Pharmacology_Katzung

Pharmacology_Katzung. The goal of treatment is to reduce bone pain and stabilize or prevent other problems such as progressive deformity, fractures, hearing loss, high-output cardiac failure, and immobilization hypercalcemia. Calcitonin and bisphosphonates are the first-line agents for this disease. Calcitonin is administered subcutaneously or intramuscularly in doses of 50–100 MRC (Medical Research Council) units every day or every other day. Nasal inhalation at 200–400 units/d is also effective. Higher or more frequent doses have been advocated when this initial regimen is ineffective. Improvement in bone pain and reduction in serum alkaline phosphatase and urine hydroxyproline levels require weeks to months. Often a patient who responds well initially loses the response to calcitonin. This refractoriness is not correlated with the development of antibodies.


Pharmacology_Katzung

Pharmacology_Katzung. Sodium etidronate, alendronate, risedronate, and tiludronate are the bisphosphonates currently approved for clinical use in Paget’s disease of bone in the United States. Other bisphosphonates, including pamidronate, are being used in other countries. The recommended doses of bisphosphonates are etidronate, 5 mg/kg per day; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludronate, 400 mg/d. Long-term remission (months to years) may be expected in patients who respond to a bisphosphonate. Treatment should not exceed 6 months per course but can be repeated after


Pharmacology_Katzung

Pharmacology_Katzung. VITAMIN D, METABOLITES, ANALOGS 6 months if necessary. The principal toxicity of etidronate is the development of osteomalacia and an increased incidence of fractures when the dosage is raised substantially above 5 mg/kg per day. The newer bisphosphonates such as risedronate and alendronate do not share this adverse effect. Some patients treated with etidronate develop bone pain similar in nature to the bone pain of osteomalacia. This subsides after stopping the drug. The principal adverse effect of alendronate and the newer bisphosphonates is gastric irritation when used at these high doses. This is reversible on cessation of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with short bowel syndromes and associated fat malabsorption can present with renal stones composed of calcium and oxalate. Such patients characteristically have normal or low urine calcium levels but elevated urine oxalate levels. The reasons for the development of oxaluria in such patients are thought to be twofold: first, in the intestinal lumen, calcium (which is now bound to fat) fails to bind oxalate and no longer prevents its absorption; second, enteric flora, acting on the increased supply of nutrients reaching the colon, produce larger amounts of oxalate. Although one would ordinarily avoid treating a patient with calcium oxalate stones with calcium supplementation, this is precisely what is done in patients with enteric oxaluria. The increased intestinal calcium binds the excess oxalate and prevents its absorption. Calcium carbonate (1–2 g) can be given daily in divided doses, with careful monitoring of urinary calcium and oxalate to be certain that urinary oxalate


Pharmacology_Katzung

Pharmacology_Katzung. excess oxalate and prevents its absorption. Calcium carbonate (1–2 g) can be given daily in divided doses, with careful monitoring of urinary calcium and oxalate to be certain that urinary oxalate falls without a dangerous increase in urinary calcium.


Pharmacology_Katzung

Pharmacology_Katzung. VITAMIN D, METABOLITES, AND ANALOGS Calcifediol (25(OH)D3) Rayaldee Oral: solution Fleet Phospho-soda, K-Phos-Neutral, Neutra-Phos, Neutra- Oral Generic, Rocaltrol Phos-K Cholecalciferol (D3) Generic, Delta-D Sevelamer carbonate or HCl Renagel, Renvela BISPHOSPHONATES Alendronate sodium Generic, Fosamax Doxercalciferol Generic, Hectorol Ergocalciferol (D2) (vitamin Generic, Drisdol, others D2, calciferol) Etidronate disodium Generic, Didronel Paricalcitol Generic,ZemplarCALCIUM Pamidronate disodium Generic, Aredia Calcium acetate (25% calcium) Generic, PhosLo Tiludronate disodium Skelid Calcium chloride (27% calcium) Generic Ibandronate sodium Generic, Boniva Risedronate sodium Actonel, Atelvia Calcium carbonate (40% calcium) Generic, Tums, Cal-Sup, Os-Cal 500 Calcium citrate (21% calcium) Generic, Cal-C-Caps, Cal-Cee Calcium glubionate Neo-Calglucon, Calcionate,


Pharmacology_Katzung

Pharmacology_Katzung. Calcium carbonate (40% calcium) Generic, Tums, Cal-Sup, Os-Cal 500 Calcium citrate (21% calcium) Generic, Cal-C-Caps, Cal-Cee Calcium glubionate Neo-Calglucon, Calcionate, Calcitonin-salmon Miacalcin, Calcimar, Salmonine (6.5% calcium) Calciquid Denosumab Prolia, Xgeva Calcium gluconate Generic Becker DJ, Kilgore ML, Morrisey MA: The societal burden of osteoporosis. Curr Rheumatol Rep 2010;12:186. Bhattacharyya N et al: Fibroblast growth factor 23: State of the field and future directions. Trends Endocrinol Metab 2012;23:610. Bikle DD: Extraskeletal actions of vitamin D. Ann NY Acad Sci 2016;1376:29. Cosman F et al: Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 2014;25:2359. Hagino H: Eldecalcitol: Newly developed active vitamin D3 analog for the treatment of osteoporosis. Expert Opin Pharmacother 2013;14:817.


Pharmacology_Katzung

Pharmacology_Katzung. Hagino H: Eldecalcitol: Newly developed active vitamin D3 analog for the treatment of osteoporosis. Expert Opin Pharmacother 2013;14:817. Holick MF et al: Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Sociey Clinical Practice Guideline. J Clin Endocrinol Metab 2011;96:1911. Martin A, David V, Quarles LD: Regulation and function of the FGF23/Klotho endocrine pathways. Physiol Rev 2012;92:131. Mirrakhimov AE: Hypercalcemia of malignancy: An update on pathogenesis and management. N Am J Med Sci 2015;7:483. Mosekilde L et al: The pathogenesis, treatment, and prevention of osteoporosis in men. Drugs 2013;73:15. Nemeth EF, Shoback D: Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Pract Res Clin Endocrinol Metab 2013;27:373. Nigwekar SU, Tamez H, Thadhani RI: Vitamin D and chronic kidney disease– mineral bone disease (CKD–MBD). Bonekey Rep 2014;3:498.


Pharmacology_Katzung

Pharmacology_Katzung. Nigwekar SU, Tamez H, Thadhani RI: Vitamin D and chronic kidney disease– mineral bone disease (CKD–MBD). Bonekey Rep 2014;3:498. Pettifor JM: Rickets and vitamin D deficiency in children and adolescents. Endocrinol Metab Clin North Am 2005;34:537. Ross AC et al: The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011;96:53. White KE, Hum JM, Michael J: Econs MJ. Hypophosphatemic rickets: Revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 2014;12:252. Zwolak P, Dudek AZ: Antineoplastic activity of zoledronic acid and denosumab. Anticancer Res 2013;33:2981.


Pharmacology_Katzung

Pharmacology_Katzung. Zwolak P, Dudek AZ: Antineoplastic activity of zoledronic acid and denosumab. Anticancer Res 2013;33:2981. There are multiple reasons for this patient’s osteoporo-sis, including a heavy smoking history, possible alco-holism, and chronic inflammatory disease treated with glucocorticoids. High levels of cytokines from the chronic inflammation activate osteoclasts. Glucocorticoids increase urinary losses of calcium, suppress bone formation, and inhibit intestinal calcium absorption as well as decreasing gonadotropin production, leading to hypogonadism. Man-agement should include measurement of serum testoster-one, calcium, 25(OH)D, and the 24-hour urine calcium and creatinine levels (to verify completeness of collection), with treatment as appropriate for these secondary causes, plus initiation of bisphosphonate or denosumab therapy as primary treatment.


