Tetracyclines PDF

44 C H A P T E R Tetracyclines, Macrolides, Clindamycin, Chloramphenicol,...

44 C H A P T E R Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins Camille E. Beauduy, PharmD, & Lisa G. Winston, MD C ASE STUDY A 22-year-old woman presents to her college medical for chlamydia and gonorrhea nucleic acid amplifica- clinic complaining of a 2-week history of vaginal dis- tion testing. A pregnancy test is also ordered, and the charge. She has not had fever or abdominal pain. She has patient reports she “missed her last period.” Pending had vaginal intercourse with two men in the last 6 months these results, the decision is made to treat her presump- and used condoms intermittently. A pelvic examination tively for chlamydial cervicitis. What are two potential is performed and is positive for mucopurulent discharge treatment options for her possible chlamydial infection? from the endocervical canal. No cervical motion tender- How does her potential pregnancy affect the treatment ness is present. A first-catch urine specimen is obtained decision? The drugs described in this chapter inhibit bacterial protein synthesis by binding to and interfering with ribosomes. Most are TETRACYCLINES bacteriostatic, but a few are bactericidal against certain organisms. All of the tetracyclines have the basic structure shown on the next Resistance to the older tetracyclines and to macrolides is common. page: Except for tigecycline, eravacycline, and the streptogramins, these antibiotics may be administered orally. 844 Katzung_Ch44_p0844-0856.indd 844 25/08/20 1:11 PM  CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins     845 OH O OH O Free tetracyclines are crystalline amphoteric substances of low OH R9 11 1 O solubility. They are available as hydrochlorides, which are more 10 12 C 9 2 NH2 soluble. Such solutions are acidic and fairly stable. Tetracyclines 8 7 3 OH chelate divalent metal ions, which can interfere with their absorp- 6 5 4 R6 OH H R5 H N(CH3)2 tion and activity. Tigecycline is a glycylcycline and a semisynthetic R7 derivative of minocycline, omadacycline is a synthetic aminometh- ylcycline derivative of minocycline, and eravacycline is a structural R7 R6 R5 R9 Chlortetracycline CI CH3 H H analog of tigecycline classified as a fluorocycline. Oxytetracycline H CH3 OH H Tetracycline H CH3 H H Demeclocycline CI H H H Mechanism of Action & Methacycline Doxycycline H H CH2* CH3* OH OH H H Antimicrobial Activity + Minocycline N(CH3)2 H H H *There is no OH at position 6 on methacycline, doxycycline, and minocycline Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. Tetracyclines enter microorganisms Tigecycline N(CH3)2 H H NH in part by passive diffusion and in part by an energy-dependent NH process of active transport. Susceptible organisms concentrate the O drug intracellularly. Once inside the cell, tetracyclines bind revers- Eravacycline F H H NH N ibly to the 30S subunit of the bacterial ribosome, blocking the O binding of aminoacyl-tRNA to the acceptor site on the mRNA- ribosome complex (Figure 44–1). This prevents addition of amino Omadacycline N(CH3)2 H H NH acids to the growing peptide. 50S ribosome Amino acid 1 C 6 2 M 3 4 2 t6 5 6 1 Charged tRNA t5 4 t6 3 mRNA 30S T t5 Uncharged tRNA 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). Katzung_Ch44_p0844-0856.indd 845 25/08/20 1:11 PM  846    SECTION VIII Chemotherapeutic Drugs Tetracyclines are active against many gram-positive and gram- Tetracyclines are 40–80% bound by serum proteins, with the negative bacteria, including certain anaerobes, rickettsiae, chla- exception of omadacycline, which is only 20% protein-bound. mydiae, and mycoplasmas. For susceptible organisms, differences Oral dosages of 500 mg every 6 hours of tetracycline hydrochlo- in clinical efficacy may be attributable to features of absorption, ride produce peak blood levels of 4–6 mcg/mL. Peak levels of distribution, and excretion of individual drugs. Tetracycline- 2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or resistant strains may be susceptible to doxycycline, minocycline, minocycline. The following are the steady-state peak serum con- and tigecycline, all of which are poor substrates for the efflux centrations after standard dosages of other tetracyclines: tigecy- pump, when that is the mechanism of resistance. Similarly, the cline 0.6 mcg/mL; eravacycline 1.8 mcg/mL; and omadacycline most recently developed drugs, eravacycline and omadacycline, 2 mcg/mL for intravenous and 0.9 mcg/mL for oral administra- retain activity against tetracycline-resistant strains. tion. 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 Resistance excreted in breast milk. As a result of chelation with calcium, tetra- Three mechanisms of resistance to tetracycline analogs have been cyclines bind to—and damage—growing bones and teeth. Carba- described: (1) impaired influx or increased efflux by an active mazepine, phenytoin, barbiturates, and chronic alcohol ingestion transport protein pump; (2) ribosome protection due to produc- may shorten the half-life of tetracycline, doxycycline, and eravacy- tion of proteins that interfere with tetracycline binding to the cline by 50% due to induction of hepatic enzymes that metabolize ribosome; and (3) enzymatic inactivation. The most important the drugs. of these are production of an efflux pump and ribosomal protec- Tetracyclines are excreted mainly in bile and urine. Concen- tion. Tet(AE) efflux pump–expressing gram-negative species are trations in bile exceed those in serum 10-fold. Some of the drug resistant to the older tetracyclines, doxycycline, and minocycline. excreted in bile is reabsorbed from the intestine (enterohepatic They are susceptible, however, to tigecycline, eravacycline, and circulation) and may contribute to maintenance of serum levels. omadacycline, which are not substrates of these pumps. Similarly, Ten to fifty percent of various tetracyclines is excreted into the a different pump [Tet(K)] of staphylococci confers resistance to urine, mainly by glomerular filtration. Ten to forty percent of the tetracycline but not to doxycycline, minocycline, tigecycline, erava- drug is excreted in feces. Doxycycline and tigecycline, in contrast cycline, or omadacycline, none of which is a pump substrate. The to other tetracyclines, are eliminated by nonrenal mechanisms and Tet(M) ribosomal protection protein expressed by gram-positives do not accumulate significantly in renal failure, requiring no dos- produces resistance to tetracycline, doxycycline, and minocycline, age adjustment. but not to tigecycline, eravacycline, or omadacycline—which, Tetracyclines are classified as short-acting (tetracycline, as well because of bulky substituents, have a steric hindering effect on as the agricultural agents chlortetracycline and oxytetracycline), Tet(M) binding to the ribosome. Tigecycline, eravacycline, and intermediate-acting (demeclocycline), or long-acting (doxycy- omadacycline are substrates of the chromosomally encoded mul- cline and minocycline) based on serum half-lives of 6–8 hours, tidrug efflux pumps of Proteus sp and Pseudomonas aeruginosa, 12 hours, and 16–18 hours, respectively. Tigecycline, eravacycline, accounting for the intrinsic resistance of these