methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability.


Pharmacology_Katzung

Pharmacology_Katzung. Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are similar with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against Mycobacterium leprae, Toxoplasma gondii, and H influenzae. Erythromycinresistant streptococci and staphylococci are also resistant to clarithromycin. A 500-mg dose of clarithromycin produces serum concentrations of 2–3 mcg/mL. The longer half-life of clarithromycin (6 hours) compared with erythromycin permits twice-daily dosing. The recommended dosage is 250–500 mg twice daily or 1000 mg of the extended-release formulation once daily. Clarithromycin penetrates most tissues well, with concentrations equal to or exceeding serum concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Clarithromycin is metabolized in the liver and is partially eliminated in the urine. The major metabolite, 14-hydroxyclarithromycin, also has antibacterial activity and is eliminated in the urine. Dosage reduction (eg, a 500-mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. Clarithromycin has drug interactions similar to those described for erythromycin. The advantages of clarithromycin compared with erythromycin are lower incidence of gastrointestinal intolerance and less frequent dosing.


Pharmacology_Katzung

Pharmacology_Katzung. The advantages of clarithromycin compared with erythromycin are lower incidence of gastrointestinal intolerance and less frequent dosing. Azithromycin, a 15-atom lactone macrolide ring compound, is derived from erythromycin by addition of a methylated nitrogen into the lactone ring. Its spectrum of activity, mechanism of action, and clinical uses are similar to those of clarithromycin. Azithromycin is active against M avium complex and T gondii. Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci and slightly more active against H influenzae. Azithromycin is highly active against Chlamydia sp.


Pharmacology_Katzung

Pharmacology_Katzung. Azithromycin differs from erythromycin and clarithromycin mainly in pharmacokinetic properties. A 500-mg dose of azithromycin produces relatively low serum concentrations of approximately 0.4 mcg/mL. However, azithromycin penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10to 100-fold. The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases. For example, a single 1-g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Azithromycin, as a 500-mg loading dose, followed by a 250-mg single daily dose for the next 4 days, is commonly used alone or in combination with a beta-lactam antibiotic to treat community-acquired pneumonia.


Pharmacology_Katzung

Pharmacology_Katzung. Azithromycin is rapidly absorbed and well tolerated orally. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and, therefore, is free of the drug interactions that occur with erythromycin and clarithromycin. Macrolide antibiotics prolong the electrocardiographic QT interval due to an effect on potassium ion channels. Prolongation of the QT interval can lead to the torsades de pointes arrhythmia. Recent studies have suggested that azithromycin may be associated with a small increased risk of cardiac death. Fidaxomicin, a minimally absorbed macrolide used to treat Clostridium difficile infections, is discussed in Chapter 50.


Pharmacology_Katzung

Pharmacology_Katzung. Fidaxomicin, a minimally absorbed macrolide used to treat Clostridium difficile infections, is discussed in Chapter 50. Ketolides are semisynthetic, 14-membered-ring macrolides, differing from erythromycin by substitution of a 3-keto group for the neutral sugar l-cladinose. Telithromycin is approved for limited clinical use. It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis, Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria gonorrhoeae, B fragilis, T gondii, and certain nontuberculous mycobacteria. Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump–mediated resistance, and they bind to ribosomes of some bacterial species with higher affinity than macrolides.


Pharmacology_Katzung

Pharmacology_Katzung. Oral bioavailability of telithromycin is 57%, and tissue and intracellular penetration is generally good. Telithromycin is metabolized in the liver and eliminated by a combination of biliary and urinary routes of excretion. It is administered as a once-daily dose of 800 mg, which results in peak serum concentrations of approximately 2 mcg/mL. It is a reversible inhibitor of the CYP3A4 enzyme system and may slightly prolong the QTc interval. In the USA, telithromycin is now indicated only for treatment of community-acquired bacterial pneumonia. Other respiratory tract infections were removed as indications when it was recognized that use of telithromycin can result in hepatitis and liver failure. Telithromycin is also contraindicated in patients with myasthenia gravis because it may exacerbate this condition. Due to its potential for serious toxicity, an FDA-approved patient medication guide detailing these risks must be dispensed to any patient receiving the medication.


Pharmacology_Katzung

Pharmacology_Katzung. Solithromycin is a novel fluoroketolide that is pending FDA approval after two phase 3 clinical trials showed noninferiority when compared with moxifloxacin in the treatment of community-acquired pneumonia. Although not yet marketed, the dose used in clinical trials was a loading dose of 800 mg orally or intravenously, followed by 400 mg daily for a total of 5 days. The intravenous formulation was associated with higher rates of infusion-related reactions compared with moxifloxacin. Similar to telithromycin, solithromycin maintains in vitro activity against macrolide-resistant bacteria, including S pneumoniae, staphylococci, enterococci, Chlamydia trachomatis, and Neisseria gonorrhoeae. Its chemical structure lacks the pyridine-imidazole side chain group, which is thought to contribute to telithromycin’s hepatotoxicity; severe toxicity has not been demonstrated in Phase II or III clinical trials.


Pharmacology_Katzung

Pharmacology_Katzung. Clindamycin is a chlorine-substituted derivative of lincomycin, an antibiotic that is elaborated by Streptomyces lincolnensis. Mechanism of Action & Antibacterial Activity


Pharmacology_Katzung

Pharmacology_Katzung. Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions. The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin. Streptococci, staphylococci, and pneumococci are inhibited by clindamycin at a concentration of 0.5–5 mcg/mL. Enterococci and Gram-negative aerobic organisms are resistant. Bacteroides sp and other anaerobes are often susceptible, though resistance may be increasing, particularly in Gram-negative anaerobes. Resistance to clindamycin, which generally confers cross-resistance to macrolides, is due to (1) mutation of the ribosomal receptor site; (2) modification of the receptor by a constitutively expressed methylase (see section on erythromycin resistance, above); and (3) enzymatic inactivation of clindamycin. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer


Pharmacology_Katzung

Pharmacology_Katzung. (see section on erythromycin resistance, above); and (3) enzymatic inactivation of clindamycin. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane.


Pharmacology_Katzung

Pharmacology_Katzung. Oral dosages of clindamycin, 0.15–0.3 g every 8 hours (10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL. When administered intravenously, 600 mg of clindamycin every 8 hours gives levels of 5–15 mcg/mL. The drug is about 90% protein-bound. Clindamycin penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells. Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine. The half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with anuria. No dosage adjustment is required for renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. It may be active against community-acquired strains of methicillin-resistant S aureus, though resistance has been increasing. It is commonly used in conjunction with penicillin G to treat toxic shock syndrome or necrotizing fasciitis caused by Group A Streptococcus. In this setting, its use is typically limited to the initial 48 to 72 hours of treatment with the goal of inhibiting toxin production. Clindamycin is also indicated for treatment of infections caused by susceptible Bacteroides sp and other anaerobes. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung and periodontal abscesses. Clindamycin is recommended for prophylaxis of endocarditis


Pharmacology_Katzung

Pharmacology_Katzung. in the female genital tract, eg, septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung and periodontal abscesses. Clindamycin is recommended for prophylaxis of endocarditis in patients with specific valvular heart disease who are undergoing certain dental procedures and have significant penicillin allergies. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.