Pharmacology_Katzung

Pharmacology_Katzung. Antimicrobial agents provide some of the most dramatic examples of the advances of modern medicine. Many infectious diseases once considered incurable and potentially lethal can now be treated effectively with antibiotics. The remarkably powerful and specific activity of antimicrobial drugs is due to their selectivity for targets that are either unique to prokaryote and fungal microorganisms or much more important in these organisms than in humans. Among these targets are bacterial and fungal cell wall-synthesizing enzymes (Chapters 43 and 48), the bacterial ribosome (Chapters 44 and 45), the enzymes required for nucleotide synthesis and DNA replication (Chapter 46), and the machinery of viral replication (Chapter 49). The special group of drugs used in mycobacterial infections is discussed in Chapter 47. Cytotoxic antiseptics and disinfectants are discussed in Chapter 50. The clinical uses of many antimicrobial agents are summarized in Chapter 51.


Pharmacology_Katzung

Pharmacology_Katzung. The major problem threatening the continued success of antimicrobial drugs is the development of resistant organisms. Antibiotic resistance mechanisms existed long before the clinical use of antibiotics, even resistance to synthetic drugs that were created in the 20th century. Because resistance mechanisms are already present in nature, an inevitable consequence of antimicrobial use is the selection of resistant microorganisms. Since the start of the antibiotic era, antibiotic use in patients and animals has fueled a major increase in the prevalence of drug-resistant pathogens. In recent years, highly resistant Gram-negative organisms with novel mechanisms of resistance have been increasingly reported. Some of these strains have spread over vast geographic areas as a result of patients seeking medical care in different countries.


Pharmacology_Katzung

Pharmacology_Katzung. Much attention has been focused on eliminating the misuse of antibiotics to slow the tide of resistance. Antibiotics are misused in a variety of ways, including use in patients who are unlikely to have bacterial infections, use over unnecessarily prolonged periods, and use of multiple agents or broad-spectrum agents when not needed. Large quantities of antibiotics have been used in agriculture to stimulate growth and prevent infection in livestock, and this has added to the selection pressure that results in resistant organisms. In December 2013, the U.S. Food and Drug Administration (FDA) announced a program to phase out the nontherapeutic use of antibiotics in livestock. In 2015, President Obama announced a 5-year National Action Plan with the goals of improving antimicrobial stewardship efforts, tools for diagnosing infectious diseases, and surveillance for resistant organisms. However, even if these programs are successful, it will take years before the benefits are apparent.


Pharmacology_Katzung

Pharmacology_Katzung. Antibiotic resistance has many negative consequences. The prevalence of resistant organisms drives the use of broader-spectrum, less efficacious, or more toxic antibiotics. Not surprisingly, infections caused by antibiotic-resistant pathogens are associated with increased costs, morbidity, and mortality. The Centers for Disease Control and Prevention estimates that every year in the United States at least 2 million people acquire infections due to and 23,000 people die from infections caused by resistant bacteria.


Pharmacology_Katzung

Pharmacology_Katzung. Unfortunately, as the need has grown in recent years, development of novel antibiotics has slowed. Several of the largest pharmaceutical companies have abandoned research and development in this area because of diminished success and profits; the resulting reduction in new drug introductions is shown in the figure below, which shows new systemic antibacterial agents approved by the FDA per 5-year period through 2012. Several new antimicrobial agents have been approved between 2013 and 2015; however, most are slight modifications of existing drugs. Some novel targets are under investigation. For example, tarocin was found to successfully inhibit teichoic acid, a structure essential for bacterial cell wall synthesis. When combined with a β-lactam antibiotic in a mouse model, tarocin effectively killed methicillin-resistant strains of Staphylococcus aureus that were resistant to either agent alone.


Pharmacology_Katzung

Pharmacology_Katzung. Decline in the number of new systemic antibacterial drugs approved by the FDA over a 30-year period. (Reproduced, with permission, from Boucher HW et al: 10 × '20 progress-development of new drugs active against Gram-negative bacilli: An update from the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1685. By permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Modified, with permission, from Spellberg B et al: Trends in antimicrobial drug development: Implications for the future. Clin Infect Dis 2004;38:1279. By permission of Oxford University Press.) Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*


Pharmacology_Katzung

Pharmacology_Katzung. A 45-year-old man is brought to the local hospital emer-gency department by ambulance. His wife reports that he had been in his normal state of health until 3 days ago when he developed a fever and a productive cough. Dur-ing the last 24 hours he has complained of a headache and is increasingly confused. His wife reports that his medical history is significant only for hypertension, for which he takes hydrochlorothiazide and lisinopril, and that he is allergic to amoxicillin. She says that he developed a rash many years ago when prescribed amoxicillin for bron-chitis. In the emergency department, the man is febrile (38.7°C [101.7°F]), hypotensive (90/54 mmHg), tachypneic (36/min), and tachycardic (110/min). He has no signs of meningismus but is oriented only to person. A stat chest x-ray shows a left lower lung consolidation consistent with pneumonia. A CT scan is not concerning for lesions or elevated intracranial pressure. The plan is to start empiric antibiotics and perform a


Pharmacology_Katzung

Pharmacology_Katzung. shows a left lower lung consolidation consistent with pneumonia. A CT scan is not concerning for lesions or elevated intracranial pressure. The plan is to start empiric antibiotics and perform a lumbar puncture to rule out bacterial meningitis. What antibiotic regimen should be prescribed to treat both pneumonia and meningitis? Does the history of amoxicillin rash affect the antibiotic choice? Why or why not?


Pharmacology_Katzung

Pharmacology_Katzung. The penicillins share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and β-lactamase inhibitors. All are β-lactam compounds, so named because of their four-membered lactam ring. All penicillins have the basic structure shown in Figure 43–1. A thiazolidine ring (A) is attached to a β-lactam ring (B) that carries a secondary amino group (RNH–). Substituents (R; examples shown in Figure 43–2) can be attached to the amino group. Structural integrity of the 6-aminopenicillanic acid nucleus (rings A plus B) is essential for the biologic activity of these compounds. Hydrolysis of the β-lactam ring by bacterial β-lactamases yields penicilloic acid, which lacks antibacterial activity. A. Classification


Pharmacology_Katzung

Pharmacology_Katzung. A. Classification Substituents of the 6-aminopenicillanic acid moiety determine the essential pharmacologic and antibacterial properties of the resulting molecules. Penicillins can be assigned to one of three groups (below). Within each of these groups are compounds that are relatively stable to gastric acid and suitable for oral administration, eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of some representatives of each group are shown in Figure 43–2. 1. Penicillins (eg, penicillin G)—These have greatest activity against Gram-positive organisms, Gram-negative cocci, and non-β-lactamase-producing anaerobes. However, they have little activity against Gram-negative rods, and they are susceptible to * The authors thank Dr. Henry F. Chambers and Dr. Daniel Deck for their contributions to this chapter in previous editions. hydrolysis by β-lactamases. R: CH2 CH2 NH CH


Pharmacology_Katzung

Pharmacology_Katzung. R: CH2 CH2 NH CH FIGURE 43–1 Core structures of four β-lactam antibiotic families. The ring marked B in each structure is the β-lactam ring. The penicillins are susceptible to inactivation by amidases and lactamases at the points shown. Note that the carbapenems have a different stereochemical configuration in the lactam ring that imparts resistance to most common β-lactamases. Substituents for the penicillin and cephalosporin families are shown in Figures 43–2 and 43–6, respectively. 2. Antistaphylococcal penicillins (eg, nafcillin)—These penicillins are resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram-negative cocci and rods. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Extended-spectrum penicillins (aminopenicillins and antipseudomonal penicillins)—These drugs retain the antibacterial spectrum of penicillin and have improved activity against Gram-negative rods. Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamases. The following structures can each be substituted at the R to produce a new penicillin. FIGURE 43–2 Side chains of some penicillins (R groups). B. Penicillin Units and Formulations


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 43–2 Side chains of some penicillins (R groups). B. Penicillin Units and Formulations The activity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g). Semisynthetic penicillins are prescribed by weight rather than units. The minimum inhibitory concentration (MIC) of any penicillin (or other antimicrobial) is usually given in mcg/mL. Most penicillins are formulated as the sodium or potassium salt of the free acid. Potassium penicillin G contains about 1.7 mEq of K+ per million units of penicillin (2.8 mEq/g). Nafcillin contains Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G provide repository forms for intramuscular injection. In dry crystalline form, penicillin salts are stable for years at 4°C. Solutions lose their activity rapidly (eg, within 24 hours at 20°C) and must be prepared fresh for administration.