organisms, and their and omadacycline have long half-lives of 36, 20, and 16 hours, resistance to all other tetracyclines. respectively. Despite these prolonged half-lives, tigecycline and eravacycline require twice-daily dosing to maintain adequate serum concentrations; however, omadacycline can be dosed once Pharmacokinetics daily after an initial loading dose. The almost complete absorption Tetracyclines differ in their absorption after oral administration and slow excretion of doxycycline and minocycline allow for once- and in their elimination. Absorption after oral administration is daily dosing for certain indications, but, by convention, these two approximately 60–70% for tetracycline and demeclocycline (not drugs are usually dosed twice daily. typically used as an antibiotic; see below) and 95–100% for doxy- cycline and minocycline. Tigecycline and eravacycline are poorly absorbed orally and must be administered intravenously. Omada- Clinical Uses cycline bioavailability is approximately 35%, so an oral formula- A tetracycline is the drug of choice in the treatment of most tion has been developed that is three times the intravenous dose. infections caused by rickettsiae and Borrelia sp, including Rocky A portion of an orally administered dose of tetracycline remains Mountain spotted fever and Lyme disease. Tetracyclines are used in the gut lumen, alters intestinal flora, and is excreted in the preferentially to treat Anaplasma phagocytophilum and Ehrlichia feces. Absorption occurs mainly in the upper small intestine and is sp. Tetracyclines are also excellent drugs for the treatment of impaired by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); by dairy Mycoplasma pneumoniae, chlamydiae, and some spirochetes. They products and antacids, which contain multivalent cations; and are used in combination regimens to treat gastric and duodenal by alkaline pH. Tetracycline, demeclocycline, and omadacycline ulcer disease caused by Helicobacter pylori. They may be used in should be administered on an empty stomach, while doxycycline various gram-positive and gram-negative bacterial infections, and minocycline absorption is not impaired by food. Specially including vibrio infections, provided the organism is not resis- buffered doxycycline and minocycline solutions are formulated for tant. In susceptible cholera, tetracyclines rapidly stop the shedding intravenous administration. of vibrios, but tetracycline resistance is an increasing problem. Katzung_Ch44_p0844-0856.indd 846 25/08/20 1:11 PM  CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins     847 Tetracyclines remain effective in most chlamydial infections, reported adverse effect for eravacycline and omadacycline as well, including sexually transmitted infections. Doxycycline is also an but it appears to be substantially less common. Neither nausea nor alternative agent recommended by the Centers for Disease Con- vomiting usually requires discontinuation of these drugs. trol and Prevention for primary and secondary syphilis in patients Tigecycline is approved for treatment of skin and skin-structure with penicillin allergy. A tetracycline—in combination with other infection, intra-abdominal infections, and community-acquired antibiotics—is indicated for plague, tularemia, brucellosis, and pneumonia. However, in a meta-analysis of clinical trials, tigecy- bartonellosis. Tetracyclines are sometimes used in the treatment or cline was associated with a small but significant increase in the risk prophylaxis of protozoal infections, eg, those due to Plasmodium of death compared with other antibiotics used to treat these infec- falciparum (see Chapter 52). Other uses include treatment of acne, tions. The increased risk was most apparent in hospital-acquired exacerbations of bronchitis, community-acquired pneumonia, and ventilator-associated pneumonia but was also seen in other leptospirosis, and some nontuberculous mycobacterial infections infections. This has led the US Food and Drug Administration (eg, Mycobacterium marinum). Tetracyclines formerly were used (FDA) to issue a black box warning that tigecycline should be for a variety of common infections, including bacterial gastroen- reserved for situations where alternative treatments are not suit- teritis and urinary tract infections. However, many strains of bac- able. Because active drug concentrations in the urine and serum teria causing these infections are now resistant, and other agents are relatively low, tigecycline may not be effective for urinary have largely supplanted tetracyclines. tract infections or primary bacteremia. Tigecycline has in vitro Minocycline, 100 mg orally twice daily for 5 days, can eradi- activity against a wide variety of multidrug-resistant pathogens cate the meningococcal carrier state, but, because of side effects (eg, methicillin-resistant S aureus, extended-spectrum β-lactamase- and resistance of many meningococcal strains, ciprofloxacin or producing gram-negatives, and Acinetobacter sp); however, its rifampin is preferred. Demeclocycline is rarely used as an antibac- clinical efficacy in infections with multidrug-resistant organisms, terial, but it has been used off-label in the treatment of inappropri- compared with other agents, is unproven. ate secretion of antidiuretic hormone because of its inhibition of Eravacycline was FDA-approved in 2018 for the treatment of antidiuretic hormone in the renal tubule (see Chapter 15). complicated intra-abdominal infections after two phase 3 trials Tigecycline, the first glycylcycline to reach clinical practice, showed noninferiority to comparators (ertapenem in one study, and the subsequently developed analogs eravacycline and oma- meropenem in the other) for this indication. Like tigecycline, it dacycline have several unique features that warrant their consid- retains activity against many multidrug-resistant organisms. In eration apart from the older tetracyclines. Their spectra of activity vitro studies suggest that it may be two to four times more potent are very broad, and many tetracycline-resistant strains are sus- than tigecycline, but clinical studies are not complete. Of note, ceptible because they are not affected by the common resistance eravacycline should not be used to treat urinary tract infections determinants. Susceptible organisms include coagulase-negative because it failed to show noninferiority to comparator agents staphylococci and Staphylococcus aureus, including methicillin- (levofloxacin or ertapenem) in two separate phase 3 trials. resistant, vancomycin-intermediate, and vancomycin-resistant Omadacycline was approved in 2018 for two different indica- strains; streptococci, penicillin-susceptible and resistant; entero- tions after phase 3 trials showed noninferiority to moxifloxacin in cocci, including vancomycin-resistant strains; gram-positive rods; the treatment of community-acquired bacterial pneumonia and to Enterobacteriaceae; multidrug-resistant strains of Acinetobacter linezolid in the treatment of acute bacterial skin and skin struc- sp; anaerobes, both gram-positive and gram-negative; rickettsiae, ture infections. Similar to tigecycline and eravacycline, omadacy- Chlamydia sp, and Legionella pneumophila; and rapidly growing cline is not