Pharmacology_Katzung

Pharmacology_Katzung. Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur. Administration of clindamycin is a risk factor for diarrhea and colitis due to C difficile.


Pharmacology_Katzung

Pharmacology_Katzung. Quinupristin-dalfopristin is a combination of two streptogramins—quinupristin, a streptogramin B, and dalfopristin, a streptogramin A—in a 30:70 ratio. The streptogramins share the same ribosomal binding site as the macrolides and clindamycin and thus inhibit protein synthesis in an identical manner. Quinupristin-dalfopristin is rapidly bactericidal for most susceptible organisms except Enterococcus faecium, which is killed slowly. Quinupristin-dalfopristin is active against Gram-positive cocci, including multidrug-resistant strains of streptococci, penicillin-resistant strains of S pneumoniae, methicillin-susceptible and resistant strains of staphylococci, and E faecium (but not Enterococcus faecalis). Resistance is due to modification of the quinupristin binding site (MLS-B type resistance), enzymatic inactivation of dalfopristin, or efflux.


Pharmacology_Katzung

Pharmacology_Katzung. Quinupristin-dalfopristin is administered intravenously at a dosage of 7.5 mg/kg every 8–12 hours. Peak serum concentrations following an infusion of 7.5 mg/kg over 60 minutes are 3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin. Quinupristin and dalfopristin are rapidly metabolized, with half-lives of 0.85 and 0.7 hours, respectively. Elimination is principally by the fecal route. Dose adjustment is not necessary for renal failure, peritoneal dialysis, or hemodialysis. Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours. Quinupristin and dalfopristin significantly inhibit CYP3A4, which metabolizes warfarin, diazepam, quetiapine, simvastatin, and cyclosporine, among many others. Dosage reduction of cyclosporine may be necessary.


Pharmacology_Katzung

Pharmacology_Katzung. Quinupristin-dalfopristin is approved for treatment of infections caused by staphylococci or by vancomycin-resistant strains of E faecium, but not E faecalis, which is intrinsically resistant, probably because of an efflux-type resistance mechanism. The principal toxicities are infusion-related events, such as pain at the infusion site, and an arthralgia-myalgia syndrome. Quinupristindalfopristin is used to a limited extent in the USA due to the availability of better-tolerated alternatives. Crystalline chloramphenicol is a neutral, stable compound with the following structure: It is soluble in alcohol but poorly soluble in water. Chloramphenicol succinate, which is used for parenteral administration, is highly water-soluble. It is hydrolyzed in vivo with liberation of free chloramphenicol. Mechanism of Action & Antimicrobial Activity


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action & Antimicrobial Activity Chloramphenicol is an inhibitor of microbial protein synthesis and is bacteriostatic against most susceptible organisms. It binds reversibly to the 50S subunit of the bacterial ribosome (Figure 44–1) and inhibits peptide bond formation (step 2). Chloramphenicol is a broad-spectrum antibiotic that is active against both aerobic and anaerobic Gram-positive and Gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Most Gram-positive bacteria are inhibited at concentrations of 1–10 mcg/mL, and many Gram-negative bacteria are inhibited by concentrations of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some strains of Bacteroides are highly susceptible; for these organisms, chloramphenicol may be bactericidal.


Pharmacology_Katzung

Pharmacology_Katzung. Low-level resistance to chloramphenicol may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug. The usual dosage of chloramphenicol is 50–100 mg/kg/d divided every 6 hours. It is no longer available in the USA as an oral formulation. The parenteral formulation is a prodrug, chloramphenicol succinate, which is hydrolyzed to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily.


Pharmacology_Katzung

Pharmacology_Katzung. Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Active chloramphenicol, about 10% of the total dose administered, and its inactive degradation products are eliminated in the urine. A small amount of active drug is excreted into bile and feces. There are no specific dosage adjustments recommended in renal or hepatic insufficiency; however, the drug will accumulate and should be used with extra caution in these situations. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d.


Pharmacology_Katzung

Pharmacology_Katzung. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d. Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used in the United States. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a β-lactam antibiotic for treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin. Adults occasionally develop gastrointestinal disturbances, including nausea, vomiting, and diarrhea. These symptoms are rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.


Pharmacology_Katzung

Pharmacology_Katzung. Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. Aplastic anemia tends to be irreversible and can be fatal, although it may respond to bone marrow transplantation or immunosuppressive therapy. Due to the severity of this reaction, a boxed warning has been added to its U.S. labeling.


Pharmacology_Katzung

Pharmacology_Katzung. Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d (or less during the first week of life) in full-term infants and 25 mg/kg/d in premature infants. Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives of these drugs are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased.


Pharmacology_Katzung

Pharmacology_Katzung. Linezolid is a member of the oxazolidinone class of synthetic antimicrobials. It is active against Gram-positive organisms including staphylococci, streptococci, enterococci, Gram-positive anaerobic cocci, and Gram-positive rods such as corynebacteria, Nocardia sp, and L monocytogenes. It is primarily a bacteriostatic agent but is bactericidal against streptococci. It is also active against Mycobacterium tuberculosis. Linezolid inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis. Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes. Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA.


Pharmacology_Katzung

Pharmacology_Katzung. Linezolid is 100% bioavailable after oral administration and has a half-life of 4–6 hours. It is metabolized by oxidative metabolism, yielding two inactive metabolites. It is neither an inducer nor an inhibitor of cytochrome P450 enzymes. Peak serum concentrations average 18 mcg/mL following a 600-mg oral dose; cerebrospinal fluid (CSF) concentrations reach approximately 60–70% of the serum level. The recommended dosage for most indications is 600 mg twice daily, either orally or intravenously. Linezolid is approved for vancomycin-resistant E faecium infections, health care–associated pneumonia, community-acquired pneumonia, and both complicated and uncomplicated skin and soft tissue infections caused by susceptible Gram-positive bacteria. Off-label uses of linezolid include treatment of multidrugresistant tuberculosis and Nocardia infections.


Pharmacology_Katzung

Pharmacology_Katzung. The principal toxicity of linezolid is hematologic; the effects are reversible and generally mild. Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Anemia and neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolidinduced inhibition of mitochondrial protein synthesis. There are case reports of serotonin syndrome (see Chapter 16) occurring when linezolid is co-administered with serotonergic drugs, most frequently selective serotonin reuptake inhibitor antidepressants. The FDA has issued a warning regarding the use of the drug with serotonergic agents.


Pharmacology_Katzung

Pharmacology_Katzung. Tedizolid is the active moiety of the prodrug tedizolid phosphate, a next-generation oxazolidinone, with high potency against Gram-positive bacteria, including methicillin-resistant S aureus. It is FDA-approved at a dose of 200 mg orally or intravenously once daily for 6 days for the treatment of skin and soft tissue infection. Potential advantages over linezolid include increased potency against staphylococci and a longer half-life of 12 hours, allowing once-daily dosing. It may be associated with a decreased risk of marrow suppression; however, it has not been studied over a prolonged duration of therapy. It is thought to have a lower risk of serotonergic toxicity, but concomitant use with serotonin reuptake inhibitors has not been formally evaluated. Tedizolid is more highly protein-bound (70–90%) than linezolid (31%); there are no data on CSF penetration of tedizolid.