Pharmacology_Katzung

Mechanism of Action

Pharmacology_Katzung. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis. The cell wall is a rigid outer layer that completely surrounds the cytoplasmic membrane (Figure 43–3), maintains cell integrity, and prevents cell lysis from high osmotic pressure. The cell wall is composed of a complex, cross-linked polymer of polysaccharides and peptides known as peptidoglycan. The polysaccharide contains alternating amino sugars, N-acetylglucosamine and N-acetylmuramic acid (Figure 43–4). A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in d-alanyl-d-alanine. Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide. Cross-links give the cell wall its rigidity. Beta-lactam antibiotics, structural analogs of the natural d-Ala-d-Ala substrate, covalently bind to the active site of PBPs. This


Pharmacology_Katzung

Pharmacology_Katzung. with a nearby peptide. Cross-links give the cell wall its rigidity. Beta-lactam antibiotics, structural analogs of the natural d-Ala-d-Ala substrate, covalently bind to the active site of PBPs. This binding inhibits the transpeptidation reaction (Figure 43–5) and halts peptidoglycan synthesis, and the cell dies. The exact mechanism of cell death is not completely understood, but autolysins are involved in addition to the disruption of cross linking of the cell wall. Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance to penicillins and other β-lactams is due to one of four general mechanisms: (1) inactivation of antibiotic by β-lactamase, (2) modification of target PBPs, (3) impaired penetration of drug to target PBPs, and (4) antibiotic efflux. Beta-lactamase production is the most common mechanism of resistance. Hundreds of different β-lactamases have been identified. Some, such as


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 43–3 A highly simplified diagram of the cell envelope of a Gram-negative bacterium. The outer membrane, a lipid bilayer, is present in Gram-negative but not Gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in Gram-positive organisms than in Gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are membrane proteins that cross-link peptidoglycan. Beta-lactamases, if present, reside in the periplasmic space or on the outer surface of the cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 43–4 The transpeptidation reaction in Staphylococcus aureus that is inhibited by β-lactam antibiotics. The cell wall of Gram-positive bacteria is made up of long peptidoglycan polymer chains consisting of the alternating aminohexoses N-acetylglucosamine (G) and N-acetylmuramic acid (M) with pentapeptide side chains linked (in S aureus) by pentaglycine bridges. The exact composition of the side chains varies among species. The diagram illustrates small segments of two such polymer chains and their amino acid side chains. These linear polymers must be cross-linked by transpeptidation of the side chains at the points indicated by the asterisk to achieve the strength necessary for cell viability.


Pharmacology_Katzung

Pharmacology_Katzung. those produced by Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli, are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. Other β-lactamases, eg, AmpC β-lactamase produced by Pseudomonas aeruginosa and Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in Enterobacteriaceae, hydrolyze both cephalosporins and penicillins. Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases, but they are hydrolyzed by metallo-β-lactamases and carbapenemases. Altered target PBPs are the basis of methicillin resistance in staphylococci and of penicillin resistance in pneumococci and most resistant enterococci. These resistant organisms produce PBPs that have low affinity for binding β-lactam antibiotics, and they are not inhibited except at relatively high, often clinically unachievable, drug concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance due to impaired penetration of antibiotic occurs only in Gram-negative species because of the impermeable outer membrane of their cell wall, which is absent in Gram-positive bacteria. Beta-lactam antibiotics cross the outer membrane and enter Gram-negative organisms via outer membrane protein channels called porins. Absence of the proper channel or down-regulation of its production can greatly impair drug entry into the cell. Poor penetration alone is usually not sufficient to confer resistance because enough antibiotic eventually enters the cell to inhibit growth. However, this barrier can become important in the presence of a β-lactamase, even a relatively inefficient one, as long as it can hydrolyze drug faster than it enters the cell. Gram-negative organisms also may produce an efflux pump, which consists of cytoplasmic and periplasmic protein components that efficiently transport some β-lactam antibiotics from the periplasm back across the cell wall outer membrane.


Pharmacology_Katzung

Pharmacology_Katzung. Absorption of orally administered drug differs greatly for individual penicillins, depending in part on their acid stability and protein binding. Gastrointestinal absorption of nafcillin is erratic, so it is not suitable for oral administration. Dicloxacillin, ampicillin, and amoxicillin are acid-stable and relatively well absorbed, producing serum concentrations in the range of 4–8 mcg/mL after a 500-mg oral dose. Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the drugs should be administered at least 1–2 hours before or after a meal.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous administration of penicillin G is preferred to the intramuscular route because of irritation and local pain from intramuscular injection of large doses. Serum concentrations 30 minutes after an intravenous injection of 1 g of penicillin G (equivalent to approximately 1.6 million units) are 20–50 mcg/mL. Only a fraction of the total drug in serum is present as free drug, the concentration of which is determined by protein binding. Highly protein-bound penicillins (eg, nafcillin) generally achieve lower free-drug concentrations in serum than less protein-bound penicillins (eg, penicillin G or ampicillin). Penicillins are widely distributed in body fluids and tissues with a few exceptions. They are polar molecules, so intracellular concentrations are well below those found in extracellular fluids.


Pharmacology_Katzung

Pharmacology_Katzung. Bacterial cell wall Periplasmic space Cytoplasmic membrane Cytoplasm Beta-lactams bind the transpeptidase at the Penicillin Binding Protein site, resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis. Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction. G = N-acetylglucos-amine (N-Ag) M = N-acetylmuramic acid (N-Am) G M M M MG G G G MG M G M G M M M M G M G M G M G G G M M M MG G G G +Transpeptidase No transpeptidation reaction FIGURE 43–5 Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Beta-lactams work by binding the transpeptidase at the penicillin-binding protein site, resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis.


Pharmacology_Katzung

Pharmacology_Katzung. Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentrations. A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infections. After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough to prevent most β-hemolytic streptococcal infections. A 600,000-unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection.


Pharmacology_Katzung

Pharmacology_Katzung. Penicillin concentrations in most tissues are equal to those in serum. Penicillin is also excreted into sputum and breast milk to levels 3–15% of those in the serum. Penetration into the eye, the prostate, and the central nervous system is poor. However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily parenteral dose of 18–24 million units. These concentrations are sufficient to kill susceptible strains of pneumococci and meningococci.


Pharmacology_Katzung

Pharmacology_Katzung. Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes. Tubular secretion accounts for about 90% of renal excretion, and glomerular filtration accounts for the remainder. The normal half-life of penicillin G is approximately 30 minutes but, in renal failure, may be as long as 10 hours. Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour. For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one-fourth to one-third the normal dose being administered if creatinine clearance is 10 mL/min or less (Table 43–1).


Pharmacology_Katzung

Pharmacology_Katzung. Nafcillin is primarily cleared by biliary excretion. Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion, and no dosage adjustment is required for these drugs in patients in renal failure. Because clearance of penicillins is less efficient in the newborn, doses adjusted for weight alone result in higher systemic concentrations for longer periods than in the adult. TABLE 43–1 Guidelines for dosing of some commonly used penicillins. 1The total dose should not exceed the adult dose. 2The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used. 3Dose is based on piperacillin component.