affected by the most common resistance mechanisms, mycobacteria. Proteus and Providencia sp and P aeruginosa, how- thus retaining activity against a broad array of pathogens resistant ever, are intrinsically resistant. to older drugs. It differs from tigecycline and eravacycline in its Tigecycline, formulated for intravenous administration only, much lower protein-binding and its availability as an oral formula- is given as a 100-mg loading dose, then 50 mg every 12 hours. tion. Of note, coadministration with any food leads to substantial Eravacycline is available only for intravenous use. It is given as a decreases in absorption of the oral form, so omadacycline must be 1-mg/kg dose every 12 hours; it must be adjusted to 1.5 mg/kg administered at least 4 hours after and 2 hours before any food or every 12 hours when coadministered with potent CYP3A induc- liquid other than water. Like other tetracyclines, its absorption is ers, such as rifampin. Omadacycline is available in both intrave- decreased by coadministration of calcium and other metal cations, nous and oral formulations; the intravenous form should be given so supplements such as antacids or multivitamins must be given at as 100 mg twice daily on the first day, then once daily thereafter. least 4 hours before or after omadacycline. The oral form can be given as 450 mg once daily on days one and two, then 300 mg daily thereafter. As with all tetracyclines, tissue A. Oral Dosage and intracellular penetration with these agents is excellent; conse- The oral dosage for tetracycline hydrochloride is 0.25–0.5 g four quently, the volume of distribution is quite large and peak serum times daily for adults and 25–50 mg/kg/d for children (8 years of concentrations are low. Elimination is primarily biliary, and no age and older). For severe systemic infections, the higher dosage dosage adjustment is needed for patients with renal insufficiency. is indicated, at least for the first few days. The dosage for dox- In addition to the tetracycline class effects, the chief adverse effect ycycline is 100 mg once or twice daily; the minocycline dose is of tigecycline is nausea, which occurs in up to one third of patients, 100 mg twice daily; the omadacycline maintenance dose is 300 mg and occasionally vomiting; nausea has been the most commonly once daily. Doxycycline is the oral tetracycline of choice for most Katzung_Ch44_p0844-0856.indd 847 25/08/20 1:11 PM  848    SECTION VIII Chemotherapeutic Drugs indications because it is generally well tolerated, it can be given twice minocycline may accumulate to toxic levels in patients with daily, and its absorption is not significantly affected by food. All impaired kidney function. Intravenous injection can lead to tetracyclines chelate with metals and should not be administered venous thrombosis. Intramuscular injection produces painful local orally with milk, antacids, or ferrous sulfate. To avoid deposition in irritation and should be avoided. Systemically administered tet- growing bones or teeth, tetracyclines should be avoided in pregnant racyclines commonly induce sensitivity to sunlight or ultraviolet women and children younger than 8 years except in unusual circum- light, particularly in fair-skinned persons. Dizziness, vertigo, and stances, eg, treatment of suspected Rocky Mountain spotted fever. tinnitus have been noted, particularly with high doses or pro- longed administration of minocycline. These symptoms may also B. Parenteral Dosage occur with higher doses of doxycycline. Doxycycline and minocycline are available for intravenous injec- tion and are given at the same doses as the oral formulations; oma- dacycline’s intravenous maintenance dose is 100 mg daily, which MACROLIDES is lower than the oral dose due to limited oral bioavailability. As described previously, tigecycline and eravacycline are available only The macrolides are a group of closely related compounds charac- as intravenous injectable forms. Intramuscular injection is not rec- terized by a macrocyclic lactone ring (usually containing 14 or 16 ommended because of pain and inflammation at the injection site. atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to Adverse Reactions a 14-atom lactone ring, was obtained in 1952 from Streptomyces Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines erythreus, now called Saccharopolyspora erythraea. Clarithromycin are uncommon. Most adverse effects are due to direct toxicity of and azithromycin are semisynthetic derivatives of erythromycin. the drug or to alteration of microbial flora. Macrolide O ring A. Gastrointestinal Adverse Effects R1 R1 Nausea, vomiting, and diarrhea are the most common reasons for OH discontinuing tetracyclines. These effects are attributable to direct R2 O R1 local irritation of the intestinal tract. Oral tetracyclines can rarely R1 6 OH R1 R1 cause esophageal ulceration, so patients should be instructed to O O C2H5 O take them with 8 ounces of water and remain upright for at least N(R1)2 30 minutes after each dose. Desosamine O O Tetracyclines alter the normal gastrointestinal flora, with sup- OH pression of susceptible coliform organisms and overgrowth of O R1 Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia, HO R1 and Candida. This can result in intestinal functional disturbances, Cladinose OR1 anal pruritus, vaginal or oral candidiasis, or Clostridioides difficile– R1 associated colitis. However, the risk of C difficile colitis may be Erythromycin (R1 = CH3, R2 = H) lower with tetracyclines than with other antibiotics. Clarithromycin (R1, R2 = CH3) 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 ERYTHROMYCIN given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia. It Chemistry can also be deposited in bone, where it may cause deformity or The general structure of erythromycin is shown with the mac- growth inhibition. Because of these effects, tetracyclines are gener- rolide ring and the sugars desosamine and cladinose. It is poorly ally avoided in pregnancy. If the drug is given for long periods to soluble in water (0.1%) but dissolves readily in organic solvents. children younger than 8 years, similar changes can result. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various C. Other Toxicities esters and salts. Tetracyclines can impair hepatic function, especially during preg- nancy, in patients with preexisting liver disease, and when high Mechanism of Action & doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. Renal tubular aci- Antimicrobial Activity dosis and Fanconi syndrome have been attributed to the admin- The antibacterial action of erythromycin and other macrolides istration of outdated tetracycline preparations. Tetracyclines given may be inhibitory or bactericidal, particularly at higher con- along with diuretics may cause nephrotoxicity. Tetracycline and centrations, for susceptible organisms. Activity is enhanced at Katzung_Ch44_p0844-0856.indd 848 25/08/20 1:11 PM  CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins     849 alkaline pH. Inhibition of protein synthesis occurs via binding to used in treatment of community-acquired pneumonia because its the 50S ribosomal RNA. The binding site is near the peptidyl- spectrum of activity includes the pneumococcus, M