Pharmacology_Katzung

Pharmacology_Katzung. • Tetracycline Prevents bacterial protein synthesis by binding to the 30S ribosomal subunit Bacteriostatic activity against susceptible bacteria Infections caused by mycoplasma, chlamydiae, rickettsiae, some spirochetes • malaria • H pylori • acne Oral • mixed clearance (half-life 8 h) • dosed every 6 h • divalent cations impair oral absorption • Toxicity: Gastrointestinal upset, hepatotoxicity, photosensitivity, deposition in bone and teeth Doxycycline: Oral and IV; longer half-life (18 h) so dosed twice daily; nonrenal elimination; absorption is minimally affected by divalent cations; used to treat community-acquired pneumonia and exacerbations of bronchitis • Minocycline: • Tigecycline: IV; unaffected by common tetracycline resistance mechanisms; very broad spectrum of activity against Gram-positive, Gram-negative, and anaerobic bacteria; nausea and vomiting are the primary toxicities


Pharmacology_Katzung

Pharmacology_Katzung. MACROLIDES •ErythromycinPrevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Community-acquired pneumonia•pertussis•corynebacterialandchlamydial infections Oral,IV•hepaticclearance(half-life1.5h)•dosedevery6h•cytochromeP450inhibitor•Toxicity: Gastrointestinal upset, hepatotoxicity, QTc prolongation Clarithromycin: Oral; longer half-life (6 h) so dosed twice daily; added activity versus M avium complex, toxoplasma, and M leprae Azithromycin: Oral, IV; very long half-life (68 h) allows for once-daily dosing and 5-day course of therapy of community-acquired pneumonia; does not inhibit cytochrome P450 enzymes


Pharmacology_Katzung

Pharmacology_Katzung. Azithromycin: Oral, IV; very long half-life (68 h) allows for once-daily dosing and 5-day course of therapy of community-acquired pneumonia; does not inhibit cytochrome P450 enzymes Telithromycin: Oral; unaffected by efflux-mediated resistance so is active versus many erythromycin-resistant strains of pneumococci; rare cases of fulminant hepatic failure • Linezolid Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit Bacteriostatic activity against susceptible bacteria Infections caused by methicillin-resistant staphylococci and vancomycinresistant enterococci Oral, IV • hepatic clearance (half-life 6 h) • dosed twice-daily • Toxicity: Duration-dependent bone marrow suppression, neuropathy, and optic co-administered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors)


Pharmacology_Katzung

Pharmacology_Katzung. Tedizolid: Oral and IV; longer half-life (12 h) so dosed once daily; increased potency versus staphylococci; approved for use in skin and soft tissue infections. Chloramphenicol Generic, Chloromycetin Doxycycline Generic, Vibramycin, others Minocycline Generic, Minocin, others Tetracycline Generic, others Azithromycin Generic, Zithromax Clarithromycin Generic, Biaxin Erythromycin Generic, others Clindamycin Generic, Cleocin Linezolid Generic, Zyvox Barrera CM et al: Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: A global, double-blind, multicenter, randomized, active-controlled, non-inferiority trial (SOLITAIRE-ORAL). Lancet 2016;16:421. Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232.


Pharmacology_Katzung

Pharmacology_Katzung. Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232. De Vriese AS et al: Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 2006;42:1111. Dryden MS: Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. 2011;66(Suppl 4):S7. File Jr. TM et al: SOLITAIRE-IV: A randomized, double-blind, multicenter study comparing the efficacy and safety of intravenous-to-oral solithromycin to intravenous-to-oral moxifloxacin for treatment of community-acquired bacterial pneumonia. Clin Infect Dis 2016;63:1007. Hancock RE: Mechanisms of action of newer antibiotics for gram-positive pathogens. Lancet Infect Dis 2005;5:209. Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clin Infect Dis 2002;34:482.


Pharmacology_Katzung

Pharmacology_Katzung. Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clin Infect Dis 2002;34:482. Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012;367:1508. Livermore DM: Tigecycline: What is it, and where should it be used? J Antimicrob Chemother 2005;56:611. Moran GJ et al: Methicillin-resistant S aureus infections among patients in the emergency department. N Engl J Med 2006;355:666. Moran GJ et al: Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): A randomized, double-blind, phase 3, non-inferiority trial. Lancet 2014;14:696. Prokocimer P et al: Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections. JAMA 2013;309:559.


Pharmacology_Katzung

Pharmacology_Katzung. Prokocimer P et al: Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections. JAMA 2013;309:559. Tasina E et al: Efficacy and safety of tigecycline for the treatment of infectious diseases: A meta-analysis. Lancet Infect Dis 2011;11:834. Van Bambeke F: Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones. Ann Med 2014;46:512. Wayne RA et al: Azithromycin and risk of cardiovascular death. N Engl J Med 2012;366:1881. Woytowish MR, Rowe AS: Clinical relevance of linezolid-associated serotonin toxicity. Ann Pharmacother 2013;47:388. Zuckerman JM: Macrolides and ketolides: Azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am 2004;18:621.


Pharmacology_Katzung

Pharmacology_Katzung. Zuckerman JM: Macrolides and ketolides: Azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am 2004;18:621. A tetracycline or a macrolide is effective in the treatment of chlamydial cervicitis. Doxycycline at a dose of 100 mg PO bid for 7 days is the preferred tetracycline, while azithro-mycin as a single 1 g dose is the preferred macrolide. If the patient is pregnant, then tetracyclines would be contraindi-cated and she should receive azithromycin, which is safe in pregnancy. Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*


Pharmacology_Katzung

Pharmacology_Katzung. A 45-year-old man with no significant medical history was admitted to the intensive care unit (ICU) 10 days ago after suffering third-degree burns over 40% of his body. He had been relatively stable until the last 24 hours. Now, he is febrile (39.5°C [103.1°F]), and his white blood cell count has risen from 8500 to 20,000/mm3. He has also had an episode of hypo-tension (86/50 mmHg) that responded to a fluid bolus. Blood cultures were obtained at the time of his fever and results are pending. The ICU attending physician is concerned about a bloodstream infection and decides to treat with empiric com-bination therapy directed against Pseudomonas aeruginosa. The combination therapy includes tobramycin. The patient weighs 70 kg (154 lb) and has an estimated creatinine clear-ance of 90 mL/min. How should tobramycin be dosed using once-daily and conventional dosing strategies? How should each regimen be monitored for efficacy and toxicity?