Pharmacology_Katzung

Pharmacology_Katzung. Except for amoxicillin, oral penicillins should be given 1–2 hours before or after a meal; they should not be given with food to minimize binding to food proteins and acid inactivation. Amoxicillin may be given without regard to meals. Blood levels of all penicillins can be raised by simultaneous administration of probenecid, 0.5 g (10 mg/kg in children) every 6 hours orally, which impairs renal tubular secretion of weak acids such as β-lactam compounds. Penicillins, like all antibacterial antibiotics, should never be used for viral infections and should be prescribed only when there is reasonable suspicion of, or documented infection with, susceptible organisms. A. Penicillin


Pharmacology_Katzung

Pharmacology_Katzung. A. Penicillin Penicillin G is a drug of choice for infections caused by streptococci, meningococci, some enterococci, penicillin-susceptible pneumococci, staphylococci confirmed to be non-β-lactamaseproducing, Treponema pallidum and certain other spirochetes, some Clostridium species, Actinomyces and certain other Gram-positive rods, and non-β-lactamase-producing Gram-negative anaerobic organisms. Depending on the organism, the site, and the severity of infection, effective doses range between 4 and 24 million units per day administered intravenously in four to six divided doses. High-dose penicillin G can also be given as a continuous intravenous infusion. Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum. Amoxicillin (see below) is often used instead.


Pharmacology_Katzung

Pharmacology_Katzung. Benzathine penicillin and procaine penicillin G for intramuscular injection yield low but prolonged drug levels. A single intramuscular injection of benzathine penicillin, 1.2 million units, is effective treatment for β-hemolytic streptococcal pharyngitis. Given intramuscularly once every 3–4 weeks, it prevents reinfection. Benzathine penicillin G, 2.4 million units intramuscularly once a week for 1–3 weeks, is effective in the treatment of syphilis. Procaine penicillin G was once a commonly used treatment for pneumococcal pneumonia and gonorrhea; however, it is rarely used now because many gonococcal strains are penicillin-resistant, and many pneumococci require higher doses of penicillin G or the use of more potent β-lactams. B. Penicillins Resistant to Staphylococcal Beta-Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins)


Pharmacology_Katzung

Pharmacology_Katzung. B. Penicillins Resistant to Staphylococcal Beta-Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins) These semisynthetic penicillins are indicated for infections caused by β-lactamase-producing staphylococci, although penicillin-susceptible strains of streptococci and pneumococci are also susceptible to these agents. Listeria monocytogenes, enterococci, and methicillin-resistant strains of staphylococci are resistant. In recent years the empirical use of these drugs has decreased substantially because of increasing rates of methicillin resistance in staphylococci. However, for infections caused by methicillin-susceptible and penicillin-resistant strains of staphylococci, these are considered drugs of choice.


Pharmacology_Katzung

Pharmacology_Katzung. An isoxazolyl penicillin such as dicloxacillin, 0.25–0.5 g orally every 4–6 hours (15–25 mg/kg/d for children), is suitable for treatment of mild to moderate localized staphylococcal infections. These drugs are relatively acid-stable and have reasonable bioavailability. However, food interferes with absorption, and the drugs should be administered 1 hour before or after meals. Methicillin, the first antistaphylococcal penicillin to be developed, is no longer used clinically due to high rates of adverse effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent intravenous infusion of 1–2 g every 4–6 hours (50–200 mg/kg/d for children), are considered drugs of choice for serious staphylococcal infections such as endocarditis. C. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypenicillins, and Ureidopenicillins)


Pharmacology_Katzung

Pharmacology_Katzung. C. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypenicillins, and Ureidopenicillins) These drugs have greater activity than penicillin against Gram-negative bacteria because of their enhanced ability to penetrate the Gram-negative outer membrane. Like penicillin G, they are inactivated by many β-lactamases.


Pharmacology_Katzung

Pharmacology_Katzung. The aminopenicillins, ampicillin and amoxicillin, have very similar spectrums of activity, but amoxicillin is better absorbed orally. Amoxicillin, 250–500 mg three times daily, is equivalent to the same amount of ampicillin given four times daily. Amoxicillin is given orally to treat bacterial sinusitis, otitis, and lower respiratory tract infections. Ampicillin and amoxicillin are the most active of the oral β-lactam antibiotics against pneumococci with elevated MICs to penicillin and are the preferred β-lactam antibiotics for treating infections suspected to be caused by these strains. Ampicillin (but not amoxicillin) is effective for shigellosis. Ampicillin, at dosages of 4–12 g/d intravenously, is useful for treating serious infections caused by susceptible organisms, including anaerobes, enterococci, L monocytogenes, and β-lactamase-negative strains of Gram-negative cocci and bacilli such as E coli, and Salmonella sp. Non-β-lactamase-producing strains of H influenzae are


Pharmacology_Katzung

Pharmacology_Katzung. anaerobes, enterococci, L monocytogenes, and β-lactamase-negative strains of Gram-negative cocci and bacilli such as E coli, and Salmonella sp. Non-β-lactamase-producing strains of H influenzae are generally susceptible, but strains that are resistant because of altered PBPs are emerging. Due to production of β-lactamases by Gram-negative bacilli, ampicillin can no longer be used for empirical therapy of urinary tract infections and typhoid fever. Ampicillin is not active against Klebsiella sp, Enterobacter sp, P aeruginosa, Citrobacter sp, Serratia marcescens, indole-positive Proteus species, and other Gram-negative aerobes that are commonly encountered in hospital-acquired infections. These organisms intrinsically produce β-lactamases that inactivate ampicillin.


Pharmacology_Katzung

Pharmacology_Katzung. The carboxypenicillins, carbenicillin and ticarcillin, were developed to broaden the spectrum of penicillins against Gram-negative pathogens, including P aeruginosa; however, neither agent is available in the USA. The ureidopenicillin piperacillin is also active against many Gram-negative bacilli, such as Klebsiella pneumoniae and P aeruginosa. Piperacillin is available only as a co-formulation with the β-lactamase inhibitor tazobactam. Due to the propensity of P aeruginosa to develop resistance during therapy, an antipseudomonal β-lactam is sometimes used in combination with an aminoglycoside or fluoroquinolone, particularly in infections outside the urinary tract, despite a lack of data supporting combination therapy over single-drug therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Ampicillin, amoxicillin, piperacillin, and, historically, ticarcillin, are available in combination with one of several β-lactamase inhibitors: clavulanic acid, sulbactam, or tazobactam. The addition of a β-lactamase inhibitor extends the activity of these penicillins to include β-lactamase-producing strains of S aureus as well as some β-lactamase-producing Gram-negative bacteria (see Beta-Lactamase Inhibitors).


Pharmacology_Katzung

Pharmacology_Katzung. The penicillins are generally well tolerated, and, unfortunately, this may encourage inappropriate use. Most of the serious adverse effects are due to hypersensitivity. The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein. A history of a penicillin reaction is not reliable. About 5–8% of people claim such a history, but only a small number of these will have a serious reaction when given penicillin. Less than 1% of persons who previously received penicillin without incident will have an allergic reaction when given penicillin. Because of the potential for anaphylaxis, however, penicillin should be administered with caution or a substitute drug given if the person has a history of serious penicillin allergy. Penicillin skin testing may also be used to evaluate Type I hypersensitivity. If skin testing is negative, most patients can safely receive penicillin.


Pharmacology_Katzung

Pharmacology_Katzung. Allergic reactions include anaphylactic shock (very rare—0.05% of recipients); serum sickness–type reactions (now rare—urticaria, fever, joint swelling, angioedema, pruritus, and respiratory compromise occurring 7–12 days after exposure); and a variety of skin rashes. Oral lesions, fever, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), eosinophilia, hemolytic anemia and other hematologic disturbances, and vasculitis may also occur. Most patients allergic to penicillins can be treated with alternative drugs. However, if necessary (eg, treatment of enterococcal endocarditis or neurosyphilis in a patient with serious penicillin allergy), desensitization can be accomplished with gradually increasing doses of penicillin.


