Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 46–2 Actions of sulfonamides and trimethoprim. CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 835 synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure. Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical. Oral absorbable sulfonamides are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Protein binding varies from 20% to over 90%. Therapeutic concentrations are in the range of 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours after oral administration.


Pharmacology_Katzung

Pharmacology_Katzung. A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactive metabolites are then excreted in the urine, mainly by glomerular filtration. The dosage of sulfonamides must be reduced in patients with significant renal failure. Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. The fixed-drug combination of trimethoprimsulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, and nocardiosis. A. Oral Absorbable Agents Sulfamethoxazole is a commonly used absorbable agent; however, in the USA, it is available only as the fixed-dosed combination trimethoprim-sulfamethoxazole. Typical dosing and indications are discussed below.


Pharmacology_Katzung

Pharmacology_Katzung. Administration of sulfadiazine with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Using sulfadiazine plus pyrimethamine, a potent inhibitor of dihydrofolate reductase, is synergistic because these drugs block sequential steps in the folate synthesis pathway (Figure 46–2). However, since 2015, there have been challenges with manufacturing, supply, and pricing of pyrimethamine in the USA. In some cases, clinicians have obtained a compounded product through specialty pharmacies or prescribed alternate agents, such as trimethoprimsulfamethoxazole. Sulfadoxine is a long-acting sulfonamide that is coformulated with pyrimethamine (Fansidar). This combination is no longer commercially available in the USA but may be found in other parts of the world where it is used as a second-line treatment for malaria (see Chapter 52). B. Oral Nonabsorbable Agents


Pharmacology_Katzung

Pharmacology_Katzung. B. Oral Nonabsorbable Agents Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease (see Chapter 62). C. Topical Agents Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds.


Pharmacology_Katzung

Pharmacology_Katzung. Historically, drugs containing a sulfonamide moiety, including antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypoglycemic agents, were considered to be cross-allergenic. However, more recent evidence suggests cross-reactivity is uncommon and many patients who are allergic to nonantibiotic sulfonamides tolerate sulfonamide antibiotics. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (<1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and psychosis. A. Urinary Tract Disturbances


Pharmacology_Katzung

Pharmacology_Katzung. A. Urinary Tract Disturbances Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine and sulfamethoxazole are relatively insoluble in acidic urine and can cause crystalluria, particularly when given in large doses or if fluid intake is poor. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to increase urine flow. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis. B. Hematopoietic Disturbances Sulfonamides can cause hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions. Sulfonamides may provoke hemolytic reactions in patients with glucose-6-phosphate dehydrogenase deficiency. Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46–2). Trimethoprim is a much less efficient inhibitor of mammalian dihydrofolic acid reductase. The combination of trimethoprim and sulfamethoxazole is often bactericidal, compared with the bacteriostatic activity of a sulfonamide alone.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding. Resistance can emerge by mutation, although more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases. These resistant enzymes may be coded within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance among numerous bacterial species. Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, which has a similar half-life. Trimethoprimsulfamethoxazole can also be given intravenously. Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid.


Pharmacology_Katzung

Pharmacology_Katzung. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro. About 30–50% of the sulfonamide and 50–60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours. The dose should be reduced by half for patients with creatinine clearances of 15–30 mL/min. Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs. A. Oral Trimethoprim


Pharmacology_Katzung

Pharmacology_Katzung. A. Oral Trimethoprim Trimethoprim can be given alone (100 mg twice daily) in acute urinary tract infections. Many community-acquired organisms are susceptible to the high concentrations that are found in the urine (200–600 mcg/mL). B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)


Pharmacology_Katzung

Pharmacology_Katzung. B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ) A combination of trimethoprim-sulfamethoxazole is effective treatment for a wide variety of infections including P jiroveci pneumonia, urinary tract infections, prostatitis, and some infections caused by susceptible strains of Shigella, Salmonella, and nontuberculous mycobacteria. It is active against most Staphylococcus aureus strains, both methicillin-susceptible and methicillin-resistant, and against respiratory tract pathogens such as Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but not Mycoplasma pneumoniae). However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empiric therapy of upper urinary tract infections or pneumonia. Trimethoprim-sulfamethoxazole is commonly used for the treatment of uncomplicated skin and soft tissue infections.


Pharmacology_Katzung

Pharmacology_Katzung. One double-strength tablet (each tablet contains trimethoprim 160 mg plus sulfamethoxazole 800 mg) given every 12 hours is effective treatment for urinary tract infections, prostatitis, uncomplicated skin and soft tissue infections, and infections caused by susceptible strains of Shigella and Salmonella. Bone and joint infections caused by S. aureus can be effectively treated, typically at doses of 8–10 mg/kg per day of the trimethoprim component. One single-strength tablet (containing trimethoprim 80 mg plus sulfamethoxazole 400 mg) given three times weekly may serve as prophylaxis in recurrent urinary tract infections of some women. The dosage for children treated for shigellosis, urinary tract infection, or otitis media is trimethoprim 8 mg/kg per day and sulfamethoxazole 40 mg/kg per day divided every 12 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Infections with P jiroveci and some other pathogens, such as Nocardia or Stenotrophomonas maltophilia, can be treated with high doses of the either the oral or intravenous combination (dosed on the basis of the trimethoprim component at 15–20 mg/kg/d). P jiroveci can be prevented in immunosuppressed patients by a number of low dose regimens such as one double-strength tablet daily or three times weekly. C. Intravenous Trimethoprim-Sulfamethoxazole


Pharmacology_Katzung

Pharmacology_Katzung. C. Intravenous Trimethoprim-Sulfamethoxazole A solution of the mixture containing 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% dextrose in water can be administered by intravenous infusion over 60–90 minutes. It is the agent of choice for moderately severe to severe pneumocystis pneumonia. It has been used for Gram-negative bacterial sepsis, but has largely been replaced by extended spectrum β-lactams and fluoroquinolones. It may be an effective alternative for infections caused by some multidrugresistant species such as Enterobacter and Serratia; shigellosis; or typhoid. It is the preferred alternate therapy for serious Listeria infections in patients unable to tolerate ampicillin. The dosage is 10–20 mg/kg/d of the trimethoprim component. D. Oral Pyrimethamine with Sulfonamide


Pharmacology_Katzung

Pharmacology_Katzung. D. Oral Pyrimethamine with Sulfonamide Pyrimethamine and sulfadiazine are used in the treatment of toxoplasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily, with pyrimethamine given as a 200-mg loading dose followed by a once-daily dose of 50–75 mg. Leucovorin, also known as folinic acid, 10 mg orally each day, should be administered to minimize bone marrow suppression seen with pyrimethamine. Some clinicians recommend using trimethoprim-sulfamethoxazole as an alternate option if pyrimethamine is not available. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used (see Chapter 52); however, it is no longer commercially available in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur. Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia. Trimethoprim inhibits secretion of creatinine at the distal renal tubule, resulting in mild elevation of serum creatinine without impairment of glomerular filtration rate. This nontoxic effect is important to distinguish from true nephrotoxicity that may be caused by sulfonamides.


Pharmacology_Katzung

Pharmacology_Katzung. The clinically relevant quinolones are synthetic fluorinated analogs of nalidixic acid (Figure 46–3). They are active against a variety of Gram-positive and Gram-negative bacteria. Mechanism of Action Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. Earlier quinolones such as nalidixic acid did not achieve systemic antibacterial levels and were useful only in the treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others; Figure 46–3 and Table 46–1) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.


Pharmacology_Katzung

Pharmacology_Katzung. Fluoroquinolones were originally developed because of their excellent activity against Gram-negative aerobic bacteria; the earliest agents had limited activity against Gram-positive organisms. Subsequent members of the group have improved activity against Gram-positive cocci. The relative activity against Gram-negative FIGURE 46–3 Structures of nalidixic acid and some fluoroquinolones.