pneumoniae, transferase center, and peptide chain elongation (ie, transpeptida- and L pneumophila, newer macrolides are better tolerated and more tion) is prevented by blocking of the polypeptide exit tunnel. As commonly selected. Macrolide resistance is increasing in pneumo- a result, peptidyl-tRNA is dissociated from the ribosome. Eryth- cocci and M pneumoniae. Erythromycin had also been useful as a romycin also inhibits the formation of the 50S ribosomal subunit penicillin substitute in penicillin-allergic individuals with infections (Figure 44–1). caused by staphylococci and streptococci. Emergence of erythromy- Erythromycin is active against susceptible strains of gram- cin resistance in staphylococci and in strains of group A streptococci positive organisms, especially pneumococci, streptococci, staphylo- has made macrolides less attractive as first-line agents for treatment cocci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, of pharyngitis and skin and soft tissue infections. Erythromycin has Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila pneu- been studied as prophylaxis against endocarditis during dental pro- moniae, H pylori, Listeria monocytogenes, and certain mycobacteria cedures in individuals with valvular heart disease who are unable to (Mycobacterium kansasii, Mycobacterium scrofulaceum) also are sus- tolerate the first-line amoxicillin, but clindamycin, which is better ceptible. Gram-negative organisms such as Neisseria sp, Bordetella tolerated, has largely replaced it. pertussis, Bartonella henselae, and Bartonella quintana as well as some The oral dosage of erythromycin base or stearate is 0.25–0.5 g Rickettsia species, Treponema pallidum, and Campylobacter species every 6 hours (for children, 40 mg/kg/d). The dosage of eryth- are susceptible. Haemophilus influenzae is somewhat less susceptible. romycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral erythro- Resistance to erythromycin is usually plasmid-encoded. Three mycin base (1 g) is sometimes combined with oral neomycin or general mechanisms have been identified: (1) reduced perme- kanamycin for preoperative preparation of the colon. The intra- ability of the cell membrane or active efflux; (2) production (by venous dosage of erythromycin lactobionate is 0.5–1.0 g every Enterobacteriaceae) of esterases that hydrolyze macrolides; and 6 hours for adults and 15–20 mg/kg/d divided every 6 hours for (3) modification of the ribosomal binding site (so-called ribosomal children. The higher dosage is recommended when treating pneu- protection) by chromosomal mutation or by a macrolide-inducible monia caused by L pneumophila. or constitutive methylase. Efflux and methylase production are the most important resistance mechanisms in gram-positive organisms. Adverse Reactions Cross-resistance occurs between erythromycin and the other mac- Anorexia, nausea, vomiting, and diarrhea are common. Gastro- rolides. Constitutive methylase production also confers resistance to intestinal intolerance, which is due to a direct stimulation of gut structurally unrelated but mechanistically similar compounds such as motility, is a common reason for selecting an alternative to eryth- clindamycin and streptogramin B (so-called macrolide-lincosamide- romycin. This side effect may actually be desirable in some cir- streptogramin, or MLS-type B, resistance), which share the same cumstances, leading to the off-label use of erythromycin to treat ribosomal binding site. Because nonmacrolides are poor inducers of patients with gastroparesis. the methylase, strains expressing an inducible methylase will appear Erythromycins, particularly the older estolate formulation, can susceptible in vitro. However, constitutive mutants that are resistant produce acute cholestatic hepatitis (fever, jaundice, impaired liver can be selected out and emerge during therapy with clindamycin. function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Pharmacokinetics Other allergic reactions include fever, eosinophilia, and rashes. Erythromycin base is destroyed by stomach acid and must be Erythromycin metabolites inhibit cytochrome P450 enzymes administered with enteric coating. Food interferes with absorp- and, thus, increase the serum concentrations of numerous drugs, tion. The stearate and ethylsuccinate formulations are fairly acid- including theophylline, warfarin, cyclosporine, and methylpred- resistant and somewhat better absorbed. A 500-mg intravenous nisolone. Erythromycin increases serum concentrations of oral dose of erythromycin lactobionate produces serum concentra- digoxin by increasing its bioavailability. tions 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. Erythromy- CLARITHROMYCIN cin is not removed by dialysis. Large amounts of an administered Clarithromycin is derived from erythromycin by addition of a dose are excreted in the bile, and only 5% is excreted in the urine. methyl group and has improved acid stability and oral absorp- Absorbed drug is distributed widely except to the brain and cere- tion compared with erythromycin. Its mechanism of action is brospinal fluid. Erythromycin is taken up by polymorphonuclear the same as that of erythromycin. Clarithromycin is available leukocytes and macrophages. It traverses the placenta and reaches as an oral preparation. Clarithromycin and erythromycin are the fetus. similar with respect to antibacterial activity except that clar- ithromycin is more active against Mycobacterium avium com- Clinical Uses plex (see Chapter 47). Clarithromycin also has activity against Erythromycin is a traditional drug of choice in corynebacterial infec- Mycobacterium leprae, Toxoplasma gondii, and H influenzae. tions (diphtheria, corynebacterial sepsis, erythrasma) and in respira- Erythromycin-resistant streptococci and staphylococci are also tory, neonatal, ocular, or genital chlamydial infections. While it was resistant to clarithromycin. Katzung_Ch44_p0844-0856.indd 849 25/08/20 1:11 PM  850    SECTION VIII Chemotherapeutic Drugs A 500-mg dose of clarithromycin produces serum concen- Recent studies have suggested that azithromycin may be associated trations of 2–3 mcg/mL. The longer half-life of clarithromycin with a small increased risk of cardiac death. (6 hours) compared with erythromycin permits twice-daily dos- ing. The recommended dosage is 250–500 mg orally twice daily or 1000 mg of the extended-release formulation once daily. Clar- FIDAXOMICIN ithromycin penetrates most tissues well, with concentrations equal Fidaxomicin, a minimally absorbed macrolide used to treat to or exceeding serum concentrations. Clostridioides difficile (formerly Clostridium difficile) infections, is Clarithromycin is metabolized in the liver and is partially elimi- discussed in Chapter 50. nated in the urine. The major metabolite, 14-hydroxyclarithromy- cin, also has antibacterial activity and is eliminated in the urine. Dosage reduction (eg, a 500-mg loading dose, then 250 mg once KETOLIDES or twice daily) is recommended for patients with creatinine clear- ances less than 30 mL/min. Clarithromycin has drug interactions Ketolides are semisynthetic, 14-membered ring macrolides, dif- similar to those described for erythromycin. fering from erythromycin by substitution of a 3-keto group for The advantages of clarithromycin compared with erythromycin the neutral sugar l-cladinose. Telithromycin was approved for are lower incidence of gastrointestinal intolerance and less frequent community-acquired bacterial pneumonia, but it is no longer avail- dosing. able in the USA. 