Pharmacology_Katzung

Pharmacology_Katzung. In patients with renal failure, penicillin in high doses can cause seizures. Nafcillin is associated with neutropenia and interstitial nephritis; oxacillin can cause hepatitis; and methicillin commonly caused interstitial nephritis (and is no longer used for this reason). Large doses of penicillins given orally may lead to gastrointestinal upset, particularly nausea, vomiting, and diarrhea. Ampicillin has been associated with pseudomembranous colitis. Secondary infections such as vaginal candidiasis may occur. Ampicillin and amoxicillin can be associated with skin rashes when prescribed in the setting of viral illnesses, particularly noted during acute Epstein-Barr virus infection, but the incidence of rash may be lower than originally reported. Piperacillin-tazobactam, when combined with vancomycin, has been associated with greater incidence of acute kidney injury compared to alternate β-lactam agents.


Pharmacology_Katzung

Pharmacology_Katzung. Cephalosporins are similar to penicillins but are more stable to many bacterial β-lactamases and, therefore, have a broader NN spectrum of activity. However, strains of E coli and Klebsiella sp Cefazolin most cephalosporins are a growing clinical concern. Cephalo-Cephalexin CH CH3 sporins are not active against L monocytogenes, and of the avail-NH2 able cephalosporins, only ceftaroline has some activity against Cefadroxil HO CH CH3 enterococci. NH2 The nucleus of the cephalosporins, 7-aminocephalosporanic acid (Figure 43–6), bears a close resemblance to 6-aminopenicillanic NH2 acid (Figure 43–1). The intrinsic antimicrobial activity of HO CH CH CH3 and R2 groups has yielded hundreds of potent compounds, many O CNH2 with low toxicity. Cephalosporins have traditionally been classi-


Pharmacology_Katzung

Pharmacology_Katzung. CH CH CH3 and R2 groups has yielded hundreds of potent compounds, many O CNH2 with low toxicity. Cephalosporins have traditionally been classi- O natural cephalosporins is low, but the attachment of various R1 fied into four major groups or generations, depending mainly groups. Their unique characteristics and spectra of activity are outlined below. on the spectrum of antimicrobial activity. Several cephalosporins developed more recently do not fit the traditional classification HOOC First-generation cephalosporins include cefazolin, cefadroxil, cephalexin, cephalothin, cephapirin, and cephradine; cefazolin H2N N and cephalexin are the only two available in the USA. These drugs are very active against Gram-positive cocci, such as streptococci and staphylococci. Traditional cephalosporins are not active against methicillin-resistant strains of staphylococci; however, methicillin-resistant strains (see below). E coli, K pneumoniae, and


Pharmacology_Katzung

Pharmacology_Katzung. Proteus mirabilis are often sensitive to first-generation cephalo-H2N S N sporins, but activity against P aeruginosa, indole-positive Proteus CH3 species, Enterobacter sp, S marcescens, Citrobacter sp, and Acineto- bacter sp is poor. Anaerobic cocci (eg, peptococci, peptostrepto cocci) are usually sensitive, but Bacteroides fragilis is not. A. Oral Cephalexin is the oral first generation agent widely used in the USA. After oral doses of 500 mg, peak serum levels are 15–20 mcg/mL. Urine concentration is usually very high, but in most tissues levels are variable and generally lower than in serum. Cephalexin is typically given in oral dosages of 0.25–0.5 g four times daily (15–30 mg/kg/d). Excretion is mainly by glomerular filtration and tubular secretion into the urine. Drugs that block tubular secretion, eg, probenecid, may increase serum levels substantially. In patients with impaired renal function, dosage must be reduced (Table 43–2).


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 43–6 Structures of some cephalosporins. R1 and R2 structures are substituents on the 7-aminocephalosporanic acid nucleus pictured at the top. Other structures (cefoxitin and below) are complete in themselves. 1Additional substituents not shown. TABLE 43–2 Guidelines for dosing of some commonly used cephalosporins and other cell-wall inhibitor antibiotics. 1The total dose should not exceed the adult dose. 2The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used. 350% of dose for Clcr <30 mL/min. B. Parenteral


Pharmacology_Katzung

Pharmacology_Katzung. B. Parenteral Cefazolin is the only first-generation parenteral cephalosporin still in general use. After an intravenous infusion of 1 g, the peak level of cefazolin is approximately 185 mcg/mL. The usual intravenous dosage of cefazolin for adults is 0.5–2 g intravenously every 8 hours. Cefazolin can also be administered intramuscularly. Excretion is via the kidney, and dose adjustments must be made for impaired renal function. Oral drugs may be used for the treatment of urinary tract infections and staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess. However, oral cephalosporins should not be relied on in serious systemic infections.


Pharmacology_Katzung

Pharmacology_Katzung. Cefazolin penetrates well into most tissues. It is a drug of choice for surgical prophylaxis and for many streptococcal and staphylococcal infections requiring intravenous therapy. Cefazolin may be used for infections due to E coli or K pneumoniae when the organism has been documented to be susceptible. Cefazolin does not penetrate the central nervous system and cannot be used to treat meningitis. Cefazolin is better tolerated than antistaphylococcal penicillins, and it has been shown to be effective for serious staphylococcal infections, eg, bacteremia. It can also be used in patients with mild penicillin allergy other than immediate hypersensitivity.


Pharmacology_Katzung

Pharmacology_Katzung. Members of the second-generation cephalosporins include cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, and ceforanide—of which cefaclor, cefuroxime, and cefprozil are available in the USA—and the structurally related cephamycins cefoxitin and cefotetan, which have activity against anaerobes. This is a heterogeneous group with individual differences in activity, pharmacokinetics, and toxicity. In general, second-generation cephalosporins are relatively active against organisms inhibited by first-generation drugs, but, in addition, they have extended Gram-negative coverage. Klebsiella sp (including those resistant to first-generation cephalosporins) are usually sensitive. Cefuroxime and cefaclor are active against H influenzae but not against Serratia or B fragilis. In contrast, cefoxitin and cefotetan are active against B fragilis and some Serratia strains but are less active against H influenzae. As with first-generation agents, no member of this group is active


Pharmacology_Katzung

Pharmacology_Katzung. contrast, cefoxitin and cefotetan are active against B fragilis and some Serratia strains but are less active against H influenzae. As with first-generation agents, no member of this group is active against enterococci or P aeruginosa. Compared with other cephalosporins, cefoxitin shows improved stability in the presence of extended-spectrum β-lactamases produced by E coli and Klebsiella sp. Clinical data are limited, but it may offer an alternative to carbapenems in treating certain infections due to these organisms. Second-generation cephalosporins may exhibit in vitro activity against Enterobacter sp, but resistant mutants that constitutively express a chromosomal β-lactamase that hydrolyzes these compounds (and third-generation cephalosporins) are readily selected, and they should not be used to treat Enterobacter infections.


Pharmacology_Katzung

Pharmacology_Katzung. A. Oral Cefuroxime axetil is the most commonly used oral cephalosporin in the USA. The usual dosage for adults is 250–500 mg orally twice daily; children should be given 20–40 mg/kg/d up to a maximum of 1 g/d. These drugs are not predictably active against penicillin-non-susceptible pneumococci. B. Parenteral After a 1-g intravenous infusion, serum levels are 75–125 mcg/mL for most second-generation cephalosporins. Intramuscular administration is painful and should be avoided. Doses and dosing intervals vary depending on the specific agent (Table 43–2). There are differences in half-life, protein binding, and interval between doses. All are renally cleared and require dosage adjustment in renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. The oral second-generation cephalosporins are active against β-lactamase-producing H influenzae or Moraxella catarrhalis and have been used primarily to treat sinusitis, otitis, and lower respiratory tract infections. Because of their activity against anaerobes (including many B fragilis strains), cefoxitin and cefotetan can be used to treat mixed anaerobic infections such as peritonitis, diverticulitis, and pelvic inflammatory disease. Cefuroxime is sometimes used to treat community-acquired pneumonia because it is active against β-lactamase-producing H influenzae and also many pneumococci. Although cefuroxime crosses the blood-brain barrier, it is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should not be used.