Pharmacology_Katzung

Pharmacology_Katzung. versus Gram-positive species is useful for differentiating these agents. Norfloxacin, which is no longer available in the USA, is the least active of the fluoroquinolones against both Gram-negative and Gram-positive organisms, with minimum inhibitory concentrations (MICs) fourfold to eightfold higher than those of ciprofloxacin. Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin comprise a second group of similar agents possessing excellent Gram-negative activity and moderate to good activity against Gram-positive bacteria. Ciprofloxacin and levofloxacin are the two agents from this group that are used systemically in the USA. MICs for Gram-negative cocci and bacilli, including Enterobacter sp, P aeruginosa, Neisseria meningitidis, Haemophilus sp, and Campylobacter jejuni, are 1–2 mcg/mL and often less. Methicillin-susceptible strains of S aureus are generally susceptible to these fluoroquinolones, but methicillin-resistant strains of staphylococci are


Pharmacology_Katzung

Pharmacology_Katzung. jejuni, are 1–2 mcg/mL and often less. Methicillin-susceptible strains of S aureus are generally susceptible to these fluoroquinolones, but methicillin-resistant strains of staphylococci are often resistant. When treating staphylococcal infections, fluoroquinolones are typically used in combination with a second active agent, such as rifampin, to prevent emergence of resistance while on therapy. Enterococci tend to be less susceptible than staphylococci, limiting the efficacy of fluoroquinolones in infections caused by these organisms. Ciprofloxacin is the most active agent of this group against Gram-negative organisms, particularly P aeruginosa. Levofloxacin, the l-isomer of ofloxacin, has superior activity against Gram-positive organisms, especially Streptococcus pneumoniae.


Pharmacology_Katzung

Pharmacology_Katzung. Gatifloxacin, gemifloxacin, and moxifloxacin make up a third group of fluoroquinolones with improved activity against Gram-positive organisms, particularly S pneumoniae and some staphylococci. Gemifloxacin is active in vitro against ciprofloxacin-resistant strains of S pneumoniae, but in vivo efficacy is unproven. Although MICs of these agents for staphylococci are lower than those of ciprofloxacin (and the other compounds mentioned in the paragraph above), it is not known whether the enhanced activity is sufficient to permit use of these agents for treatment of infections caused by TABLE 46–1 Pharmacokinetic properties of some fluoroquinolones.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 46–1 Pharmacokinetic properties of some fluoroquinolones. Norfloxacin 3.5–5 80 1.5 400 twice daily Renal Ofloxacin 5–7 95 2.9 400 twice daily Renal ciprofloxacin-resistant strains. In general, none of these agents is as active as ciprofloxacin against Gram-negative organisms. Fluoroquinolones also are active against agents of atypical pneumonia (eg, mycoplasmas and chlamydiae) and against intracellular pathogens such as Legionella and some mycobacteria, including Mycobacterium tuberculosis and Mycobacterium avium complex. Moxifloxacin has modest activity against anaerobic bacteria but lacks appreciable activity against P aeruginosa. Because of toxicity when systemically administered, gatifloxacin is available only as an ophthalmic solution in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. During fluoroquinolone therapy, resistant organisms emerge in about 1 of every 107–109 organisms, especially among staphylococci, P aeruginosa, and Serratia marcescens. Emerging resistance is due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism. However, additional mechanisms seem to account for the relative ease with which resistance develops in highly susceptible bacteria. Two types of plasmid-mediated resistance have been described. The first type utilizes Qnr proteins, which protect DNA gyrase from the fluoroquinolones. The second is a variant of an aminoglycoside acetyltransferase capable of modifying ciprofloxacin. Both mechanisms confer low-level resistance that may facilitate the point mutations that confer high-level resistance and also may be associated with resistance to other antibacterial drug classes. Resistance to one fluoroquinolone, particularly if it is of high level, generally


Pharmacology_Katzung

Pharmacology_Katzung. that confer high-level resistance and also may be associated with resistance to other antibacterial drug classes. Resistance to one fluoroquinolone, particularly if it is of high level, generally confers cross-resistance to all other members of this class.


Pharmacology_Katzung

Pharmacology_Katzung. After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80–95%) and distributed widely in body fluids and tissues (Table 46–1). Serum half-lives range from 3 to 10 hours. The relatively long half-lives of levofloxacin, gemifloxacin, and moxifloxacin permit once-daily dosing. Oral absorption is impaired by divalent and trivalent cations, including those in antacids. Therefore, oral fluoroquinolones should be taken 2 hours before or 4 hours after any products containing these cations. Serum concentrations of intravenously administered drug are similar to those of orally administered drug. Most fluoroquinolones, moxifloxacin being an important exception, are eliminated by renal mechanisms, either tubular secretion or glomerular filtration (Table 46–1). Dosage adjustment is required for patients with creatinine clearances less than 50 mL/min, the exact adjustment depending on the degree of renal impairment and the specific fluoroquinolone being used. Dosage


Pharmacology_Katzung

Pharmacology_Katzung. is required for patients with creatinine clearances less than 50 mL/min, the exact adjustment depending on the degree of renal impairment and the specific fluoroquinolone being used. Dosage adjustment for renal failure is not necessary for moxifloxacin since it is metabolized in the liver; it should be used with caution in patients with hepatic failure.


Pharmacology_Katzung

Pharmacology_Katzung. Fluoroquinolones (other than moxifloxacin, which achieves relatively low urinary levels) are effective in urinary tract infections caused by many organisms, including P aeruginosa. These CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 839 agents are also effective for bacterial diarrhea caused by Shigella, Salmonella, toxigenic E coli, and Campylobacter. Fluoroquinolones (except norfloxacin, which does not achieve adequate systemic concentrations) are used in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections, including those caused by multidrug-resistant organisms such as Pseudomonas and Enterobacter. Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax; the newer fluoroquinolones are active in vitro, and levofloxacin is also approved by the U.S. Food and Drug Administration (FDA) for prophylaxis.


Pharmacology_Katzung

Pharmacology_Katzung. U.S. Food and Drug Administration (FDA) for prophylaxis. Ciprofloxacin and levofloxacin are no longer recommended for the treatment of gonococcal infection in the USA, as resistance is now common; however, gemifloxacin may be used in combination with azithromycin as an alternate to ceftriaxone. Levofloxacin and ofloxacin are recommended by the Centers for Disease Control and Prevention as alternative treatment options for chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used as part of a treatment regimen for tuberculosis and non-tuberculous mycobacterial infections. These agents are suitable for eradication of meningococci from carriers and for prophylaxis of bacterial infection in neutropenic cancer patients.


Pharmacology_Katzung

Pharmacology_Katzung. With their enhanced Gram-positive activity and activity against atypical pneumonia agents (chlamydiae, Mycoplasma, and Legionella), levofloxacin, gemifloxacin, and moxifloxacin— so-called respiratory fluoroquinolones—are effective for treatment of lower respiratory tract infections.


Pharmacology_Katzung

Pharmacology_Katzung. Fluoroquinolones are generally well tolerated. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop. Photosensitivity has been reported with lomefloxacin and pefloxacin. Prolongation of the QTc interval may occur with gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin; these drugs should be avoided or used with caution in patients with known QTc interval prolongation or uncorrected hypokalemia; in those receiving class 1A (eg, quinidine or procainamide) or class 3 antiarrhythmic agents (sotalol, ibutilide, amiodarone); and in patients receiving other agents known to increase the QTc interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin has been associated with hyperglycemia in diabetic patients and with hypoglycemia in patients also receiving oral hypoglycemic agents. Because of these serious effects (including some fatalities), gatifloxacin was withdrawn from


Pharmacology_Katzung

Pharmacology_Katzung. in diabetic patients and with hypoglycemia in patients also receiving oral hypoglycemic agents. Because of these serious effects (including some fatalities), gatifloxacin was withdrawn from sale in the United States in 2006.