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 AZITHROMYCIN gonorrhoeae, B fragilis, T gondii, and certain nontuberculous mycobacteria. Many macrolide-resistant strains are susceptible to Azithromycin, a 15-atom lactone macrolide ring compound, is ketolides because the structural modification of these compounds derived from erythromycin by addition of a methylated nitrogen renders them poor substrates for efflux pump–mediated resistance, into the lactone ring. Its spectrum of activity, mechanism of action, and they bind to ribosomes of some bacterial species with higher and clinical uses are similar to those of clarithromycin. Azithro- affinity than macrolides. mycin can be administered orally or intravenously. Azithromycin Oral bioavailability of telithromycin is 57%, and tissue and is active against M avium complex and T gondii. Azithromycin is intracellular penetration is generally good. Telithromycin is slightly less active than erythromycin and clarithromycin against metabolized in the liver and eliminated by a combination of bili- staphylococci and streptococci and slightly more active against ary and urinary routes of excretion. It is administered as a once- H influenzae. Azithromycin is highly active against Chlamydia sp. daily dose of 800 mg, which results in peak serum concentrations Azithromycin differs from erythromycin and clarithromycin of approximately 2 mcg/mL. It is a reversible inhibitor of the mainly in pharmacokinetic properties. A 500-mg dose of azithro- CYP3A4 enzyme system and may slightly prolong the QTc inter- mycin produces relatively low serum concentrations of approxi- val. In the USA, telithromycin was indicated only for treatment of mately 0.4 mcg/mL. However, azithromycin penetrates into most community-acquired bacterial pneumonia after it was recognized tissues (except cerebrospinal fluid) and phagocytic cells extremely that telithromycin can cause hepatitis and liver failure. Telithro- well, with tissue concentrations exceeding serum concentrations mycin is also contraindicated in patients with myasthenia gravis by 10- to 100-fold. The drug is slowly released from tissues (tissue because it may exacerbate this condition. half-life of 2–4 days) to produce an elimination half-life approach- Solithromycin, although not yet approved, is a novel fluoro- ing 3 days. These unique properties permit once-daily dosing ketolide that has undergone FDA review after two phase 3 clinical and shortening of the duration of treatment in many cases. For trials showed noninferiority when compared with moxifloxacin example, a single 1-g dose of azithromycin is as effective as a 7-day in the treatment of community-acquired pneumonia. The dos- course of doxycycline for chlamydial cervicitis and urethritis. age used was a loading dose of 800 mg orally or intravenously, Azithromycin, as a 500-mg loading dose, followed by a 250-mg followed by 400 mg daily for a total of 5 days. The intravenous single daily dose for the next 4 days, is commonly used alone or formulation was associated with higher rates of infusion-related in combination with a beta-lactam antibiotic to treat community- reactions compared with moxifloxacin. Similar to telithromy- acquired pneumonia. cin, solithromycin maintains in vitro activity against macrolide- Azithromycin is rapidly absorbed and well tolerated orally. resistant bacteria, including S pneumoniae, staphylococci, entero- Aluminum and magnesium antacids do not alter bioavailability but cocci, Chlamydia trachomatis, and Neisseria gonorrhoeae. Its delay absorption and reduce peak serum concentrations. Because chemical structure lacks the pyridine-imidazole side chain group, it has a 15-member (not 14-member) lactone ring, azithromycin which is thought to contribute to telithromycin’s hepatotoxicity. does not inactivate cytochrome P450 enzymes and, therefore, is While severe hepatotoxicity has not been demonstrated in phase free of the drug interactions that occur with erythromycin and 2 or 3 clinical trials, the FDA review panel expressed concerns clarithromycin. that this potential adverse effect was inadequately studied in clin- Macrolide antibiotics prolong the electrocardiographic QT ical trials and solithromycin’s approval for community-acquired interval due to an effect on potassium channels. Prolongation of pneumonia was declined until further safety analyses have been the QT interval can lead to the torsades de pointes arrhythmia. completed. There has been additional interest in solithromycin’s Katzung_Ch44_p0844-0856.indd 850 25/08/20 1:11 PM  CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins     851 efficacy in treating sexually transmitted infections; however, early Clinical Use results of a phase 3 trial in patients with infections caused by Neis- Clindamycin is indicated for the treatment of skin and soft-tissue seria gonorrhoeae with or without concomitant C trachomatis failed to infections caused by streptococci and staphylococci. It may be show noninferiority against the standard regimen of ceftriaxone with active against community-acquired strains of methicillin-resistant azithromycin. Solithromycin’s future place in therapy remains unclear. S aureus, although resistance has been increasing. It is commonly used in conjunction with penicillin G to treat toxic shock syn- drome or necrotizing fasciitis caused by Group A Streptococcus. In CLINDAMYCIN this setting, its use is typically limited to the initial 48 to 72 hours of treatment with the goal of inhibiting toxin production. Clindamy- Clindamycin is a chlorine-substituted derivative of lincomycin, cin is also indicated for treatment of infections caused by suscep- an antibiotic that is elaborated by Streptomyces lincolnensis. tible Bacteroides sp and other anaerobes. Clindamycin, sometimes CH3 in combination with an aminoglycoside or cephalosporin, is used CH3 to treat penetrating wounds of the abdomen and the gut; infec- N CI CH tions originating in the female genital tract, eg, septic abortion, C3H7 C NH CH pelvic abscesses, or pelvic inflammatory disease; and lung and O periodontal abscesses. Clindamycin is recommended for prophy- O HO laxis of endocarditis in patients with specific valvular heart disease OH who are undergoing certain dental procedures and have significant S CH3 penicillin allergies. Clindamycin plus primaquine is an effective OH alternative to trimethoprim-sulfamethoxazole for moderate to Clindamycin moderately severe Pneumocystis jiroveci pneumonia in patients with acquired immunodeficiency syndrome (AIDS). It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis Mechanism of Action & of the brain. Antibacterial Activity Adverse Effects Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the formation of initiation complexes and with Common adverse effects are diarrhea, nausea, and skin rashes. aminoacyl translocation reactions. The binding site for clindamy- Impaired liver function (with or without jaundice) and neutro- cin on the 50S subunit of the bacterial ribosome is identical penia sometimes occur. Administration of clindamycin is a risk with that for erythromycin. Streptococci, staphylococci, and factor for diarrhea and colitis due to C difficile. 