Pharmacology_Katzung

Pharmacology_Katzung. Third-generation agents include cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil, cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam. Cefoperazone, ceftizoxime, and moxalactam are no longer commercially available in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Compared with second-generation agents, these drugs have expanded Gram-negative coverage, and some are able to cross the blood-brain barrier. Third-generation drugs may be active against Citrobacter, S marcescens, and Providencia. They are also effective against β-lactamase-producing strains of Haemophilus and Neisseria. Ceftazidime is the only agent with useful activity against P aeruginosa. Like the second-generation drugs, third-generation cephalosporins are hydrolyzed by constitutively produced AmpC β-lactamase, and they are not reliably active against Enterobacter species. Serratia, Providencia, Acinetobacter, and Citrobacter also produce a chromosomally encoded cephalosporinase that, when constitutively expressed, can confer resistance to third-generation cephalosporins. Cefixime, cefdinir, ceftibuten, and cefpodoxime proxetil are oral agents possessing similar activity except that cefixime and ceftibuten are much less active against pneumococci and have poor activity against S


Pharmacology_Katzung

Pharmacology_Katzung. ceftibuten, and cefpodoxime proxetil are oral agents possessing similar activity except that cefixime and ceftibuten are much less active against pneumococci and have poor activity against S aureus.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous infusion of 1 g of a parenteral cephalosporin produces serum levels of 60–140 mcg/mL. Third-generation cephalosporins penetrate body fluids and tissues well and intravenous cephalosporins achieve levels in the cerebrospinal fluid sufficient to inhibit most susceptible pathogens.


Pharmacology_Katzung

Pharmacology_Katzung. The half-lives of these drugs and the necessary dosing intervals vary greatly: ceftriaxone (half-life 7–8 hours) can be injected once every 24 hours at a dosage of 15–50 mg/kg/d. A single daily 1-g dose is sufficient for most serious infections, with 2 g every 12 hours recommended for treatment of meningitis and 2 g every 24 hours recommended for endocarditis. The remaining drugs in the group (half-life 1–1.7 hours) can be infused every 6–8 hours in dosages between 2 and 12 g/d, depending on the severity of infection. Cefixime can be given orally (200 mg twice daily or 400 mg once daily) for urinary tract infections. Due to increasing resistance, cefixime is no longer recommended for the treatment of uncomplicated gonococcal urethritis and cervicitis. Intramuscular ceftriaxone in combination with azithromycin is the regimen of choice for treating most gonococcal infections. The adult dose for cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg twice daily; for ceftibuten, 400 mg


Pharmacology_Katzung

Pharmacology_Katzung. with azithromycin is the regimen of choice for treating most gonococcal infections. The adult dose for cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg twice daily; for ceftibuten, 400 mg once daily; and for cefdinir, 300 mg/12 h. Ceftriaxone excretion is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. The other third-generation cephalosporins are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Third-generation cephalosporins are used to treat a wide variety of serious infections caused by organisms that are resistant to most other drugs. Strains expressing extended-spectrum β-lactamases, however, are not susceptible. Third-generation cephalosporins should be avoided in treatment of Enterobacter infections—even if the clinical isolate appears susceptible in vitro—because of emergence of resistance. Ceftriaxone and cefotaxime are approved for treatment of meningitis, including meningitis caused by pneumococci, meningococci, H influenzae, and susceptible enteric Gram-negative rods, but not by L monocytogenes. Ceftriaxone and cefotaxime are the most active cephalosporins against penicillinnon-susceptible strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains. Meningitis caused by strains of pneumococci with penicillin MICs >1 mcg/mL may not respond even to these agents, and addition of vancomycin is


Pharmacology_Katzung

Pharmacology_Katzung. serious infections that may be caused by these strains. Meningitis caused by strains of pneumococci with penicillin MICs >1 mcg/mL may not respond even to these agents, and addition of vancomycin is recommended. Other potential indications include empirical therapy of sepsis in both the immunocompetent and the immunocompromised patient and treatment of infections for which a cephalosporin is the least toxic drug available.


Pharmacology_Katzung

Pharmacology_Katzung. Cefepime is the only available fourth-generation cephalosporin. It is more resistant to hydrolysis by chromosomal β-lactamases (eg, those produced by Enterobacter). However, like the third-generation compounds, it is hydrolyzed by extended-spectrum β-lactamases. Cefepime has good activity against P aeruginosa, Enterobacteriaceae, methicillin-susceptible S aureus, and S pneumoniae. It is highly active against Haemophilus and Neisseria sp. It penetrates well into cerebrospinal fluid. It is cleared by the kidneys and has a half-life of 2 hours, and its pharmacokinetic properties are very similar to those of ceftazidime. Unlike ceftazidime, however, cefepime has good activity against most penicillin-nonsusceptible strains of streptococci, and it is useful in treatment of Enterobacter infections. The standard dose for cefepime is 1–2 g infused every 12 hours; however, when treating more complicated infections due to P aeruginosa or in the setting of immunocompromise, doses are typically


Pharmacology_Katzung

Pharmacology_Katzung. The standard dose for cefepime is 1–2 g infused every 12 hours; however, when treating more complicated infections due to P aeruginosa or in the setting of immunocompromise, doses are typically increased to 2 g every 8 hours. Because of its broad-spectrum activity, cefepime is commonly used empirically in patients presenting with febrile neutropenia, in combination with other agents.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-lactam antibiotics with activity against methicillin-resistant staphylococci are currently under development. Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is the first such drug to be approved for clinical use in the USA. Ceftaroline has increased binding to penicillin-binding protein 2a, which mediates methicillin resistance in staphylococci, resulting in bactericidal activity against these strains. It has some in vitro activity against enterococci and a broad Gram-negative spectrum similar to ceftriaxone. It is not active against AmpC or extended-spectrum β-lactamase-producing organisms. Ceftaroline is currently approved for the treatment of skin and soft tissue infections and community-acquired pneumonia at a dose of 600 mg infused every 12 hours. It has been used off-label to treat complicated infections such as bacteremia, endocarditis, and osteomyelitis, sometimes in combination with other agents and often at an increased dose of 600 mg every 8


Pharmacology_Katzung

Pharmacology_Katzung. been used off-label to treat complicated infections such as bacteremia, endocarditis, and osteomyelitis, sometimes in combination with other agents and often at an increased dose of 600 mg every 8 hours. The normal half-life is about 2.7 hours; ceftaroline is primarily excreted renally and requires dose adjustment in renal impairment.


Pharmacology_Katzung

Pharmacology_Katzung. Cephalosporins Combined with a-lactamase Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. Novel cephalosporin-β-lactamase inhibitor combinations have been developed to combat resistant Gram-negative infections; see the subsequent section for more information on β-lactamase inhibitors. Ceftolozane-tazobactam and ceftazidime-avibactam were both FDA-approved for the treatment of complicated intra-abdominal infections and urinary tract infections. Both agents have potent in vitro activity against Gram-negative organisms, including P aeruginosa and AmpC and extended-spectrum β-lactamase producing Enterobacteriaceae. While neither agent is active against organisms producing metallo-β-lactamases, ceftazidime-avibactam may be an option for carbapenemase-producing organisms. Due to limited activity against anaerobic pathogens, both should be combined with metronidazole when treating complicated intra-abdominal infections. Both agents have short half-lives of 2–3 hours and are dosed every 8 hours. Both are primarily renally excreted and require dose adjustment in patients with


Pharmacology_Katzung

Pharmacology_Katzung. complicated intra-abdominal infections. Both agents have short half-lives of 2–3 hours and are dosed every 8 hours. Both are primarily renally excreted and require dose adjustment in patients with impaired renal clearance.