Pharmacology_Katzung

Pharmacology_Katzung. In animal models, fluoroquinolones may damage growing cartilage and cause an arthropathy. Thus, these drugs have not been recommended as first-line agents for patients under 18 years of age. However, there is a growing consensus that fluoroquinolones may be used in children if needed (eg, for treatment of pseudomonal infections in patients with cystic fibrosis). Tendinitis, a complication in adults, can be serious because of the risk of tendon rupture. Risk factors for tendinitis include advanced age, renal insufficiency, and concurrent steroid use. Fluoroquinolones should be avoided during pregnancy in the absence of specific data documenting their safety. Oral or intravenously administered fluoroquinolones have also been associated with peripheral neuropathy. Neuropathy can occur at any time during treatment with fluoroquinolones and may persist for months to years after the drug is stopped. In some cases it may be permanent. Although many potential adverse effects are uncommon, the


Pharmacology_Katzung

Pharmacology_Katzung. time during treatment with fluoroquinolones and may persist for months to years after the drug is stopped. In some cases it may be permanent. Although many potential adverse effects are uncommon, the FDA called for updated warnings for all fluoroquinolones in 2016, stating that these agents should be reserved for patients who do not have alternative options, particularly in less severe infections such as upper respiratory infections or uncomplicated cystitis.


Pharmacology_Katzung

Pharmacology_Katzung. Sulfadiazine: Oral; first-line therapy for toxoplasmosis when combined with pyrimethamine Trimethoprim: Oral; used alone only for lower urinary tract infections; may be safely prescribed to patients with sulfonamide allergy Pyrimethamine: Oral; first-line therapy for toxoplasmosis when combined with sulfadiazine; coadminister with leucovorin to limit bone marrow toxicity Pyrimethamine-sulfadoxine: Oral; second-line malaria treatment Oral, IV • mixed clearance (half-life 4 h) • dosed every 12 h • divalent and trivalent cations impair oral absorption • Toxicity: Gastrointestinal upset, neurotoxicity, tendonitis Levofloxacin: Oral, IV; L-isomer of ofloxacin; once-daily dosing; renal clearance; “respiratory” fluoroquinolone with improved activity versus pneumococcus


Pharmacology_Katzung

Pharmacology_Katzung. Levofloxacin: Oral, IV; L-isomer of ofloxacin; once-daily dosing; renal clearance; “respiratory” fluoroquinolone with improved activity versus pneumococcus Moxifloxacin: Oral, IV; “respiratory” fluoroquinolone; once-daily dosing; improved activity versus anaerobes and M tuberculosis; hepatic clearance results in lower urinary levels so use in urinary tract infections is not recommended Gemifloxacin: Oral; “respiratory” fluoroquinolone


Pharmacology_Katzung

Pharmacology_Katzung. Gemifloxacin: Oral; “respiratory” fluoroquinolone GENERIC NAME AVAILABLE AS GENERAL-PURPOSE SULFONAMIDES Sulfadiazine Generic SULFONAMIDES FOR SPECIAL APPLICATIONS Mafenide Generic, Sulfamylon Silver sulfadiazine Generic, Silvadene Sulfacetamide sodium (ophthalmic)Generic TRIMETHOPRIM TrimethoprimGeneric, Proloprim, TrimpexTrimethoprim-sulfamethoxazole(co-trimoxazole,TMP-SMZ)Generic, Bactrim, Septra, others GENERIC NAME AVAILABLE AS PYRIMETHAMINE Pyrimethamine Daraprim Pyrimethamine-sulfadoxine Generic, Fansidar QUINOLONES & FLUOROQUINOLONES Ciprofloxacin Generic, Cipro, Cipro I.V., Ciloxan (ophthalmic)Gemifloxacin Factive Levofloxacin Levaquin,Quixin(ophthalmic)Moxifloxacin Generic, Avelox, others Norfloxacin Noroxin Ofloxacin Generic, Floxin, Ocuflox (ophthalmic),FloxinOtic(otic)PREP AR A TIONS A V AIL ABLE Briasoulis A et al: QT prolongation and torsade de pointes induced by fluoroquinolones: Infrequent side effects from commonly used medications. Cardiology 2011;120:103.


Pharmacology_Katzung

Pharmacology_Katzung. Briasoulis A et al: QT prolongation and torsade de pointes induced by fluoroquinolones: Infrequent side effects from commonly used medications. Cardiology 2011;120:103. Cohen JS: Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother 2001;35:1540. Davidson R et al: Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747. Gupta K et al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women. Clin Infect Dis 2011;52:103. Keating GM, Scott LJ: Moxifloxacin: A review of its use in the management of bacterial infections. Drugs 2004;64:2347. Mandell LA et al: Infectious Disease Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia. Clin Infect Dis 2007;44:S27.


Pharmacology_Katzung

Pharmacology_Katzung. Mandell LA et al: Infectious Disease Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia. Clin Infect Dis 2007;44:S27. Mwenya DM et al: Impact of cotrimoxazole on carriage and antibiotic resistance of Streptococcus pneumoniae and Haemophilus influenzae in HIV-infected children in Zambia. Antimicrob Agents Chemother 2010;54:3756. Nouira S et al: Standard versus newer antibacterial agents in the treatment of severe acute exacerbation of chronic obstructive pulmonary disease: A randomized trial of trimethoprim-sulfamethoxazole versus ciprofloxacin. Clin Infect Dis 2010;51:143. Rodriguez-Martinez JM et al: Plasmid-mediated quinolone resistance: An update. J Infect Chemother 2011;17:149. Scheld WM: Maintaining fluoroquinolone class efficacy: Review of influencing factors. Emerg Infect Dis 2003;9:1.


Pharmacology_Katzung

Pharmacology_Katzung. Scheld WM: Maintaining fluoroquinolone class efficacy: Review of influencing factors. Emerg Infect Dis 2003;9:1. Schmitz GR et al: Randomized controlled trial of trimethoprim-sulfamethoxazole for uncomplicated skin abscesses in patients at risk for community-associated methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med 2010;56:283. Strom BL et al: Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628. Talan DA et al: Prevalence of and risk factor analysis of trimethoprim-sulfamethoxazoleand fluoroquinolone-resistant E. coli infection among emergency department patients with pyelonephritis. Clin Infect Dis 2008;47:1150. Workowski KA et al: Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Recomm Rep 2015;64(RR-03):1. Ziganshina LE et al: Fluoroquinolones for treating tuberculosis (presumed drug sensitive). Cochrane Database Syst Rev 2013;(6):CD004795.


Pharmacology_Katzung

Pharmacology_Katzung. Ziganshina LE et al: Fluoroquinolones for treating tuberculosis (presumed drug sensitive). Cochrane Database Syst Rev 2013;(6):CD004795. A fluoroquinolone that achieves good urinary and systemic levels (ciprofloxacin or levofloxacin) would be a reasonable choice for empiric treatment of this patient’s complicated urinary tract infection. Given the possibility of a fluoroqui-nolone-resistant organism, one dose of a parenteral agent such as ceftriaxone (given IV or IM) would be reason-able pending culture results confirming fluoroquinolone susceptibility. Her recent exposure to multiple courses of trimethoprim-sulfamethoxazole increases her chances of having a urinary tract infection with an isolate that is resis-tant to this antibiotic. The patient should be told to take the oral fluoroquinolone 2 hours before or 4 hours after her calcium supplement, as divalent and trivalent cations can significantly impair the absorption of oral fluoroquinolones.


Pharmacology_Katzung

Pharmacology_Katzung. Camille E. Beauduy, PharmD, & Lisa G. Winston, MD* A 60-year-old man presents to the emergency department with a 2-month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough. He is currently living with friends and has been intermittently homeless, spending time in shelters. He reports drinking about 6 beers per day. In the emergency department, a chest x-ray shows a right apical infiltrate. Given the high suspicion for pulmonary tuberculosis, the patient is placed in respiratory isolation. His first sputum smear shows many acid-fast bacilli, and an HIV test returns with a positive result. What drugs should be started for treatment of presumptive pulmonary tubercu-losis? Does the patient have a heightened risk of developing medication toxicity? If so, which medication(s) would be likely to cause toxicity?