Pharmacology_Katzung

Pharmacology_Katzung. The drugs described in this chapter are bactericidal inhibitors of protein synthesis that interfere with ribosomal function. These agents are useful mainly against aerobic Gram-negative microorganisms. The aminoglycosides include streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others. They are used most widely in combination with other agents to treat drug-resistant organisms; for example, they are used with a β-lactam antibiotic in serious infections with Gram-negative bacteria, with a β-lactam antibiotic or vancomycin for Gram-positive endocarditis, and with one or more agents for treatment of mycobacterial infections, such as tuberculosis. General Properties of Aminoglycosides A. Physical and Chemical Properties


Pharmacology_Katzung

Pharmacology_Katzung. General Properties of Aminoglycosides A. Physical and Chemical Properties Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (in other aminoglycosides), to * The authors thank Drs. Henry F. Chambers and Daniel H. Deck for their contributions to previous editions. which various amino sugars are attached by glycosidic linkages (Figures 45–1 and 45–2). They are water-soluble, stable in solution, and more active at alkaline than at acid pH. B. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. B. Mechanism of Action The mode of action of streptomycin has been studied more closely than that of other aminoglycosides, but all aminoglycosides are thought to act similarly. Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise mechanism for bactericidal activity is unclear. The initial event is passive diffusion via porin channels across the outer membrane (see Figure 43–3). Drug is then actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process. The transmembrane electrochemical gradient supplies the energy for this process, and transport is coupled to a proton pump. Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient. Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin; this enhancement may be the basis of the synergism of those antibiotics with aminoglycosides.


Pharmacology_Katzung

Pharmacology_Katzung. Inside the cell, aminoglycosides bind to 30S-subunit ribosomal proteins. Protein synthesis is inhibited by aminoglycosides in at least three ways (Figure 45–3): (1) interference with the initiation complex of peptide formation; (2) misreading of mRNA, which NH2 causes incorporation of incorrect amino acids into the peptide and C NH results in a nonfunctional protein; and (3) breakup of polysomes into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irreversible and leads to cell death. C. Mechanisms of Resistance Three principal mechanisms of resistance have been established: (1) production of a transferase enzyme that inactivates the amino- FIGURE 45–1 Structure of streptomycin.


Pharmacology_Katzung

Pharmacology_Katzung. Three principal mechanisms of resistance have been established: (1) production of a transferase enzyme that inactivates the amino- FIGURE 45–1 Structure of streptomycin. glycoside by adenylylation, acetylation, or phosphorylation. This is the principal type of resistance encountered clinically. (2) There is impaired entry of aminoglycoside into the cell. This may result from mutation or deletion of a porin protein involved in transport and maintenance of the electrochemical gradient or from growth Gentamicin, netilmicin


Pharmacology_Katzung

Pharmacology_Katzung. Gentamicin, netilmicin FIGURE 45–2 Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. Plazomicin’s ring II and III are similar to the other structures; it shares the same hydroxyl-aminobutyric acid R group as amikacin. Its ring I differs from amikacin in that it is unsaturated. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. ➀, ➁, and ➂, acetyltransferase; ➃, phosphotransferase; ➄, adenylyltransferase. Amikacin is resistant to modification at ➁,➂,➃, and ➄; whereas plazomicin is resistant to modification at ➀, ➁, ➃, and ➄.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 45–3 Putative mechanisms of action of the aminoglycosides in bacteria. Normal protein synthesis is shown in the top panel. At least three aminoglycoside effects have been described, as shown in the bottom panel: block of formation of the initiation complex; miscoding of amino acids in the emerging peptide chain due to misreading of the mRNA; and block of translocation on mRNA. Block of movement of the ribosome may occur after the formation of a single initiation complex, resulting in an mRNA chain with only a single ribosome on it, a so-called monosome. (Reproduced, with permission, from Trevor AT, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 6th ed. McGraw-Hill, 2002. Copyright © The McGraw-Hill Companies, Inc.) conditions under which the oxygen-dependent transport process is not functional. (3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation. D. Pharmacokinetics and Once-Daily Dosing


Pharmacology_Katzung

Pharmacology_Katzung. Aminoglycosides are absorbed very poorly from the intact gastrointestinal tract, and almost the entire oral dose is excreted in feces after oral administration. However, the drugs may be absorbed if ulcerations are present. Aminoglycosides are usually administered intravenously as a 30–60 minute infusion. After intramuscular injection, aminoglycosides are well absorbed, giving peak concentrations in blood within 30–90 minutes. After a brief distribution phase, peak serum concentrations are identical to those following intravenous injection. The normal half-life of aminoglycosides in serum is 2–3 hours, increasing to 24–48 hours in patients with significant impairment of renal function. Aminoglycosides are only partially and irregularly removed by hemodialysis—eg, 40–60% for gentamicin—and even less effectively by peritoneal dialysis. Aminoglycosides are highly polar compounds that do not enter cells readily. They are largely excluded from the central nervous system and the eye. In the


Pharmacology_Katzung

Pharmacology_Katzung. even less effectively by peritoneal dialysis. Aminoglycosides are highly polar compounds that do not enter cells readily. They are largely excluded from the central nervous system and the eye. In the presence of active inflammation, however, cerebrospinal fluid levels reach 20% of plasma levels, and, in neonatal meningitis, the levels may be higher. Intrathecal or intraventricular injection is required for high levels in cerebrospinal fluid. Even after parenteral administration, concentrations of aminoglycosides are not high in most tissues except the renal cortex. Concentration in most secretions is also modest; in the bile, the level may reach 30% of that in blood. With prolonged therapy, diffusion into pleural or synovial fluid may result in concentrations 50–90% of that of plasma.


Pharmacology_Katzung

Pharmacology_Katzung. Traditionally, aminoglycosides have been administered in two or three equally divided doses per day in patients with normal renal function. However, administration of the entire daily dose in a single injection may be preferred in many clinical situations for at least two reasons. Aminoglycosides exhibit concentration-dependent killing; that is, higher concentrations kill a larger proportion of bacteria and kill at a more rapid rate. They also have a significant postantibiotic effect, such that the antibacterial activity persists beyond the time during which measurable drug is present. The postantibiotic effect of aminoglycosides can last several hours. Because of these properties, a given total amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses.


Pharmacology_Katzung

Pharmacology_Katzung. When administered with a cell wall-active antibiotic (a β-lactam or vancomycin), aminoglycosides may exhibit synergistic killing against certain bacteria. The effect of the drugs in combination is greater than the anticipated effect of each individual drug; ie, the killing effect of the combination is more than additive. This synergy may be important in certain clinical situations, such as endocarditis. Adverse effects from aminoglycosides are both timeand concentration-dependent. Toxicity is unlikely to occur until a certain threshold concentration is reached, but, once that concentration is achieved, the time beyond this threshold becomes critical. This threshold is not precisely defined, but a trough concentration above 2 mcg/mL is predictive of toxicity. At clinically relevant doses, the total time above this threshold is greater with multiple smaller doses of drug than with a single large dose.


Pharmacology_Katzung

Pharmacology_Katzung. Numerous clinical studies demonstrate that a single daily dose of aminoglycoside is just as effective—and probably less toxic— than multiple smaller doses. Therefore, many authorities recommend that aminoglycosides be administered as a single daily dose in most clinical situations. However, the efficacy of once-daily aminoglycoside dosing in combination therapy of enterococcal and staphylococcal endocarditis in patients with a prosthetic valve remains to be defined, and administration of lower doses two or three times daily is still recommended. In contrast, limited data do support once-daily dosing in streptococcal endocarditis. The role of once-daily dosing in pregnancy, obesity, and in neonates also is not well defined.