Pharmacology_Katzung

A. Allergy

Pharmacology_Katzung. A. Allergy


Pharmacology_Katzung

Pharmacology_Katzung. Like penicillins, cephalosporins may elicit a variety of hypersensitivity reactions, including anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia. Patients with documented penicillin anaphylaxis have an increased risk of reacting to cephalosporins compared with patients without a history of penicillin allergy. However, the chemical nucleus of cephalosporins is sufficiently different from that of penicillins such that many individuals with a history of penicillin allergy tolerate cephalosporins. Overall, the frequency of cross-allergenicity between the two groups of drugs is low (~1%). Cross-allergenicity appears to be most common among penicillin, aminopenicillins, and early-generation cephalosporins, which share similar R-1 side chains. Patients with a history of anaphylaxis to penicillins should not receive firstor second-generation cephalosporins, while thirdand fourth-generation cephalosporins should be administered with caution, preferably in a


Pharmacology_Katzung

Pharmacology_Katzung. history of anaphylaxis to penicillins should not receive firstor second-generation cephalosporins, while thirdand fourth-generation cephalosporins should be administered with caution, preferably in a monitored setting.


Pharmacology_Katzung

Pharmacology_Katzung. B. Toxicity Local irritation can produce pain after intramuscular injection and thrombophlebitis after intravenous injection. Renal toxicity, including interstitial nephritis and tubular necrosis, may occur uncommonly. Cephalosporins that contain a methylthiotetrazole group may cause hypoprothrombinemia and bleeding disorders. Historically, this group included cefamandole, cefmetazole, and cefoperazone; however, cefotetan is the only methylthiotetrazole-containing agent used in the USA. Oral administration of vitamin K, 10 mg twice weekly, can prevent this uncommon problem. Drugs with the methylthiotetrazole ring can also cause severe disulfiram-like reactions; consequently, alcohol and alcohol-containing medications must be avoided.


Pharmacology_Katzung

Pharmacology_Katzung. Monobactams are drugs with a monocyclic β-lactam ring (Figure 43–1). Their spectrum of activity is limited to aerobic Gram-negative organisms (including P aeruginosa). Unlike other β-lactam antibiotics, they have no activity against Gram-positive bacteria or anaerobes. Aztreonam is the only monobactam available in the USA. It has structural similarities to ceftazidime, and its Gram-negative spectrum is similar to that of the third-generation cephalosporins. It is stable to many β-lactamases with notable exceptions being AmpC β-lactamases and extended-spectrum β-lactamases. It penetrates well into the cerebrospinal fluid. Aztreonam is given intravenously every 8 hours in a dose of 1–2 g, providing peak serum levels of 100 mcg/mL. The half-life is 1–2 hours and is greatly prolonged in renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. Penicillin-allergic patients tolerate aztreonam without reaction. Notably, because of its structural similarity to ceftazidime, there is potential for cross-reactivity; aztreonam should be used with caution in the case of documented severe allergies to ceftazidime. Occasional skin rashes and elevations of serum aminotransferases occur during administration of aztreonam, but major toxicity is uncommon. In patients with a history of penicillin anaphylaxis, aztreonam may be used to treat serious infections such as pneumonia, meningitis, and sepsis caused by susceptible Gram-negative pathogens. BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM, TAZOBACTAM, & AVIBACTAM)


Pharmacology_Katzung

Pharmacology_Katzung. BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM, TAZOBACTAM, & AVIBACTAM) Traditional β-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) resemble β-lactam molecules (Figure 43–7), but they have very weak antibacterial action. They are potent inhibitors of many but not all bacterial β-lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. The traditional β-lactamase inhibitors are most active against Ambler class A β-lactamases (plasmid-encoded transposable element [TEM] β-lactamases in particular), such as those produced by FIGURE 43–7 Beta-lactamase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 43–7 Beta-lactamase inhibitors. staphylococci, H influenzae, N gonorrhoeae, Salmonella, Shigella, E coli, and K pneumoniae. They are not good inhibitors of class C β-lactamases, which typically are chromosomally encoded and inducible, produced by Enterobacter sp, Citrobacter sp, S marcescens, and P aeruginosa, but they do inhibit chromosomal β-lactamases of B fragilis and M catarrhalis. The novel non-βlactam β-lactamase inhibitor avibactam is active against Ambler class A β-lactamases but also active against Ambler class C and some Ambler class D β-lactamases.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-lactamase inhibitors are available only in fixed combinations with specific penicillins and cephalosporins. (The fixed combinations available in the USA are listed in Preparations Available.) An inhibitor extends the spectrum of its companion β-lactam provided that the inactivity against a particular organism is due to destruction by a β-lactamase and that the inhibitor is active against the β-lactamase that is produced. Thus, ampicillin-sulbactam is active against β-lactamase-producing S aureus and H influenzae but not against Serratia, which produces a β-lactamase that is not inhibited by sulbactam. Similarly, if a strain of P aeruginosa is resistant to piperacillin, it is also resistant to piperacillin-tazobactam because tazobactam does not inhibit the chromosomal β-lactamase produced by P aeruginosa.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-lactam–β-lactamase inhibitor combinations are frequently used as empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immunocompetent patients. Adjustments for renal insufficiency are made based on the β-lactam component.


Pharmacology_Katzung

Pharmacology_Katzung. The carbapenems are structurally related to other β-lactam antibiotics (Figure 43–1). Doripenem, ertapenem, imipenem, and meropenem are licensed for use in the USA. Imipenem, the first drug of this class, has a wide spectrum with good activity against most Gram-negative rods, including P aeruginosa, Gram-positive organisms, and anaerobes. It is resistant to most β-lactamases but not carbapenemases or metallo-β-lactamases. Enterococcus faecium, methicillin-resistant strains of staphylococci, Clostridium difficile, Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use. Doripenem and meropenem are similar to imipenem but have slightly greater activity against Gram-negative aerobes and slightly less activity against Gram-positives. They are not


Pharmacology_Katzung

Pharmacology_Katzung. for clinical use. Doripenem and meropenem are similar to imipenem but have slightly greater activity against Gram-negative aerobes and slightly less activity against Gram-positives. They are not significantly degraded by renal dehydropeptidase and do not require an inhibitor. Unlike the other carbapenems, ertapenem does not have appreciable activity against P aeruginosa and Acinetobacter species. It is not degraded by renal dehydropeptidase.


Pharmacology_Katzung

Pharmacology_Katzung. Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid for all but ertapenem. All are cleared renally, and the dose must be reduced in patients with renal insufficiency. The usual dosage of imipenem is 0.25–0.5 g given intravenously every 6–8 hours (half-life 1 hour). The usual adult dosage of meropenem is 0.5–1 g intravenously every 8 hours. The usual adult dosage of doripenem is 0.5 g administered as a 1or 4-hour infusion every 8 hours. Ertapenem has the longest half-life (4 hours) and is administered as a once-daily dose of 1 g intravenously or intramuscularly. Intramuscular ertapenem is irritating, and the drug is formulated with 1% lidocaine for administration by this route.