Pharmacology_Katzung

Pharmacology_Katzung. Mycobacteria are intrinsically resistant to most antibiotics. Because they grow more slowly than other bacteria, antibiotics that are most active against rapidly growing cells are relatively ineffective. Mycobacterial cells can also be dormant and, thus, resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Finally, mycobacteria are notorious for their ability to develop resistance. Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are


Pharmacology_Katzung

Pharmacology_Katzung. is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are described in this chapter.


Pharmacology_Katzung

Pharmacology_Katzung. Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide, and ethambutol are the traditional first-line agents for treatment of tuberculosis (Table 47–1). Isoniazid and rifampin are the most * The authors thank Henry F. Chambers, MD and Daniel H. Deck, PharmD for their contributions to previous editions.


Pharmacology_Katzung

Pharmacology_Katzung. active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis caused by susceptible strains. An initial intensive phase of treatment is recommended for the first 2 months due to the prevalence of resistant strains. The addition of pyrazinamide during this intensive phase allows the total duration of therapy to be reduced to 6 months without loss of efficacy. In practice, therapy is usually initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility of the clinical isolate has been determined. In susceptible isolates, the continuation phase consists of an additional 4 months with isoniazid and rifampin (Table 47–2). Neither ethambutol nor other drugs such as streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if another drug is used), but the fourth drug provides additional coverage if the isolate proves to be


Pharmacology_Katzung

Pharmacology_Katzung. to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if another drug is used), but the fourth drug provides additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. If therapy is initiated after the isolate is known to be susceptible to isoniazid and rifampin, ethambutol does not need to be added. The prevalence of isoniazid resistance among clinical isolates in the USA is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (which is termed multidrug resistance) ranged from 1 to 1.6% from the years 2000 to 2013 in the USA. Multidrug resistance is much more prevalent in many other parts of the world. Resistance to rifampin alone is rare.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 47–1 Antimicrobials used in the treatment of tuberculosis. 1Assuming normal renal function. 2150 mg/d if used concurrently with a protease inhibitor or cobicistat; 600 mg/d with efavirenz. 3No longer recommended, but may be considered in selected cases if HIV-uninfected without cavitation on chest radiograph. Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is a small molecule (molecular weight 137) that is freely soluble in water. The structural similarity to pyridoxine is shown below. In vitro, isoniazid inhibits most tubercle bacilli at a concentration of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against nontuberculous mycobacteria. Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms. Mechanism of Action & Basis of Resistance


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action & Basis of Resistance Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis. Resistance to isoniazid is associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase; mutation or deletion of the katG gene; promoter mutations resulting in overexpression of ahpC, a gene involved in protection of the cell from oxidative stress; and mutations in kasA. Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance and often are not cross-resistant to ethionamide.


Pharmacology_Katzung

Pharmacology_Katzung. Drug-resistant mutants are normally present in susceptible mycobacterial populations at about 1 bacillus in 106. Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant mutants are readily selected if isoniazid or any other drug is given as a single agent. The use of two independently acting drugs in combination is much more effective. The probability that a bacillus is initially resistant to both drugs is approximately 1 in 106 × 106, or 1 in 1012, several orders of magnitude greater than the number of infecting organisms. Thus, at least two (or more in certain cases) active agents should always be used to treat active tuberculosis to prevent emergence of resistance during therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Isoniazid is readily absorbed from the gastrointestinal tract, optimally on an empty stomach; peak concentrations may be decreased by up to 50% when taken with a fatty meal. A 300 mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3–5 mcg/mL within 1–2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined (see Chapter 4). The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption. Isoniazid metabolites and a small amount of unchanged drug are excreted in the urine. The dosage need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe TABLE 47–2 Recommended treatment for drug-susceptible tuberculosis.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 47–2 Recommended treatment for drug-susceptible tuberculosis. 1Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive treatment phase. 2May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen. DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin. preexisting hepatic insufficiency and should be guided by serum concentrations if a reduction in dose is contemplated. Isoniazid inhibits several cytochrome P450 enzymes, leading to increased concentrations of such medications as phenytoin, carbamazepine, and benzodiazepines. However, when used in combination with rifampin, a potent CYP enzyme inducer, the concentrations of these medications are usually decreased.


Pharmacology_Katzung

Pharmacology_Katzung. The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15-mg/kg dose, or 900 mg, may be used in a twice to three times-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage. Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly, and the duration is usually 9 months. The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration. A. Immunologic Reactions Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.


Pharmacology_Katzung

Pharmacology_Katzung. A. Immunologic Reactions Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported. B. Direct Toxicity


Pharmacology_Katzung

Pharmacology_Katzung. B. Direct Toxicity Isoniazid-induced hepatitis is the most common major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal), which do not require cessation of the drug and which are seen in 10–20% of patients, who usually are asymptomatic. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those age 21–35, 1.2% of those age 36–50, and 2.3% for those age 50 and above. The risk of hepatitis is greater in individuals with alcohol dependence and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Peripheral neuropathy is observed in 10–20% of patients given dosages greater than 5 mg/kg/d, but it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, ataxia, and seizures. These effects may also respond to pyridoxine. Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort.


Pharmacology_Katzung

Pharmacology_Katzung. Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort. Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Amycolatopsis rifamycinica, formerly named Streptomyces mediterranei. It is active in vitro against Gram-positive organisms, some Gram-negative organisms, such as Neisseria and Haemophilus species, mycobacteria, and chlamydiae. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 106 organisms and are rapidly selected out if rifampin is used as a single drug, especially in a patient with active infection. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine. Mechanism of Action, Resistance, & Pharmacokinetics


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action, Resistance, & Pharmacokinetics Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the β subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and penetrates into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.


Pharmacology_Katzung

Pharmacology_Katzung. Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount excreted in the urine. Dosage adjustment for renal or hepatic insufficiency is not necessary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin is distributed widely in body fluids and tissues. The drug is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.


Pharmacology_Katzung

Pharmacology_Katzung. Rifampin strongly induces most cytochrome P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors or integrase strand transfer inhibitors, contraceptives, and a host of others (see Chapters 4 and 66). Co-administration of rifampin results in significantly lower serum levels of these drugs. A. Mycobacterial Infections


Pharmacology_Katzung

Pharmacology_Katzung. A. Mycobacterial Infections Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin is given twice weekly. Rifampin, 600 mg daily or twice weekly for 6 months, also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid for patients with latent tuberculosis who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain. B. Other Indications


Pharmacology_Katzung

Pharmacology_Katzung. B. Other Indications Rifampin has other uses in bacterial infections. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg (maximum 600 mg) once daily for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is sometimes used to eradicate staphylococcal carriage. Rifampin combination therapy is also used for treatment of serious staphylococcal infections such as osteomyelitis, prosthetic joint infections, and prosthetic valve endocarditis.


Pharmacology_Katzung

Pharmacology_Katzung. Rifampin imparts a harmless orange color to urine, sweat, and tears (soft contact lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. Rifampin may cause cholestatic jaundice and occasionally hepatitis, and it commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin may cause a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia. Its use has been associated with acute tubular necrosis. Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro-isomer of the structure shown below, dispensed as the dihydrochloride salt. Mechanism of Action & Clinical Uses


Pharmacology_Katzung

Pharmacology_Katzung. Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro-isomer of the structure shown below, dispensed as the dihydrochloride salt. Mechanism of Action & Clinical Uses Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene. Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1–5 mcg/mL.