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 suscep- STREPTOGRAMINS tible, although reported resistance rates appear to be increasing, particularly in gram-negative anaerobes. Resistance to clindamy- MECHANISM OF ACTION & cin, which generally confers cross-resistance to macrolides, is due ANTIBACTERIAL ACTIVITY to (1) mutation of the ribosomal receptor site; (2) modification of the receptor by a constitutively expressed methylase (see section on Quinupristin-dalfopristin is a combination of two strepto- erythromycin resistance, above); and (3) enzymatic inactivation of gramins—quinupristin, a streptogramin B, and dalfopristin, a clindamycin. Gram-negative aerobic species are intrinsically resis- streptogramin A—in a 30:70 ratio. The streptogramins share the tant because of poor permeability of the outer membrane. same ribosomal binding site as the macrolides and clindamycin and thus inhibit protein synthesis in an identical manner. Quinupristin- Pharmacokinetics dalfopristin is rapidly bactericidal for most susceptible organisms except Enterococcus faecium, which is killed slowly. Quinupristin- Oral dosages of clindamycin, 0.15–0.3 g every 8 hours dalfopristin is active against gram-positive cocci, including multi- (10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL. drug-resistant strains of streptococci, penicillin-resistant strains of When administered intravenously, 600 mg of clindamycin every S pneumoniae, methicillin-susceptible and resistant strains of staphy- 8 hours gives levels of 5–15 mcg/mL. The drug is about 90% pro- lococci, and E faecium (but not Enterococcus faecalis). Resistance is tein-bound. Clindamycin penetrates well into most tissues, with due to modification of the quinupristin binding site (MLS-B type brain and cerebrospinal fluid being important exceptions. It pene- resistance), enzymatic inactivation of dalfopristin, or efflux. trates 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 Pharmacokinetics half-life is about 3 hours in adults, increasing to 6 hours in patients Quinupristin-dalfopristin is administered intravenously at a dos- with anuria. No dosage adjustment is required for renal failure. age of 7.5 mg/kg every 8–12 hours. Peak serum concentrations Katzung_Ch44_p0844-0856.indd 851 25/08/20 1:11 PM  852    SECTION VIII Chemotherapeutic Drugs following an infusion of 7.5 mg/kg over 60 minutes are 3 mcg/mL strains of Bacteroides are highly susceptible; for these organisms, for quinupristin and 7 mcg/mL for dalfopristin. Quinupristin chloramphenicol may be bactericidal. and dalfopristin are rapidly metabolized, with half-lives of 0.85 Low-level resistance to chloramphenicol may emerge from and 0.7 hours, respectively. Elimination is principally by the large populations of chloramphenicol-susceptible cells by selec- fecal route. Dose adjustment is not necessary for renal failure, tion of mutants that are less permeable to the drug. Clinically peritoneal dialysis, or hemodialysis. Patients with hepatic insuffi- significant resistance is due to production of chloramphenicol ciency may not tolerate the drug at usual doses, however, because acetyltransferase, a plasmid-encoded enzyme that inactivates the of increased area under the concentration curve of both parent drug. drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours. Qui- Pharmacokinetics nupristin and dalfopristin significantly inhibit CYP3A4, which metabolizes warfarin, diazepam, quetiapine, simvastatin, and The usual dosage of chloramphenicol is 50–100 mg/kg/d divided cyclosporine, among many others. Dosage reduction of cyclo- every 6 hours. It is no longer available in the USA as an oral for- sporine may be necessary. mulation and may become unavailable for intravenous use. The parenteral formulation is a prodrug, chloramphenicol succinate, which is hydrolyzed to yield free chloramphenicol, giving blood Clinical Uses & Adverse Effects levels somewhat lower than those achieved with orally adminis- Quinupristin-dalfopristin is approved for treatment of infec- tered drug. Chloramphenicol is widely distributed to virtually all tions caused by staphylococci or by vancomycin-resistant strains tissues and body fluids, including the central nervous system and of E faecium, but not E faecalis, which is intrinsically resistant, cerebrospinal fluid, such that the concentration of chlorampheni- probably because of an efflux-type resistance mechanism. The col in brain tissue may be equal to that in serum. The drug pen- principal toxicities are infusion-related events, such as pain at the etrates cell membranes readily. infusion site, and an arthralgia-myalgia syndrome. Quinupristin- Most of the drug is inactivated either by conjugation with gluc- dalfopristin is used to a limited extent in the USA due to the avail- uronic acid (principally in the liver) or by reduction to inactive ability of better-tolerated alternatives. 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 CHLORAMPHENICOL in renal or hepatic insufficiency; however, the drug will accumu- late and should be used with extra caution in these situations. Crystalline chloramphenicol is a neutral, stable compound with Newborns less than a week old and premature infants also clear the following structure: chloramphenicol less well, and the dosage should be reduced to OH CH2OH O 25 mg/kg/d. NO2 C C N C CHCI2 Clinical Uses H H H Chloramphenicol Because of potential toxicity, bacterial resistance, and the avail- ability of many other effective alternatives, chloramphenicol has been used rarely in the United States for many years. It may be It is soluble in alcohol but poorly soluble in water. Chloram- considered for treatment of serious rickettsial infections such as phenicol succinate, which is used for parenteral administration, is typhus and Rocky Mountain spotted fever. It is an alternative highly water-soluble. It is hydrolyzed in vivo with liberation of free to a β-lactam antibiotic for treatment of bacterial meningitis chloramphenicol. occurring in patients who have major hypersensitivity reactions to penicillin. Mechanism of Action & Antimicrobial Activity Adverse Reactions Chloramphenicol is an inhibitor of microbial protein synthesis and Adults occasionally develop gastrointestinal disturbances, includ- is bacteriostatic against most susceptible organisms. It binds revers- ing nausea, vomiting, and diarrhea. These symptoms are rare in ibly to the 50S subunit of the bacterial ribosome (Figure 44–1) children. Oral or vaginal candidiasis may occur as a result of altera- and inhibits peptide bond formation (step 2). Chloramphenicol tion of normal microbial flora. is a broad-spectrum antibiotic that is active against both aerobic Chloramphenicol commonly causes a dose-related reversible and anaerobic gram-positive and gram-negative organisms. It is suppression of red cell production at dosages exceeding 50 mg/kg/d active also against rickettsiae but not chlamydiae. Most gram- after 1–2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 positive bacteria are inhibited at concentrations