Pharmacology_Katzung

Pharmacology_Katzung. Once-daily dosing has potential practical advantages. For example, repeated determinations of serum concentrations are unnecessary unless an aminoglycoside is given for more than 3 days. A drug administered once a day rather than three times a day is less labor intensive. And once-a-day dosing is more feasible for outpatient therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Aminoglycosides are cleared by the kidney, and excretion is directly proportional to creatinine clearance. To avoid accumulation and toxic levels, once-daily dosing of aminoglycosides is generally avoided if renal function is impaired. Rapidly changing renal function, which may occur with acute kidney injury, must also be monitored to avoid overdosing or underdosing. Provided these pitfalls are avoided, once-daily aminoglycoside dosing is safe and effective. If the creatinine clearance is >60 mL/min, then a single daily dose of 5–7 mg/kg of gentamicin or tobramycin is recommended (15 mg/kg for amikacin). For patients with creatinine clearance <60 mL/min, traditional dosing as described below is recommended. With once-daily dosing, serum concentrations need not be routinely checked until the second or third day of therapy, depending on the stability of renal function and the anticipated duration of therapy. In most circumstances, it is unnecessary to check peak concentrations; an


Pharmacology_Katzung

Pharmacology_Katzung. the second or third day of therapy, depending on the stability of renal function and the anticipated duration of therapy. In most circumstances, it is unnecessary to check peak concentrations; an exception may be when ensuring adequately high peak concentrations for treating infections caused by drug-resistant pathogens. The goal is to administer drug so that concentrations of <1 mcg/mL are present between 18 and 24 hours after dosing. This provides sufficient time for washout of drug to occur before the next dose is given. Several nomograms have been developed and validated to assist clinicians with once-daily dosing (eg, Freeman reference).


Pharmacology_Katzung

Pharmacology_Katzung. With traditional dosing, adjustments must be made to prevent accumulation of drug and toxicity in patients with renal insufficiency. Either the dose of drug is kept constant and the interval between doses is increased, or the interval is kept constant and the dose is reduced. Nomograms and formulas have been constructed relating serum creatinine levels to adjustments in traditional treatment regimens. Because aminoglycoside clearance is directly proportional to the creatinine clearance, a method for determining the aminoglycoside dose is to estimate creatinine clearance using the Cockcroft-Gault formula described in Chapter 60. For a traditional twiceor thrice-daily dosing regimen, peak serum concentrations should be determined from a blood sample obtained 30–60 minutes after a dose, and trough concentrations from a sample obtained just before the next dose. Doses of gentamicin and tobramycin should be adjusted to maintain peak levels between 5 and 10 mcg/mL (typically between 8 and


Pharmacology_Katzung

Pharmacology_Katzung. trough concentrations from a sample obtained just before the next dose. Doses of gentamicin and tobramycin should be adjusted to maintain peak levels between 5 and 10 mcg/mL (typically between 8 and 10 mcg/mL in more serious infections) and trough levels <2 mcg/mL (<1 mcg/mL is optimal).


Pharmacology_Katzung

E. Adverse Effects

Pharmacology_Katzung. E. Adverse Effects


Pharmacology_Katzung

Pharmacology_Katzung. All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided if possible. Ototoxicity can manifest either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage with vertigo, ataxia, and loss of balance. Nephrotoxicity results in rising serum creatinine levels or reduced creatinine clearance, although the earliest indication often is an increase in trough serum aminoglycoside concentrations. Neomycin, kanamycin, and amikacin are the agents most likely to cause auditory damage. Streptomycin and gentamicin are the most vestibulotoxic. Neomycin, tobramycin, and


Pharmacology_Katzung

Pharmacology_Katzung. concentrations. Neomycin, kanamycin, and amikacin are the agents most likely to cause auditory damage. Streptomycin and gentamicin are the most vestibulotoxic. Neomycin, tobramycin, and gentamicin are the most nephrotoxic.


Pharmacology_Katzung

Pharmacology_Katzung. In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate, when given promptly, or neostigmine. Hypersensitivity occurs infrequently. F. Clinical Uses


Pharmacology_Katzung

Pharmacology_Katzung. F. Clinical Uses Aminoglycosides are mostly used against aerobic Gram-negative bacteria, especially when there is concern for drug-resistant pathogens or in critically ill patients. They are almost always used in combination with a β-lactam antibiotic to extend empiric coverage and to take advantage of the potential synergism between these two classes of drugs. Penicillin-aminoglycoside combinations have also been used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal endocarditis. Due to toxicity, these combinations are used less frequently when alternate regimens are available. For example, in the case of enterococcal endocarditis, studies suggest that the combination of ampicillin and ceftriaxone is an effective regimen with less risk for nephrotoxicity. When aminoglycosides are used, the selection of agent and dose depends on the infection being treated and the susceptibility of the isolate.


Pharmacology_Katzung

Pharmacology_Katzung. Streptomycin (Figure 45–1) was isolated from a strain of Streptomyces griseus. The antimicrobial activity of streptomycin is typical of that of other aminoglycosides, as are the mechanisms of resistance. Resistance has emerged in most species, restricting the current usefulness of streptomycin, with the exceptions listed below. Ribosomal resistance to streptomycin develops readily, limiting its role as a single agent. A. Mycobacterial Infections Streptomycin is mainly used as a second-line agent for treatment of tuberculosis. The dosage is 15 mg/kg/d with a maximum of 1 g/d (20–40 mg/kg/d for children), and it may be given intramuscularly or intravenously. It should be used only in combination with other agents to prevent emergence of resistance. See Chapter 47 for additional information regarding the use of streptomycin in mycobacterial infections. B. Nontuberculous Infections


Pharmacology_Katzung

Pharmacology_Katzung. B. Nontuberculous Infections In plague, tularemia, and sometimes, brucellosis, streptomycin, 1 g twice daily (15 mg/kg twice daily for children), is given intramuscularly in combination with an oral tetracycline. Penicillin plus streptomycin is effective for enterococcal endocarditis and 2-week therapy of viridans streptococcal endocarditis; however, for susceptible strains, gentamicin is used more commonly when an aminoglycoside is selected as adjunct therapy. Streptomycin remains a useful agent for treating gentamicin non-susceptible enterococcal infections, as some isolates that are resistant to gentamicin (and therefore resistant to netilmicin, tobramycin, and amikacin) will remain susceptible to streptomycin. Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to streptomycin. This occurs most frequently with a prolonged course of treatment (eg, for tuberculosis).


Pharmacology_Katzung

Pharmacology_Katzung. Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to streptomycin. This occurs most frequently with a prolonged course of treatment (eg, for tuberculosis). Pain at the injection site is common but usually not severe. The most serious toxic effect with streptomycin is disturbance of vestibular function—vertigo and loss of balance. The frequency and severity of this disturbance are in proportion to the age of the patient, the blood levels of the drug, and the duration of administration. Vestibular dysfunction may follow a few weeks of unusually high blood levels (eg, in individuals with impaired renal function) or months of relatively low blood levels. Vestibular toxicity tends to be irreversible. Streptomycin given during pregnancy can cause deafness in the newborn.