Pharmacology_Katzung

Pharmacology_Katzung. Ethambutol is well absorbed from the gut. After ingestion of 25 mg/kg, a blood level peak of 2–5 mcg/mL is reached in 2–4 hours. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced to three times weekly if creatinine clearance is less than 30 mL/min. Ethambutol crosses the blood-brain barrier only when the meninges are inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4% to 64% of serum levels in the setting of meningeal inflammation.


Pharmacology_Katzung

Pharmacology_Katzung. As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs. Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose in combination with isoniazid, rifampin, and pyrazinamide during the initial intensive phase of active tuberculosis treatment. The higher dose may be used for treatment of tuberculous meningitis. Higher doses have been used with intermittent dosing regimens for directly observed therapy; for example, 25–30 mg/kg three times weekly or 50 mg/kg administered twice weekly. Ethambutol is also used in combination with other agents for the treatment of nontuberculous mycobacterial infections, such as Mycobacterium avium complex (MAC) or M. kansasii; the typical dose for these infections is 15 mg/kg once daily.


Pharmacology_Katzung

Pharmacology_Katzung. Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness. This dose-related adverse effect is more likely to occur at dosages of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances occur in approximately 2% of patients, typically after at least one month of treatment. Experts recommend baseline and monthly visual acuity and color discrimination testing, with particular attention to patients on higher doses or with impaired renal function. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrazinamide (PZA) is a relative of nicotinamide, and it is used only for treatment of tuberculosis. It is stable and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of approximately 20 mcg/mL. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes. Mechanism of Action & Clinical Uses Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by mycobacterial pyrazinamidase, which is encoded by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of PZA to its active form.


Pharmacology_Katzung

Pharmacology_Katzung. Serum concentrations of 30–50 mcg/mL at 1–2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8–11 hours. The parent compound is metabolized by the liver, but metabolites are renally cleared; therefore, PZA should be administered at 25–35 mg/kg three times weekly (not daily) in hemodialysis patients and those in whom the creatinine clearance is less than 30 mL/min. In patients with normal renal function, a dose of 30–50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6-month) regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse. Tubercle bacilli develop resistance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs. Major adverse effects of PZA include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy if patients are asymptomatic.


Pharmacology_Katzung

Pharmacology_Katzung. The alternative drugs listed below are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; and (3) in case of serious treatment-limiting adverse drug reactions. Expert guidance is desirable in dealing with the toxic effects of these second-line drugs. For many drugs listed in the following text, the dosage, emergence of resistance, and long-term toxicity have not been fully established.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of action and other pharmacologic features of streptomycin, an aminoglycoside, are discussed in Chapter 45. The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dosage is 15 mg/kg two or three times per week. Most tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL, in vitro. Nontuberculous species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10–100 mcg/mL. Resistance may be due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein or the rrs gene encoding 16S ribosomal RNA, which alters the ribosomal binding site.


Pharmacology_Katzung

Pharmacology_Katzung. Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. The drug crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges. Streptomycin sulfate is used when an injectable drug is needed or desirable and in the treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20–40 mg/kg/d for children, not to exceed 1 g) for several weeks, followed by 15 mg/kg two or three times weekly for several months. Serum concentrations of approximately 40 mcg/mL are achieved 30–60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given in combination to prevent emergence of resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common adverse effects and may be permanent. Toxicity is dose-related, and the risk is increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to renal function (see Chapter 45). Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible. Ethionamide is chemically related to isoniazid and similarly blocks the synthesis of mycolic acids. It is poorly water soluble and available only for oral use. It is metabolized by the liver. Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 mcg/mL. Serum concentrations in plasma and tissues of approximately 1-5 mcg/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum.


Pharmacology_Katzung

Pharmacology_Katzung. Ethionamide is administered at an initial dose of 250 mg once daily, which is increased in 250 mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The 1-g/d dosage, though theoretically desirable, is poorly tolerated because of gastric irritation and neurologic symptoms, often limiting the tolerable daily dose to 500–750 mg. Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine. Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be low-level cross-resistance between isoniazid and ethionamide. Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 15 mg/kg intramuscularly results in peak serum levels of 35–45 mcg/mL 2 hours after a dose. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis.


Pharmacology_Katzung

Pharmacology_Katzung. Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis. Strains of M tuberculosis that are resistant to streptomycin usually are susceptible to capreomycin, though some data suggest cross-resistance with strains resistant to amikacin and kanamycin. Resistance to capreomycin, when it occurs, has been associated with rrs, eis, or tlyA gene mutations. Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may develop. Typical dosing of capreomycin is 15 mg/kg/day initially, which is then reduced to two or three times weekly after an initial response has been achieved with a daily dosing schedule. The intermittent dosing regimen may minimize risk of toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Cycloserine—a structural analog of d-alanine—inhibits cell wall synthesis, as discussed in Chapter 43. Concentrations of 15–20 mcg/mL inhibit many strains of M tuberculosis. The usual dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided oral doses. The drug is widely distributed to tissues, including the central nervous system. This drug is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. Alternatively, it may be reduced to 500 mg three times weekly.


Pharmacology_Katzung

Pharmacology_Katzung. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychoses. Pyridoxine, 100 mg or more per day, should be given with cycloserine because this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses leading to peak concentrations greater than 35 mcg/mL. Adverse effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–35 mcg/mL.


Pharmacology_Katzung

Pharmacology_Katzung. Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis. It is structurally similar to p-amino-benzoic acid (PABA) and is thought to have a similar mechanism of action to the sulfonamides (see Chapter 46). In the USA, PAS is commercially available as a 4-g packet of delayed-release granules. In order to protect the integrity of the delayed-release coating, the granules must be administered sprinkled over applesauce or yogurt, or swirled in fruit juice and swallowed whole.


Pharmacology_Katzung

Pharmacology_Katzung. Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 mcg/mL. The granule formulation of aminosalicylic acid results in improved absorption from the gastrointestinal tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children, administered in two or three divided doses. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid. Aminosalicylic acid is rapidly excreted in the urine, in part as active PAS and in part as the acetylated compound and other metabolic products. To avoid accumulation in renal impairment, the maximum dose is 4 g twice daily when creatinine clearance is less than 30 mL/min. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.


Pharmacology_Katzung

Pharmacology_Katzung. Aminosalicylic acid is used infrequently in the USA because other oral drugs are better tolerated. Gastrointestinal symptoms are common but occur less frequently with the delayed-release granules; they may be diminished by giving the drug with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3–8 weeks of PAS therapy, making it necessary to stop administration temporarily or permanently. The aminoglycoside antibiotics are discussed in Chapter 45. Kanamycin had been used for treatment of tuberculosis caused by streptomycin-resistant strains, but it is no longer available in the USA, and less toxic alternatives (eg, capreomycin and amikacin) have taken its place.


Pharmacology_Katzung

Pharmacology_Katzung. Amikacin is playing a greater role in the treatment of tuberculosis due to the prevalence of multidrug-resistant strains. Prevalence of amikacin-resistant strains is low (<5%), and most multidrugresistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 mcg/mL or less. Amikacin is also active against atypical mycobacteria. There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Peak serum concentrations of 30–45 mcg/mL are achieved 30–60 minutes after a 15-mg/kg intravenous infusion or intramuscular injection. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrugresistant strains. This drug must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosage is 15 mg/kg once daily


Pharmacology_Katzung

Pharmacology_Katzung. used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosage is 15 mg/kg once daily initially, followed by intermittent dosing two or three times per week.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to their activity against many Gram-positive and Gram-negative bacteria (discussed in Chapter 46), ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL. They are also active against atypical mycobacteria. Moxifloxacin is the most active against M tuberculosis in vitro. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis, whereas ciprofloxacin is slightly more active against atypical mycobacteria.