of 1–10 mcg/mL, to 40,000 courses of therapy) of chloramphenicol administra- and many gram-negative bacteria are inhibited by concentrations tion by any route, is an idiosyncratic reaction unrelated to dose, of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some although it occurs more frequently with prolonged use. Aplastic Katzung_Ch44_p0844-0856.indd 852 25/08/20 1:11 PM  CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins     853 anemia tends to be irreversible and can be fatal, although it may Adverse Effects respond to bone marrow transplantation or immunosuppressive The principal toxicity of linezolid is hematologic; the effects are therapy. Due to the severity of this reaction, a boxed warning has reversible and generally mild. Thrombocytopenia is the most been added to its US labeling. common manifestation (seen in approximately 3% of treatment Newborn infants lack an effective glucuronic acid conjuga- courses), particularly when the drug is administered for longer tion mechanism for the degradation and detoxification of chlor- than 2 weeks. Anemia and neutropenia also may occur, most com- amphenicol. Consequently, when infants are given dosages above monly in patients with a predisposition to or underlying bone 50 mg/kg/d, the drug may accumulate, resulting in the gray baby marrow suppression. Cases of optic and peripheral neuropathy syndrome, with vomiting, flaccidity, hypothermia, gray color, and lactic acidosis have been reported with prolonged courses of shock, and vascular collapse. To avoid this toxic effect, chloram- linezolid. These side effects are thought to be related to linezolid- phenicol should be used with caution in infants and the dosage induced inhibition of mitochondrial protein synthesis. There are limited to 50 mg/kg/d (or less during the first week of life) in full- case reports of serotonin syndrome (see Chapter 16) occurring term infants and 25 mg/kg/d in premature infants. when linezolid is coadministered with serotonergic drugs, most Chloramphenicol inhibits hepatic microsomal enzymes that frequently selective serotonin reuptake inhibitor antidepressants. metabolize several drugs. Half-lives of these drugs are prolonged, The FDA has issued a warning regarding the use of the drug with and the serum concentrations of phenytoin, tolbutamide, chlor- serotonergic agents. propamide, and warfarin are increased. 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, vancomy- OXAZOLIDINONES cin-resistant enterococci, streptococci, and gram-positive anaerobes. It has 91% oral bioavailability and is FDA-approved at a dose of MECHANISM OF ACTION & 200 mg orally or intravenously once daily for 6 days for the treatment ANTIMICROBIAL ACTIVITY of skin and soft tissue infection. Potential advantages over linezolid include increased potency against staphylococci and a longer half- Linezolid is a member of the oxazolidinone class of synthetic anti- life of 12 hours, allowing once-daily dosing. There is no need for microbials. It is active against gram-positive organisms including dose adjustment in renal or hepatic impairment. It may be associated staphylococci, streptococci, enterococci, gram-positive anaerobic with a decreased risk of bone marrow suppression; however, it has cocci, and gram-positive rods such as corynebacteria, Nocardia sp, not been studied over a prolonged duration of therapy. It is thought and L monocytogenes. It is primarily a bacteriostatic agent but is to have a lower risk of serotonergic toxicity, but concomitant use bactericidal against streptococci. It is also active against Mycobac- with serotonin reuptake inhibitors has not been formally evaluated. terium tuberculosis. Tedizolid is more highly protein-bound (70–90%) than linezolid Linezolid inhibits protein synthesis by preventing formation of the (31%). Plasma concentrations are a good indicator for tissue con- ribosome complex that initiates protein synthesis. Its unique binding centrations as it penetrates well into muscle, adipose, and pulmonary site, located on 23S ribosomal RNA of the 50S subunit, results in no tissues; there are no data regarding CSF penetration of tedizolid. cross-resistance with other drug classes. Resistance is caused by muta- tion of the linezolid binding site on 23S ribosomal RNA. PLEUROMUTILINS Pharmacokinetics Lefamulin is a novel antibacterial agent approved in 2019 for the Linezolid is 100% bioavailable after oral administration and has a treatment of pneumonia; it is the first systemic agent available in half-life of 4–6 hours. It is metabolized by oxidative metabolism, the pleuromutilin class for human use. The pleuromutilin class yielding two inactive metabolites. It is neither an inducer nor an was discovered in the 1950s, but previously it was used only in inhibitor of cytochrome P450 enzymes. Peak serum concentra- veterinary medicine. tions average 18 mcg/mL following a 600-mg oral dose; cerebro- spinal fluid (CSF) concentrations reach approximately 60–70% of the serum level. The recommended dosage for most indications is MECHANISM OF ACTION & 600 mg twice daily, either orally or intravenously. ANTIBACTERIAL ACTIVITY Lefamulin works by binding the 50S ribosome, thus inhibiting Clinical Uses bacterial protein synthesis. Its mechanism is unique in that it causes Linezolid is approved for vancomycin-resistant E faecium infec- the binding pocket to close around the drug molecule, preventing tions, health care–associated pneumonia, community-acquired bacterial transfer RNA from binding appropriately. It has bacteri- pneumonia, and both complicated and uncomplicated skin and cidal activity against organisms commonly seen in lower respira- soft tissue infections caused by susceptible gram-positive bacteria. tory tract infections such as Streptococcus pneumoniae, Haemophilus Off-label uses of linezolid include treatment of multidrug-resistant influenzae, and atypical pathogens such as Legionella pneumophila, tuberculosis and Nocardia infections. Mycoplasma pneumoniae, and Chlamydophila pneumoniae. It also has Katzung_Ch44_p0844-0856.indd 853 25/08/20 1:11 PM  854    SECTION VIII Chemotherapeutic Drugs in vitro activity against most aerobic gram-positive organisms, includ- state (at least 1 hour before or 2 hours after a meal). It is 95–97% ing S pyogenes, Staphylococcus aureus, and Enterococcus faecium. It may protein-bound and is excreted primarily through hepatic metabo- also have activity against certain organisms causing sexually transmit- lism via the CYP3A4 enzyme pathway. The elimination half-life ted infections, such as Mycoplasma genitalium, Neisseria gonorrhoeae, is about 8 hours, so the standard dose is administered twice daily; and Chlamydia trachomatis. Notably, lefamulin lacks activity against the dose may require adjustment for severe hepatic impairment. Enterococcus faecalis, Pseudomonas aeruginosa, Acinetobacter bauman- Common adverse effects seen in clinical trials included infusion- nii, and the Enterobacteriaceae group of gram-negative organisms. site reactions for the intravenous formulation and gastrointestinal disturbances, particularly nausea and diarrhea, for the oral formu- lation. Lefamulin should be avoided in pregnancy because animal Resistance studies show increased risk of congenital