Pharmacology_Katzung

Pharmacology_Katzung. Gentamicin is a mixture of three closely related constituents, C1, C1A, and C2 (Figure 45–2) isolated from Micromonospora purpurea. It is effective against both Gram-positive and Gram-negative organisms, and many of its properties resemble those of other aminoglycosides. Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many strains of staphylococci and Gram-negative bacteria, including P. aeruginosa and Enterobacteriaceae. Like all aminoglycosides, it has no activity against anaerobes.


Pharmacology_Katzung

Pharmacology_Katzung. Streptococci and enterococci are relatively resistant to gentamicin owing to failure of the drug to penetrate into the cell. However, gentamicin in combination with some penicillins or vancomycin produces a potent bactericidal effect, which in part is due to enhanced uptake of drug that occurs with inhibition of cell wall synthesis. Resistance to gentamicin rapidly emerges in staphylococci during monotherapy owing to selection of permeability mutants. Ribosomal resistance is rare. Among Gram-negative bacteria, resistance is most commonly due to plasmid-encoded aminoglycoside-modifying enzymes. Gram-negative bacteria that are gentamicin-resistant usually are susceptible to amikacin, which is much more resistant to modifying enzyme activity. The enterococcal enzyme that modifies gentamicin is a bifunctional enzyme that also inactivates amikacin, netilmicin, and tobramycin but not streptomycin; the latter is modified by a different enzyme. This is why some gentamicin-resistant


Pharmacology_Katzung

Pharmacology_Katzung. is a bifunctional enzyme that also inactivates amikacin, netilmicin, and tobramycin but not streptomycin; the latter is modified by a different enzyme. This is why some gentamicin-resistant enterococci are susceptible to streptomycin.


Pharmacology_Katzung

Pharmacology_Katzung. A. Intramuscular or Intravenous Administration Gentamicin is used mainly in severe infections caused by Gram-negative bacteria that are likely to be resistant to other drugs, especially P aeruginosa, Enterobacter sp, Serratia marcescens, Proteus sp, Acinetobacter sp, and Klebsiella sp. It usually is used in combination with a second agent because an aminoglycoside alone may not be effective for infections outside the urinary tract. Aminoglycosides should not be used as single agents for therapy of pneumonia because penetration of infected lung tissue is poor and local conditions of low pH and low oxygen tension contribute to limited activity. Gentamicin 5–7 mg/kg/d traditionally is given intravenously in three equal doses, but once-daily administration is just as effective for some organisms and less toxic (see above).


Pharmacology_Katzung

Pharmacology_Katzung. Gentamicin, in combination with a cell wall-active antibiotic, may also be indicated in the treatment of endocarditis caused by Gram-positive bacteria (streptococci, staphylococci, and enterococci) as discussed earlier. B. Topical and Ocular Administration Creams, ointments, and solutions containing 0.1–0.3% gentamicin sulfate have been used for the treatment of infected burns, wounds, or skin lesions and in attempts to prevent intravenous catheter infections. The effectiveness of topical preparations for these indications is unclear. Topical gentamicin is partly inactivated by purulent exudates. Gentamicin can be injected intraocularly for treatment of certain eye infections. C. Intrathecal Administration


Pharmacology_Katzung

Pharmacology_Katzung. C. Intrathecal Administration Meningitis caused by Gram-negative bacteria has been treated by the intrathecal injection of gentamicin sulfate, 1–10 mg/d. However, neither intrathecal nor intraventricular gentamicin was beneficial in neonates with meningitis, and intraventricular gentamicin was toxic, raising questions about the usefulness of this form of therapy. Moreover, the availability of third-generation cephalosporins for Gram-negative meningitis has rendered this therapy obsolete in most cases. It may be used in cases of drug-resistant meningitis or severe β-lactam allergy.


Pharmacology_Katzung

Pharmacology_Katzung. Nephrotoxicity is usually reversible upon drug discontinuation. It occurs in 5–25% of patients receiving gentamicin for longer than 3–5 days. Such toxicity requires, at the very least, adjustment of the dosing regimen and should prompt reconsideration of the need for the drug, particularly if there is a less toxic alternative agent. Measurement of gentamicin serum levels is essential. Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular dysfunction. Loss of hearing can also occur. Ototoxicity is in part genetically determined, having been linked to point mutations in mitochondrial DNA, and occurs in 1–5% for patients receiving gentamicin for more than 5 days. Hypersensitivity reactions to gentamicin are uncommon.


Pharmacology_Katzung

Pharmacology_Katzung. This aminoglycoside (Figure 45–2) has an antibacterial spectrum similar to that of gentamicin. Although there is some cross-resistance between gentamicin and tobramycin, it is unpredictable in individual strains. Separate laboratory susceptibility tests are therefore necessary. A. Intramuscular or Intravenous Administration The pharmacokinetic properties of tobramycin are virtually identical with those of gentamicin. The daily dose of tobramycin is 5–7 mg/kg intramuscularly or intravenously, traditionally divided into three equal amounts and given every 8 hours but now often given as a single daily dose. Monitoring blood levels in renal insufficiency is an essential guide to proper dosing.


Pharmacology_Katzung

Pharmacology_Katzung. Tobramycin has almost the same antibacterial spectrum as gentamicin with a few exceptions. Gentamicin is slightly more active against S marcescens, whereas tobramycin is slightly more active against P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and tobramycin, but E faecium is resistant to tobramycin. Gentamicin and tobramycin are otherwise interchangeable clinically. Like other aminoglycosides, tobramycin is ototoxic and nephrotoxic. Nephrotoxicity of tobramycin may be slightly less than that of gentamicin. B. Inhaled and Ophthalmic Administration


Pharmacology_Katzung

Pharmacology_Katzung. B. Inhaled and Ophthalmic Administration Tobramycin is formulated in solution (300 mg in 5 mL) for inhalation for treatment of P aeruginosa lower respiratory tract infections complicating cystic fibrosis. The drug is recommended as a 300-mg dose regardless of the patient’s age or weight for administration twice daily in repeated cycles of 28 days on therapy, followed by 28 days off therapy. Serum concentrations 1 hour after inhalation average 1 mcg/mL; consequently, nephrotoxicity and ototoxicity rarely occur. Caution should be used when administering tobramycin to patients with preexisting renal, vestibular, or hearing disorders. Tobramycin is also available as 0.3% ophthalmic ointment and drops for the treatment of superficial eye infections. These formulations result in minimal systemic absorption and are unlikely to cause systemic adverse effects.


Pharmacology_Katzung

Pharmacology_Katzung. Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent molecule (Figure 45–2). It is resistant to many enzymes that inactivate gentamicin and tobramycin, and, therefore, can be used against some microorganisms resistant to the latter drugs. Many Gram-negative bacteria, including many strains of Proteus, Pseudomonas, Enterobacter, and Serratia, are inhibited by 1–20 mcg/mL amikacin in vitro. After injection of 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly, peak levels in serum are 10–30 mcg/mL. Strains of multidrug-resistant Mycobacterium tuberculosis, including streptomycin-resistant strains, are usually susceptible to amikacin. Kanamycin-resistant strains may be cross-resistant to amikacin. The dosage of amikacin for tuberculosis is 10–15 mg/kg/d as a once-daily or two to three times weekly injection and always in combination with other drugs to which the isolate is susceptible.