Pharmacology_Katzung

Pharmacology_Katzung. Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. The World Health Organization recommends using a later generation fluoroquinolone such as moxifloxacin or levofloxacin. Resistance, which may result from one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more additional active agents. Typically, resistance to one fluoroquinolone indicates class resistance. However, moxifloxacin may retain some activity in strains resistant to ofloxacin. The dosage of levofloxacin is 500–750 mg once a day, and some clinicians increase to 1000 mg daily if tolerated. The dosage of moxifloxacin is 400 mg once a day. Some experts recommend checking peak serum concentrations. Expected levels at about two hours post-dose are 8–12 mcg/mL for levofloxacin and 3–5 mcg/mL for


Pharmacology_Katzung

Pharmacology_Katzung. of moxifloxacin is 400 mg once a day. Some experts recommend checking peak serum concentrations. Expected levels at about two hours post-dose are 8–12 mcg/mL for levofloxacin and 3–5 mcg/mL for moxifloxacin.


Pharmacology_Katzung

Pharmacology_Katzung. Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis in vitro at concentrations of 4–8 mcg/mL. It achieves good intracellular concentrations, and it is active in murine models of tuberculosis. Linezolid has been used in combination with other second-and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains. Conversion of sputum cultures to negative was associated with linezolid use in these cases. Significant adverse effects, including bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses of therapy that are necessary for treatment of tuberculosis. A 600-mg (adult) dose administered once a day (half of that used for treatment of other bacterial infections) seems to be sufficient and may limit the occurrence of these adverse effects. Experts recommend supplemental pyridoxine for patients treated with linezolid. Although linezolid may prove to be an important new


Pharmacology_Katzung

Pharmacology_Katzung. be sufficient and may limit the occurrence of these adverse effects. Experts recommend supplemental pyridoxine for patients treated with linezolid. Although linezolid may prove to be an important new agent for treatment of tuberculosis, at this point it should be used only for multidrug-resistant strains that also are resistant to several other firstand second-line agents. It is generally avoided in patients on concomitant serotonergic agents due to concern for serotonin syndrome.


Pharmacology_Katzung

Pharmacology_Katzung. Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, MAC, and Mycobacterium fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is often used in place of rifampin for treatment of tuberculosis in patients with HIV infection who are receiving antiretroviral therapy with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor (eg, efavirenz), or an integrase strand transfer inhibitor (eg dolutegravir), drugs that also are cytochrome P450 or UDP glucuronosyltransferase (UGT) substrates.


Pharmacology_Katzung

Pharmacology_Katzung. The typical dosage of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dosage should be reduced, typically by half. If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of rifabutin is 600 mg/d. Rifabutin may accumulate in severe renal impairment, and the dose should be reduced by half if creatinine clearance is less than 30 mL/min. Rifabutin is associated with similar rates of hepatotoxicity or rash compared to rifampin; it can also cause leukopenia, thrombocytopenia, and optic neuritis.


Pharmacology_Katzung

Pharmacology_Katzung. Rifapentine is another analog of rifampin. It is active against both M tuberculosis and MAC. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile; however, when rifapentine is administered intermittently, induction of metabolism of other medications is less pronounced compared to rifampin. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly, has been used for treatment of tuberculosis caused by rifampinsusceptible strains during the continuation phase (ie, after the first 2 months of therapy and ideally after conversion of sputum cultures to negative); however, this regimen has decreased efficacy compared with the standard


Pharmacology_Katzung

Pharmacology_Katzung. the continuation phase (ie, after the first 2 months of therapy and ideally after conversion of sputum cultures to negative); however, this regimen has decreased efficacy compared with the standard rifampin-based regimen. Revised guidelines for treatment of drug-susceptible tuberculosis published in 2016 recommend against it. In particular, its use should be avoided in patients at higher risk of failure, including those with positive cultures at the end of the intensive treatment phase and those with evidence of cavitation on chest radiographs. Rifapentine should not be used to treat active tuberculosis in patients with HIV infection because of an unacceptably high relapse rate with rifampin-resistant organisms. Rifapentine in combination with isoniazid, typically both dosed at 900 mg once weekly for 3 months (12 doses each in total), is an effective short course treatment for latent tuberculosis infection.


Pharmacology_Katzung

Pharmacology_Katzung. Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M tuberculosis to be approved since 1971. Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase in mycobacteria, has in vitro activity against both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murine model of tuberculosis. Cross-resistance has been reported between bedaquiline and clofazimine, likely via upregulation of the multisubstrate efflux pump, MmpL5.


Pharmacology_Katzung

Pharmacology_Katzung. Peak plasma concentration and plasma exposure to bedaquiline increase approximately twofold when administered with high-fat food. Bedaquiline is highly protein-bound (>99%), is metabolized chiefly through the cytochrome P450 system, and is excreted primarily via the feces. The mean terminal half-life of bedaquiline and its major metabolite (M2), which is four to six times less active in terms of antimycobacterial potency, is approximately 5.5 months. This long elimination phase probably reflects slow release of bedaquiline and M2 from peripheral tissues. CYP3A4 is the major isoenzyme involved in the metabolism of bedaquiline, and potent inhibitors or inducers of this enzyme cause clinically significant drug interactions.


Pharmacology_Katzung

Pharmacology_Katzung. Current recommendations state that bedaquiline, in combination with at least three other active medications, may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary tuberculosis if the isolate is resistant to both isoniazid and rifampin. The recommended dosage for bedaquiline is 400 mg once daily orally for 2 weeks, followed by 200 mg three times a week for 22 weeks taken orally with food in order to maximize absorption. The most common adverse effects, occurring at rates of 25% or more, are nausea, arthralgia, and headache. Bedaquiline has been associated with both hepatotoxicity and cardiac toxicity. The FDA has issued a black-box warning related to the risk of QTc prolongation and associated mortality. It should be reserved for patients who do not have other treatment options and used with caution in patients with other risk factors for cardiac conduction abnormalities.


Pharmacology_Katzung

Pharmacology_Katzung. Many mycobacterial infections seen in clinical practice in the United States are caused by nontuberculous mycobacteria (NTM), formerly known as “atypical mycobacteria.” These organisms have distinctive laboratory characteristics, are present in the environment, and are generally not communicable from person to person. As a rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs. On the other hand, agents TABLE 47–3 Clinical features and treatment options for infections with atypical mycobacteria.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 47–3 Clinical features and treatment options for infections with atypical mycobacteria. such as macrolides, sulfonamides, and tetracyclines, which are not active against M tuberculosis, may be effective for infections caused by NTM. Emergence of resistance during therapy is also a problem with these mycobacterial species, and active infection should be treated with combinations of drugs. M kansasii is susceptible to rifampin and ethambutol, partially susceptible to isoniazid, and completely resistant to pyrazinamide. A three-drug combination of isoniazid, rifampin, and ethambutol is the conventional treatment for M kansasii infection. A few representative pathogens, with the clinical presentation and the drugs to which they are often susceptible, are given in Table 47–3.


Pharmacology_Katzung

Pharmacology_Katzung. M avium complex (MAC), which includes both M avium and M intracellulare, is an important and common cause of disseminated disease in late stages of AIDS (CD4 counts < 50/μL). MAC is much less susceptible than M tuberculosis to most anti-tuberculous drugs. Combinations of agents are required to suppress the infection. Azithromycin, 500–600 mg once daily, or clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d, is an effective and well-tolerated regimen for treatment of disseminated disease. Some authorities recommend use of a third agent, especially rifabutin, 300 mg once daily. Other agents that may be useful are listed in Table 47–3. Azithromycin and clarithromycin are the prophylactic drugs of choice for preventing disseminated MAC in AIDS patients with CD4 cell counts less than 50/μL. Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence of MAC bacteremia but is less effective than macrolides.