malformations. It has not Thus far, the risk for inducing bacterial resistance mutations with been studied in pregnant humans to date. lefamulin appears to be low, but resistance mutations have been observed in vitro. It is unclear how common clinical resistance will be, but some potential mechanisms for resistance include ribo- Clinical Use somal target site alteration and active efflux from the site of action. At the time of writing, lefamulin is approved only for the treatment of adult patients with community-acquired pneumonia, based on results of two randomized clinical trials in which lefamulin was Pharmacokinetics and Adverse Effects deemed noninferior to moxifloxacin. There is interest in its poten- Lefamulin is available as both intravenous and oral formulations. It tial use for other indications, such as skin and skin-structure infec- is 25% bioavailable, so a 600-mg oral dose is roughly equivalent to tions or sexually transmitted infections based on in vitro activity 150 mg given intravenously, with optimal absorption in an unfed and some success in phase 2 trials. SUMMARY Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins Mechanism of Pharmacokinetics, Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions TETRACYCLINES Tetracycline Prevents bacterial Bacteriostatic activity Infections caused by Oral mixed clearance (half-life 8 h) dosed every protein synthesis by against susceptible mycoplasma, chlamydiae, 6 h divalent cations impair oral absorption binding to the 30S bacteria rickettsiae, some spirochetes Toxicity: Gastrointestinal upset, hepatotoxicity, ribosomal subunit malaria H pylori acne 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: Oral and IV; longer half-life (16 h) so dosed twice daily; frequently causes reversible vestibular toxicity  Tigecycline: IV; dosed twice daily; 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  Eravacycline: IV; dosed twice daily; 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  Omadacycline: Oral and IV; dosed once daily after initial loading dose; oral absorption impeded by food, cations, must be administered on empty stomach; 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 but thought to be lower than with other new tetracyclines MACROLIDES Erythromycin Prevents bacterial Bacteriostatic activity Community-acquired Oral, IV hepatic clearance (half-life 1.5 h) protein synthesis by against susceptible pneumonia pertussis dosed every 6 h cytochrome P450 inhibitor binding to the 50S bacteria corynebacterial and Toxicity: Gastrointestinal upset, hepatotoxicity, ribosomal subunit chlamydial infections 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 LINCOSAMIDE Clindamycin Prevents bacterial Bacteriostatic activity Skin and soft tissue infections Oral, IV hepatic clearance (half-life 2.5 h) protein synthesis by against susceptible anaerobic infections dosed every 6–8 h Toxicity: Gastrointestinal binding to the 50S bacteria upset, colitis ribosomal subunit (continued) Katzung_Ch44_p0844-0856.indd 854 25/08/20 1:11 PM  CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins     855 Mechanism of Pharmacokinetics, Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions STREPTOGRAMINS  Quinupristin- Prevents bacterial Rapid bactericidal Infections caused by IV hepatic clearance dosed every 8–12 h dalfopristin protein synthesis by activity against most staphylococci or vancomycin- cytochrome P450 inhibitor Toxicity: Severe binding to the 50S susceptible bacteria resistant strains of infusion-related myalgias and arthralgias ribosomal subunit enterococci CHLORAMPHENICOL Prevents bacterial Bacteriostatic activity Use is rare in the developed IV hepatic clearance (half-life 2.5 h) dosage is protein synthesis by against susceptible world because of serious 50–100 mg/kg/d in four divided doses Toxicity: binding to the 50S bacteria toxicities Dose-related anemia, idiosyncratic aplastic ribosomal subunit anemia, gray baby syndrome OXAZOLIDINONES Linezolid Prevents bacterial Bacteriostatic activity Infections caused by Oral, IV hepatic clearance (half-life 6 h) dosed protein synthesis by against susceptible methicillin-resistant twice-daily Toxicity: Duration-dependent bone binding to the 23S bacteria staphylococci and marrow suppression, neuropathy, and optic ribosomal RNA of 50S vancomycin-resistant neuritis serotonin syndrome may occur when subunit enterococci coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors) Tedizolid: Oral and IV; longer half-life (12 h) so dosed once daily; increased efficacy versus staphylococci; approved for use in skin and soft tissue infections. PLEUROMUTILINS Lefamulin Prevents bacterial Bactericidal activity Community-acquired Oral, IV hepatic clearance (half-life 8 h) dosed protein synthesis by against most pneumonia twice daily cytochrome P450 3A4 substrate binding to the 50S susceptible bacteria; Toxicity: Infusion-related reactions and ribosomal subunit bacteriostatic against gastrointestinal disturbances some P R E P A R A T I O N S REFERENCES A V A I L A B L E Barrera CM et al: Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: A global, dou- ble-blind, multicenter, randomized, active-controlled, non-inferiority trial GENERIC NAME AVAILABLE AS (SOLITAIRE-ORAL). Lancet 2016;16:421. Chloramphenicol Generic, Chloromycetin Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol TETRACYCLINES Biol Rev 2001;65:232. Demeclocycline Generic, Declomycin De Vriese AS et al: Linezolid-induced inhibition of mitochondrial protein synthesis. Doxycycline Generic, Vibramycin, others Clin Infect Dis 2006;42:1111. Minocycline Generic, Minocin, others Dryden MS: Linezolid pharmacokinetics and pharmacodynamics in clinical treat- ment. J Antimicrob Chemother. 2011;66(Suppl 4):S7. Tetracycline Generic, others File Jr. TM et al: SOLITAIRE-IV: A randomized, double-blind, multicenter study Tigecycline Tygacil comparing the efficacy and safety of intravenous-to-oral solithromycin to Eravacycline Xerava intravenous-to-oral moxifloxacin for treatment of community-acquired bac- Omadacycline Nuzyra terial pneumonia. Clin Infect Dis 2016;63:1007. MACROLIDES Hancock RE: Mechanisms of action of newer antibiotics for gram-positive patho- gens. Lancet Infect Dis 2005;5:209. Azithromycin Generic, Zithromax Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature of Clarithromycin Generic, Biaxin the resistance elements and their clinical implications. Clin Infect Dis Erythromycin Generic, others 2002;34:482. LINCOMYCIN Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu- losis. N Engl J Med 2012;367:1508. Clindamycin Generic, Cleocin Livermore DM: Tigecycline: What is it, and where should it be used? J Antimicrob STREPTOGRAMINS Chemother 2005;56:611. Quinupristin and dalfopristin Synercid Moran GJ et al: Methicillin-resistant S aureus infections among patients in the OXAZOLIDINONES emergency department. N Engl J Med 2006;355:666. Linezolid Generic, Zyvox 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- Tedizolid Sivextro blind, phase 3, non-inferiority trial. Lancet 2014;14:696. PLEUROMUTILIN O’Riordan W et al: Omadacycline for acute bacterial skin and skin structure infec- Lefamulin Xenleta tions. N Engl J Med 2019;380:528. Katzung_Ch44_p0844-0856.indd 855 25/08/20 1:11 PM