Pharmacology_Katzung

Pharmacology_Katzung. Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Serum concentrations should be monitored. Target peak serum concentrations for an every-12-hours dosing regimen are 20–40 mcg/mL, and trough levels should be maintained between 4 and 8 mcg/mL. Netilmicin shares many characteristics with gentamicin and tobramycin. However, the addition of an ethyl group to the 1-amino position of the 2-deoxystreptamine ring (ring II, Figure 45–2) sterically protects the netilmicin molecule from enzymatic degradation at the 3-amino (ring II) and 2-hydroxyl (ring III) positions. Consequently, netilmicin may be active against some gentamicinresistant and tobramycin-resistant bacteria. The dosage (5–7 mg/kg/d) and the routes of administration are the same as for gentamicin. Netilmicin is largely interchangeable with gentamicin or tobramycin but is no longer available in the United States. NEOMYCIN, KANAMYCIN, & PAROMOMYCIN


Pharmacology_Katzung

Pharmacology_Katzung. NEOMYCIN, KANAMYCIN, & PAROMOMYCIN Neomycin, kanamycin, and paromomycin have similar pharmacologic properties. Drugs of the neomycin group are active against Gram-positive and Gram-negative bacteria and some mycobacteria. P aeruginosa and streptococci are generally resistant. Mechanisms of antibacterial action and resistance are the same as with other aminoglycosides. The former widespread use of these drugs in bowel preparation for elective surgery contributed to the selection of resistant organisms and some outbreaks of enterocolitis in hospitals. Cross-resistance between kanamycin and neomycin is complete and may result in amikacin cross-resistance. Like all aminoglycosides, drugs of the neomycin group are poorly absorbed from the gastrointestinal tract. After oral administration, the intestinal flora is suppressed or modified, and the drug is excreted in the feces. Excretion of any absorbed drug is mainly through glomerular filtration into the urine.


Pharmacology_Katzung

Pharmacology_Katzung. Neomycin is generally limited to topical and oral use due to toxicity associated with parenteral use and higher resistance rates compared to other aminoglycosides. Kanamycin use is limited to treatment of multi-drug-resistant tuberculosis, although alternate agents, such as amikacin, may be preferred. It is no longer available in the USA. Paromomycin has been shown to be effective against visceral leishmaniasis when given parenterally (see Chapter 52), and this serious infection may represent an important use for this drug. Paromomycin can be used for intestinal Entamoeba histolytica infection and is sometimes used for intestinal infections with other parasites. A. Topical Administration


Pharmacology_Katzung

Pharmacology_Katzung. A. Topical Administration Solutions containing 1–5 mg/mL neomycin have been used on infected surfaces or injected into joints, the pleural cavity, tissue spaces, or abscess cavities where infection is present. The total amount of drug given in this fashion must be limited to 15 mg/kg/d because at higher doses enough drug may be absorbed to produce systemic toxicity. Whether topical application for active infection adds anything to appropriate systemic therapy is questionable. Ointments, often formulated as a neomycin-polymyxin-bacitracin combination, can be applied to infected skin lesions or in the nares for suppression of staphylococci but they are largely ineffective. B. Oral Administration


Pharmacology_Katzung

Pharmacology_Katzung. B. Oral Administration In preparation for elective bowel surgery, 1 g of neomycin may be given orally every 6–8 hours for 1–2 days, often combined with 1 g of erythromycin base. This reduces the aerobic bowel flora with little effect on anaerobes. In hepatic encephalopathy, coliform flora can be suppressed by giving 1 g every 6–8 hours together with reduced protein intake, thus reducing ammonia production. Use of neomycin for hepatic encephalopathy has been largely supplanted by lactulose and other medications that are less toxic. Use of paromomycin in the treatment of protozoal infections is discussed in Chapter 52. C. Intravenous and Intramuscular Administration


Pharmacology_Katzung

Pharmacology_Katzung. C. Intravenous and Intramuscular Administration When used intravenously, the standard dose for kanamycin is 15 mg/kg/day in two to three divided doses, whereas for treatment of tuberculosis, 15 mg/kg is usually given intramuscularly as a single daily dose. In the case of once daily administration, kanamycin peak concentrations are typically between 35 and 45 mcg/mL, while trough concentrations should be undetectable. All members of the neomycin group have significant nephrotoxicity and ototoxicity. Auditory function is affected more than vestibular function. Deafness may occur, especially in adults with impaired renal function and prolonged elevation of drug levels. The sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3–5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest. Calcium gluconate and neostigmine can act as antidotes.


Pharmacology_Katzung

Pharmacology_Katzung. Although hypersensitivity is not common, prolonged application of neomycin-containing ointments to skin and eyes has resulted in severe allergic reactions.


Pharmacology_Katzung

Pharmacology_Katzung. Plazomicin is a new aminoglycoside under development and is expected to undergo review by the U.S. Food and Drug Administration in 2017. It has been studied in phase II clinical trials for treatment of urinary tract infections; phase III clinical trials are underway for treatment of carbapenem-resistant Enterobacteriaceae. It is a synthetic molecule derived from sisomicin, an aminoglycoside no longer available,. Various structural modifications have yielded a compound less susceptible to most aminoglycoside modifying enzymes, thus retaining activity against aminoglycoside-resistant pathogens. It appears to have similarly potent in vitro activity against Enterobacteriaceae and displays twoto four-fold lower MICs against nonfermenting Gram-negative bacilli (eg, P aeruginosa) when compared with gentamicin, tobramycin, and amikacin. It has activity similar to gentamicin against staphylococci. A 15-mg/kg dose yields mean peak and trough concentrations of 113 mcg/mL and 0.43 mcg/mL,


Pharmacology_Katzung

Pharmacology_Katzung. with gentamicin, tobramycin, and amikacin. It has activity similar to gentamicin against staphylococci. A 15-mg/kg dose yields mean peak and trough concentrations of 113 mcg/mL and 0.43 mcg/mL, respectively. The half-life is about 4 hours, and it is being studied as a single daily dose. Due to limited clinical experience, it is unclear whether the toxicity profile will be similar to other aminoglycosides; however, no ototoxicity or nephrotoxicity has been observed in early trials.


Pharmacology_Katzung

Pharmacology_Katzung. Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides. It lacks amino sugars and glycosidic bonds.


Pharmacology_Katzung

Pharmacology_Katzung. Spectinomycin is active in vitro against many Gram-positive and Gram-negative organisms, but it is used almost solely as an alternative treatment for drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients. The majority of gonococcal isolates are inhibited by 6 mcg/mL of spectinomycin. Strains of gonococci may be resistant to spectinomycin, but there is no cross-resistance with other drugs used in gonorrhea. Notably, it is not recommended for treatment of pharyngeal gonococcal infec-children).There is pain at the injection site and, occasionally, fever tions due to high failure rates regardless of in vitro susceptibility. and nausea. Nephrotoxicity and anemia have been observed rarely. Spectinomycin is rapidly absorbed after intramuscular injection. Spectinomycin is no longer available for use in the USA but is still The standard regimen is a single dose of 2–4 g/d (40 mg/kg in recommended elsewhere.