Pharmacology_Katzung

Pharmacology_Katzung. Mycobacterium leprae has never been grown in vitro, but animal models, such as growth in injected mouse footpads, have permitted laboratory evaluation of drugs. Only those drugs with the widest clinical use are presented here. Because of increasing reports of dapsone resistance, treatment of leprosy with combinations of the drugs listed below is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Several drugs closely related to the sulfonamides have been used effectively in the long-term treatment of leprosy. The most widely used is dapsone (diaminodiphenylsulfone). Like the sulfonamides, it inhibits folate synthesis. Resistance can emerge in large populations of M leprae, eg, in lepromatous leprosy, particularly if low doses are given. Therefore, the combination of dapsone, rifampin, and clofazimine is recommended for initial therapy of lepromatous leprosy. A combination of dapsone plus rifampin is commonly used for leprosy with a lower organism burden. Dapsone may also be used to prevent and treat Pneumocystis jiroveci pneumonia in AIDS patients.


Pharmacology_Katzung

Pharmacology_Katzung. Sulfones are well absorbed from the gut and widely distributed throughout body fluids and tissues. Dapsone’s half-life is 1–2 days, and drug tends to be retained in skin, muscle, liver, and kidney. Skin heavily infected with M leprae may contain several times more drug than normal skin. Sulfones are excreted into bile and reabsorbed in the intestine. Excretion into urine is variable, and most excreted drug is acetylated. In renal failure, the dose may have to be adjusted. The usual adult dosage in leprosy is 100 mg daily. For children, the dose is proportionately less, depending on weight.


Pharmacology_Katzung

Pharmacology_Katzung. Dapsone is usually well tolerated. Many patients develop some hemolysis, particularly if they have glucose-6-phosphate dehydrogenase deficiency. Methemoglobinemia is common but usually is not clinically significant. Gastrointestinal intolerance, fever, pruritus, and rash occur. During dapsone therapy of lepromatous leprosy, erythema nodosum leprosum often develops. It is sometimes difficult to distinguish reactions to dapsone from manifestations of the underlying illness. Erythema nodosum leprosum may be suppressed by thalidomide (see Chapter 55). Rifampin (see earlier discussion) in a dosage of 600 mg daily is highly effective in leprosy and is given with at least one other drug to prevent emergence of resistance. Even a dose of 600 mg per month may be beneficial in combination therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Clofazimine is a phenazine dye used in the treatment of multi-bacillary leprosy, which is defined as having a positive smear from any site of infection. Its mechanism of action has not been clearly established. Absorption of clofazimine from the gut is variable, and a major portion of the drug is excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen inside phagocytic reticuloendothelial cells. It is slowly released from these deposits, so the serum half-life may be 2 months. A common dosage of clofazimine is 100–200 mg/d orally. The most prominent adverse effect is discoloration of the skin and conjunctivae. Gastrointestinal side effects are common. This medication is no longer commercially available, but it can be obtained through established programs. For example, an investigational new drug (IND) program is established in the USA through the National Hansen’s Disease Program. Internationally, ministries of health can


Pharmacology_Katzung

Pharmacology_Katzung. through established programs. For example, an investigational new drug (IND) program is established in the USA through the National Hansen’s Disease Program. Internationally, ministries of health can make requests directly to the World Health Organization.


Pharmacology_Katzung

Pharmacology_Katzung. rapidly emerges when used as a single drug in the treatment of active infection First-line agent for tuberculosis • nontuberculous mycobacterial infections • eradication of meningococcal colonization, staphylococcal infections •RifampinInhibits DNA-dependent RNA polymerase, thereby blocking production of RNA •Rifabutin: Oral; similar to rifampin but less cytochrome P450 induction and fewer drug interactions •Rifapentine: Oral; long-acting analog of rifampin that may be given once weekly in select cases during the continuation phase of tuberculosis treatment or for treatment Oral, IV • hepatic clearance (half-life 3.5 h) • potent cytochrome P450 inducer • turns body fluids orange color • Toxicity: Rash, nephritis, thrombocytopenia, cholestasis, flu-like syndrome with intermittent dosing Ethambutol Generic, Myambutol Ethionamide Trecator, Trecator-SC Rifabutin Generic, Mycobutin


Pharmacology_Katzung

Pharmacology_Katzung. Ethambutol Generic, Myambutol Ethionamide Trecator, Trecator-SC Rifabutin Generic, Mycobutin Rifampin Generic, Rifadin, Rimactane *Drugs used against nontuberculous mycobacteria are listed in Chapters 43–46. Centers for Disease Control and Prevention (CDC): Provisional CDC Guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 2013;62:1. Centers for Disease Control and Prevention (CDC): Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011;60:1650. Centers for Disease Control and Prevention (CDC): Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:735.


Pharmacology_Katzung

Pharmacology_Katzung. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition [1-305]. Gillespie SH et al: Early bactericidal activity of a moxifloxacin and isoniazid combination in smear-positive pulmonary tuberculosis. J Antimicrob Chemother 2005;56:1169. Griffith DE et al: An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care Med 2007;175:367. Hugonnet J-E et al: Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 2009;323:1215. Jasmer RM, Nahid P, Hopewell PC: Latent tuberculosis infection. N Engl J Med 2002;347:1860. Kinzig-Schippers M et al: Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733.


Pharmacology_Katzung

Pharmacology_Katzung. Kinzig-Schippers M et al: Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733. Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012;367:1508. Mitnick CD et al: Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008;359:563. Nahid P et al: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016;63:e147. Sulochana S, Rahman F, Paramasivan CN: In vitro activity of fluoroquinolones against Mycobacterium tuberculosis. J Chemother 2005;17:169. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Part 2):S221.


Pharmacology_Katzung

Pharmacology_Katzung. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Part 2):S221. Zhang Y, Yew WW: Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009;13:1320. Zumla A et al: Current concepts—Tuberculosis. N Engl J Med 2013;368:745.


Pharmacology_Katzung

Pharmacology_Katzung. Zhang Y, Yew WW: Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009;13:1320. Zumla A et al: Current concepts—Tuberculosis. N Engl J Med 2013;368:745. The patient should be started on four-drug therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. He should also be started on antiretroviral therapy for HIV. If a protease-inhibitor-based antiretroviral regimen is used to treat his HIV, rifabutin should replace rifampin because of the serious drug-drug interactions between rifampin and protease inhibitors. If dolutegravir is chosen, it must be administered twice daily due to the interaction with rifampin; alternatively, rifabutin can be used in place of rifampin, and dolutegravir can be dosed once daily. The patient is at increased risk of developing hepatotoxicity from both isoniazid and pyrazinamide given his history of alcohol use. Harry W. Lampiris, MD, & Daniel S. Maddix, Pharm D


Pharmacology_Katzung

Pharmacology_Katzung. Harry W. Lampiris, MD, & Daniel S. Maddix, Pharm D The patient is a 37-year-old African-American man who lives in San Jose, California. He was recently incarcerated near Bakersfield, California and returned to Oakland about 3 months ago. He is currently experiencing one month of severe headache and double vision. He has a temperature of 38.6°C (101.5°F) and the physical exam reveals nuchal rigidity and right-sided sixth cranial nerve palsy. MRI of his brain is normal, and lumbar puncture reveals 330 WBC with 20% eosinophils, protein 75, and glucose 20. HIV test is negative, TB skin test is negative, CSF cryptococcal antigen is negative, and CSF gram stain is negative. Patient receives empiric therapy for bacterial meningitis with van-comycin and ceftriaxone, and is unimproved after 72 hours of treatment. After 3 days a white mold is identified growing from his CSF culture. What medical therapy would be most appropriate now?


Pharmacology_Katzung

Pharmacology_Katzung. Human fungal infections have increased dramatically in incidence and severity in recent years, owing mainly to advances in surgery, cancer treatment, treatment of patients with solid organ and bone marrow transplantation, the HIV epidemic, and increasing use of broad-spectrum antimicrobial therapy in critically ill patients. These changes have resulted in increased numbers of patients at risk for fungal infections.


Pharmacology_Katzung

Pharmacology_Katzung. For many years, amphotericin B was the only efficacious antifungal drug available for systemic use. While highly effective in many serious infections, it is also quite toxic. In the last several decades, pharmacotherapy of fungal disease has been revolutionized by the introduction of the relatively nontoxic azole drugs (both oral and parenteral formulations) and the echinocandins (only available for parenteral administration). The new agents in these classes offer more targeted, less toxic therapy than older agents such as amphotericin B for patients with serious systemic fungal infections. Combination therapy is being reconsidered, and new formulations of old agents are becoming available. Unfortunately, the appearance of azoleresistant and echinocandin-resistant organisms, as well as the rise in the number of patients at risk for mycotic infections, has created new challenges.


Pharmacology_Katzung

Pharmacology_Katzung. The antifungal drugs presently available fall into the following categories: systemic drugs (oral or parenteral) for systemic infections, oral systemic drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections. Amphotericin A and B are antifungal antibiotics produced by Streptomyces nodosus. Amphotericin A is not in clinical use. Amphotericin B is an amphoteric polyene macrolide (polyene = containing many double bonds; macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin B and sodium deoxycholate for intravenous injection. Several formulations have been developed in which amphotericin B is TABLE 48–1 Properties of conventional amphotericin B and some lipid formulations.1 1Changes in Cmax (peak plasma concentration), clearance, nephrotoxicity, and infusional toxicity are relative to conventional amphotericin B.


Pharmacology_Katzung

Pharmacology_Katzung. packaged in a lipid-associated delivery system (Table 48–1 and Box: Lipid Formulation of Amphotericin B). Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease. The intravenous injection of 0.6 mg/kg/d of amphotericin B results in average blood levels of 0.3–1 mcg/mL; the drug is more than 90% bound by serum proteins. Although it is mostly metabolized, some amphotericin B is excreted slowly in the urine over a period of several days. The serum half-life is approximately 15 days. Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations, and therefore no dose adjustment is required. The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.


Pharmacology_Katzung

Pharmacology_Katzung. Mechanisms of Action & Resistance Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol. Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin B–associated pores in the cell membrane (Figure 48–1). As suggested by its chemistry, amphotericin B combines avidly with lipids (ergosterol) along the double bond– rich side of its structure and associates with water molecules


Pharmacology_Katzung

Pharmacology_Katzung. Therapy with amphotericin B is often limited by toxicity, espe-cially drug-induced renal impairment. This has led to the devel-opment of lipid drug formulations on the assumption that lipid-packaged drug binds to the mammalian membrane less readily, permitting the use of effective doses of the drug with lower toxicity. Liposomal amphotericin preparations package the active drug in lipid delivery vehicles, in contrast to the colloidal suspensions, which were previously the only available forms. Amphotericin binds to the lipids in these vehicles with an affinity between that for fungal ergosterol and that for human choles-terol. The lipid vehicle then serves as an amphotericin reservoir, reducing nonspecific binding to human cell membranes. This preferential binding allows for a reduction of toxicity without sacrificing efficacy and permits use of larger doses. Furthermore, some fungi contain lipases that may liberate free amphotericin B directly at the site of infection. Three such


Pharmacology_Katzung

Pharmacology_Katzung. of toxicity without sacrificing efficacy and permits use of larger doses. Furthermore, some fungi contain lipases that may liberate free amphotericin B directly at the site of infection. Three such formulations are now available and have differing pharmacologic properties as summarized in Table 48–1. Although clinical trials have demonstrated different renal and infusion-related toxicities for these preparations compared with regular amphotericin B, there are no trials comparing the different formula-tions with each other. Limited studies have suggested at best a moderate improvement in the clinical efficacy of the lipid formulations compared with conventional amphotericin B. Because the lipid preparations are much more expensive, their use is usually restricted to patients intolerant to, or not responding to, conventional ampho-tericin treatment.


Pharmacology_Katzung

Pharmacology_Katzung. ˜-glucans Cell membrane bilayer Squalene Ergosterol Terbinafine Azoles Amphotericin B, nystatin Flucytosine ˜-glucansynthaseEchinocandins ––––Proteins Chitin DNA, RNA synthesis FIGURE 48–1 Targets of antifungal drugs. Except for flucytosine (and possibly griseofulvin, not shown), all currently available antifungals target the fungal cell membrane or cell wall. along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug’s prominent toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance to amphotericin B occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol or by modifying the sterol target molecule to reduce its affinity for the drug. Amphotericin B remains the antifungal agent with the broadest spectrum of action. It has activity against the clinically significant yeasts, including Candida albicans and Cryptococcus neoformans; the organisms causing endemic mycoses, including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and the pathogenic molds, such as Aspergillus fumigatus and the agents of mucormycosis. Some fungal organisms such as Candida lusitaniae and Pseudallescheria boydii display intrinsic amphotericin B resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful agent for nearly all life-threatening mycotic infections, although newer, less toxic agents have largely replaced it for most conditions. Amphotericin B is often used as the initial induction regimen to rapidly reduce fungal burden and then replaced by one of the newer azole drugs (described below) for chronic therapy or prevention of relapse. Such induction therapy is especially important for immunosuppressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis, or disseminated infections with one of the endemic mycoses such as histoplasmosis or coccidioidomycosis. Once a clinical response has been elicited, these patients then often continue maintenance therapy with an azole; therapy may be lifelong in patients at high risk for disease relapse. For treatment of systemic fungal disease, amphotericin B is given by slow intravenous infusion at a dosage of 0.5–1


Pharmacology_Katzung

Pharmacology_Katzung. an azole; therapy may be lifelong in patients at high risk for disease relapse. For treatment of systemic fungal disease, amphotericin B is given by slow intravenous infusion at a dosage of 0.5–1 mg/kg/d. Intrathecal therapy for fungal meningitis is poorly tolerated and fraught with difficulties related to maintaining cerebrospinal fluid access. Thus, intrathecal therapy with amphotericin B is being increasingly supplanted by other therapies but remains an option in cases of fungal central nervous system infections that have not responded to other agents.


Pharmacology_Katzung

Pharmacology_Katzung. Local or topical administration of amphotericin B has been used with success. Mycotic corneal ulcers and keratitis can be cured with topical drops as well as by direct subconjunctival injection. Fungal arthritis has been treated with adjunctive local injection directly into the joint. Candiduria responds to bladder irrigation with amphotericin B, and this route has been shown to produce no significant systemic toxicity. The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly. A. Infusion-Related Toxicity


Pharmacology_Katzung

Pharmacology_Katzung. The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly. A. Infusion-Related Toxicity Infusion-related reactions are nearly universal and consist of fever, chills, muscle spasms, vomiting, headache, and hypotension. They can be ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. This can serve as a guide to an initial dosing regimen and premedication strategy. B. Cumulative Toxicity


Pharmacology_Katzung

Pharmacology_Katzung. B. Cumulative Toxicity Renal damage is the most significant toxic reaction. Renal impairment occurs in nearly all patients treated with clinically significant doses of amphotericin. The degree of azotemia is variable and often stabilizes during therapy, but it can be serious enough to necessitate dialysis. A reversible component is associated with decreased renal perfusion and represents a form of prerenal renal failure. An irreversible component results from renal tubular injury and subsequent dysfunction. The irreversible form of amphotericin nephrotoxicity usually occurs in the setting of prolonged administration (>4 g cumulative dose). Renal toxicity commonly manifests as renal tubular acidosis and severe potassium and magnesium wasting. There is some evidence that the prerenal component can be attenuated with sodium loading, and it is common practice to administer normal saline infusions with the daily doses of amphotericin B.


Pharmacology_Katzung

Pharmacology_Katzung. Abnormalities of liver function tests are occasionally seen, as is a varying degree of anemia due to reduced erythropoietin production by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae. Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. Though devoid of anti-cancer properties, it became apparent that it is a potent antifungal agent. Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent 5-fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B.