Pharmacology_Katzung

Pharmacology_Katzung. • Gentamicin Prevents bacterial protein synthesis by binding to the 30S ribosomal subunit Bactericidal activity against effects against Gram-positive bacteria when combined with β-lactams or endocarditis caused by streptococci, staphylococci, and enterococci IV • renal clearance (half-life 2.5 h) • conventional dosing 1.3–1.7 mg/kg q8h with goal peak levels 5–8 mcg/mL • trough levels <2 mcg/mL • once-daily dosing at 5–7 mg/kg as effective and • Toxicity: Nephrotoxicity (reversible), ototoxicity (irreversible), neuromuscular blockade Tobramycin: Intravenous; more active than gentamicin versus Pseudomonas; may also have less nephrotoxicity Amikacin: Intravenous; resistant to many enzymes that inactivate gentamicin and tobramycin; higher doses and target peaks and troughs than gentamicin and tobramycin Streptomycin: Intramuscular, widespread resistance limits use to specific indications such as tuberculosis and enterococcal endocarditis


Pharmacology_Katzung

Pharmacology_Katzung. Streptomycin: Intramuscular, widespread resistance limits use to specific indications such as tuberculosis and enterococcal endocarditis Neomycin: Oral or topical, poor bioavailability; used before bowel surgery to decrease aerobic flora Spectinomycin: Intramuscular; sole use is for treatment of antibiotic-resistant gonococcal infections or gonococcal infections in penicillin-allergic patients; not available in the USA Amikacin Generic, Amikin Kanamycin Generic, Kantrex Neomycin Generic, Mycifradin Paromomycin Generic, Humatin Tobramycin Generic, Nebcin Baddour L et al: Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications. Circulation 2015;132:1435.


Pharmacology_Katzung

Pharmacology_Katzung. Tobramycin Generic, Nebcin Baddour L et al: Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications. Circulation 2015;132:1435. Busse H-J, Wöstmann C, Bakker EP: The bactericidal action of streptomycin: Membrane permeabilization caused by the insertion of mistranslated proteins into the cytoplasmic membrane of Escherichia coli and subsequent caging of the antibiotic inside the cells due to degradation of these proteins. J Gen Microbiol 1992;138:551. Cheer SM, Waugh J, Noble S: Inhaled tobramycin (TOBI): A review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis. Drugs 2003;63:2501. Freeman CD et al: Once-daily dosing of aminoglycosides: Review and recommendations for clinical practice. J Antimicrob Chemother 1997;39:677. Jackson J et al: Aminoglycosides: How should we use them in the 21st century? Curr Opin Infect Dis 2013;26:516.


Pharmacology_Katzung

Pharmacology_Katzung. Jackson J et al: Aminoglycosides: How should we use them in the 21st century? Curr Opin Infect Dis 2013;26:516. Le T, Bayer AS: Combination antibiotic therapy for infective endocarditis. Clin Infect Dis 2003;36:615. Olsen KM et al: Effect of once-daily dosing vs. multiple daily dosing of tobramycin on enzyme markers of nephrotoxicity. Crit Care Med 2004;32:1678. Paul M et al: Beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev 2013 Jun 29;6:CD003038. Peña C et al: Effect of adequate single-drug versus combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections. Clin Infect Dis 2013;57:208. Poole K: Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005;49:479. Zhanel G et al: Comparison of the next generation aminoglycoside plazomicin to gentamicin, tobramycin, and amikacin. Expert Rev Anti Infect Ther 2012;10:459.


Pharmacology_Katzung

Pharmacology_Katzung. Zhanel G et al: Comparison of the next generation aminoglycoside plazomicin to gentamicin, tobramycin, and amikacin. Expert Rev Anti Infect Ther 2012;10:459. The patient has normal renal function and thus qualifies for once-daily dosing. Tobramycin could be administered as a single once-daily injection at a dose of 350–490 mg (5–7 mg/kg). A serum level between 1.5 and 6 mcg/mL mea-sured 8 hours after infusion correlates with an appropriate trough level. Alternatively, the same total daily dose could be divided and administered every 8 hours, as a conventional dosing strategy. With conventional dosing, peak and trough concentrations should be monitored with the target peak concentration of 5–10 mcg/mL and the target trough con-centration of <2 mcg/mL. CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*


Pharmacology_Katzung

Pharmacology_Katzung. A 59-year-old woman presents to an urgent care clinic with a 4-day history of frequent and painful urination. She has had fevers, chills, and flank pain for the past 2 days. Her physician advised her to come immediately to the clinic for evaluation. In the clinic she is febrile (38.5°C [101.3°F]) but otherwise stable and states she is not experiencing any nausea or vomiting. Her urine dipstick test is positive for leukocyte esterase. Urinalysis and urine culture are ordered. Her past medical history is significant for three urinary tract infections in the past year. Each episode was uncom-plicated, treated with trimethoprim-sulfamethoxazole, and promptly resolved. She also has osteoporosis for which she takes a daily calcium supplement. The decision is made to treat her with oral antibiotics for a complicated urinary tract infection with close follow-up. Given her history, what would be a reasonable empiric antibiotic choice? Depending on the antibiotic choice are there potential drug


Pharmacology_Katzung

Pharmacology_Katzung. for a complicated urinary tract infection with close follow-up. Given her history, what would be a reasonable empiric antibiotic choice? Depending on the antibiotic choice are there potential drug interactions?


Pharmacology_Katzung

Pharmacology_Katzung. The basic formulas of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA) are shown in Figure 46–1. Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group ( ⎯ SO2 ⎯ NH ⎯ R) or the amino group ( ⎯ NH2) of the sulfanilamide nucleus. Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can be prepared as sodium salts, which are used for intravenous administration. Mechanism of Action & Antimicrobial Activity


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action & Antimicrobial Activity Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA. This pathway (Figure 46–2) is thus essential for production of purines and nucleic acid synthesis. As structural analogs of PABA, sulfonamides inhibit dihydropteroate synthase and folate production. Sulfonamides inhibit both Gram-positive bacteria, such as Staphylococcus sp and Gram-negative enteric bacteria such as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and Enterobacter sp, as well as Nocardia sp, Chlamydia trachomatis, and some protozoa. Rickettsiae are not inhibited by sulfonamides but are instead stimulated in their growth. Activity is poor against anaerobes. Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics.


Pharmacology_Katzung

Pharmacology_Katzung. Combination of a sulfonamide with an inhibitor of dihy * The authors thank Henry F. Chambers, MD and Daniel H. Deck, for drofolate reductase (trimethoprim or pyrimethamine) provides their contributions to previous editions. FIGURE 46–1 Structures of some sulfonamides and p-aminobenzoic acid. synergistic activity because of sequential inhibition of folate synthesis (Figure 46–2). Some bacteria lack the enzymes required for folate synthesis from PABA and, like mammals, depend on exogenous sources of folate; therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may also occur as a result of mutations that (1) cause overproduction of PABA, (2) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or (3) impair permeability to the sulfonamide. Dihydropteroate FIGURE 46–2 Actions of sulfonamides and trimethoprim.