Pharmacology_Katzung

Pharmacology_Katzung. A carbapenem is indicated for infections caused by susceptible organisms that are resistant to other available drugs, eg, P aeruginosa, and for treatment of mixed aerobic and anaerobic infections. Carbapenems are active against many penicillin-nonsusceptible strains of pneumococci. Carbapenems are highly active in the treatment of Enterobacter infections because they are resistant to destruction by the β-lactamase produced by these organisms. Clinical experience suggests that carbapenems are also the treatment of choice for serious infections caused by extended-spectrum β-lactamase-producing Gram-negative bacteria. Ertapenem is insufficiently active against P aeruginosa and should not be used to treat infections caused by this organism. Imipenem, meropenem, or doripenem, with or without an aminoglycoside, may be effective treatment for febrile neutropenic patients.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects of carbapenems—which tend to be more common with imipenem—are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Excessive levels of imipenem in patients with renal failure may lead to seizures. Meropenem, doripenem, and ertapenem are much less likely to cause seizures than imipenem. Patients allergic to penicillins may be allergic to carbapenems, but the incidence of cross-reactivity is thought to be less than 1%. Vancomycin is an antibiotic isolated from the bacterium now known as Amycolatopsis orientalis. It is active primarily against Gram-positive bacteria due to its large molecular weight and lack of penetration through Gram-negative cell membranes. The intravenous product is water soluble and stable for 14 days in the refrigerator following reconstitution. Mechanisms of Action & Basis of Resistance


Pharmacology_Katzung

Pharmacology_Katzung. Mechanisms of Action & Basis of Resistance Vancomycin inhibits cell wall synthesis by binding firmly to the d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide (Figure 43–8). This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect. Resistance to vancomycin in enterococci is due to modification of the d-Ala-d-Ala binding site of the peptidoglycan building block in which the terminal d-Ala is replaced by d-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus


Pharmacology_Katzung

Pharmacology_Katzung. Bacterial cell wall Periplasmic space Cytoplasm Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction. G = N-acetylglucos-amine (N-Ag) M = N-acetylmuramic acid (N-Am) G M M M MG G G G MG M G M G M M M M G M G M G M G G G M M M MG G G G +Transpeptidase Crosslinking Cytoplasmic membrane Vancomycin binds the D-Alanine D-Alanine terminus of the amino acid peptide, inhibiting crosslinkage. MG M G M M GG+Vancomycin V A N No crosslinking V A N V A N FIGURE 43–8 Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Vancomycin binds the D-Alanine D-Alanine (D-Ala D-Ala) terminus of the amino acid peptide, inhibiting cross-linkage of the cell wall.


Pharmacology_Katzung

Pharmacology_Katzung. strains (MIC ≥ 16 mcg/mL), which have acquired the enterococcal resistance determinants. The underlying mechanism for reduced vancomycin susceptibility in vancomycin-intermediate strains (MIC = 4–8 mcg/mL) of S aureus is not fully known. However, these strains have altered cell wall metabolism that results in a thickened cell wall with increased numbers of d-Ala-d-Ala residues, which serve as dead-end binding sites for vancomycin. Vancomycin is sequestered within the cell wall by these false targets and may be unable to reach its site of action.


Pharmacology_Katzung

Pharmacology_Katzung. Vancomycin is bactericidal for Gram-positive bacteria in concentrations of 0.5–10 mcg/mL. Most pathogenic staphylococci, including those producing β-lactamase and those resistant to nafcillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; the rate is less than that of the penicillins both in vitro and in vivo. Vancomycin is synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and Enterococcus faecalis strains that do not exhibit high levels of aminoglycoside resistance. Vancomycin is active against many Gram-positive anaerobes including C difficile.


Pharmacology_Katzung

Pharmacology_Katzung. Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of colitis caused by C difficile. Parenteral doses must be administered intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15–30 mcg/mL for 1–2 hours. The drug is widely distributed in the body including adipose tissue. Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is meningeal inflammation. Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, striking accumulation may occur (Table 43–2). In functionally anephric patients, the half-life of vancomycin is 6–10 days. A significant amount of vancomycin is removed during a standard hemodialysis run using a high-flux membrane.


Pharmacology_Katzung

Pharmacology_Katzung. Important indications for parenteral vancomycin are bloodstream infections and endocarditis caused by methicillin-resistant staphylococci. However, vancomycin is not as effective as an antistaphylococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomycin in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a penicillin-resistant strain of pneumococcus. The recommended dosage in a patient with normal renal function is 30–60 mg/kg/d in two or three divided doses. The traditional dosing regimen in adults with normal renal function is 1 g every 12 hours (~30 mg/kg/d); however, this dose will not typically achieve the trough concentrations (15–20 mcg/mL) recommended for serious


Pharmacology_Katzung

Pharmacology_Katzung. dosing regimen in adults with normal renal function is 1 g every 12 hours (~30 mg/kg/d); however, this dose will not typically achieve the trough concentrations (15–20 mcg/mL) recommended for serious infections. For serious infections (see below), a starting dose of 45–60 mg/kg/d should be given with titration of the dose to achieve trough levels of 15–20 mcg/mL. The dosage in children is 40 mg/kg/d in three or four divided doses. Clearance of vancomycin is directly proportional to creatinine clearance, and the dosage is reduced accordingly in patients with renal insufficiency. For patients receiving hemodialysis, a common dosing regimen is a 1-g loading dose followed by 500 mg after each dialysis session. Patients receiving a prolonged course of therapy should have serum trough concentrations checked. For S aureus infections, recommended trough concentrations are 10–15 mcg/mL for mild to moderate infections and 15–20 mcg/mL for more serious infections such as endocarditis,


Pharmacology_Katzung

Pharmacology_Katzung. concentrations checked. For S aureus infections, recommended trough concentrations are 10–15 mcg/mL for mild to moderate infections and 15–20 mcg/mL for more serious infections such as endocarditis, meningitis, and necrotizing pneumonia.


Pharmacology_Katzung

Pharmacology_Katzung. Oral vancomycin, 0.125–0.5 g every 6 hours, is used to treat colitis caused by C difficile. Because of the emergence of vancomycin-resistant enterococci and the potential selective pressure of oral vancomycin for these resistant organisms, metronidazole had been preferred as initial therapy. However, use of oral vancomycin does not appear to be a significant risk factor for acquisition of vancomycin-resistant enterococci. Additionally, recent clinical data suggest that vancomycin is associated with higher initial response rates than metronidazole, particularly for moderate to severe cases of C difficile colitis. Therefore, oral vancomycin may be used as a first-line treatment, especially for severe cases.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse reactions with parenteral administration of vancomycin are encountered fairly frequently. Most reactions are relatively minor and reversible. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Chills and fever may occur. Ototoxicity is rare but nephrotoxicity is still encountered regularly with current preparations, especially with high trough levels. Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL. Among the more common reactions is the so-called “red man” syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours (preferred) or pretreatment with an antihistamine such as diphenhydramine.


Pharmacology_Katzung

Pharmacology_Katzung. Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. Unlike vancomycin, it can be given intramuscularly as well as intravenously. Teicoplanin has a long half-life (45–70 hours), permitting once-daily dosing. This drug is available in Europe but has not been approved for use in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Telavancin is a semisynthetic lipoglycopeptide derived from vancomycin. Telavancin is active versus Gram-positive bacteria and has in vitro activity against many strains with reduced susceptibility to vancomycin. Telavancin has two mechanisms of action. Like vancomycin, telavancin inhibits cell wall synthesis by binding to the d-Ala-d-Ala terminus of peptidoglycan in the growing cell wall. In addition, it disrupts the bacterial cell membrane potential and increases membrane permeability. The half-life of telavancin is approximately 8 hours, which supports once-daily intravenous dosing. The drug is approved for treatment of complicated skin and soft tissue infections and hospital-acquired pneumonia at a dose of 10 mg/kg IV daily. Unlike vancomycin therapy, monitoring of serum telavancin levels is not required. Telavancin was associated with substantial nephrotoxicity and concern for increased mortality associated with renal impairment in clinical trials, leading to boxed warnings. It


Pharmacology_Katzung

Pharmacology_Katzung. is not required. Telavancin was associated with substantial nephrotoxicity and concern for increased mortality associated with renal impairment in clinical trials, leading to boxed warnings. It is potentially teratogenic, so administration to pregnant women must be avoided.


Pharmacology_Katzung

Pharmacology_Katzung. Dalbavancin and oritavancin are semisynthetic lipoglycopeptides derived from teicoplanin. Dalbavancin and oritavancin inhibit cell wall synthesis via the same mechanism of action as vancomycin and teicoplanin; oritavancin works by additional mechanisms, including disruption of cell membrane permeability and inhibition of RNA synthesis. Compared with vancomycin, both agents have lower MICs against many Gram-positive bacteria including methicillin-resistant and vancomycin-intermediate S aureus. Dalbavancin is not active against most strains of vancomycin-resistant enterococci (VRE). Oritavancin has in vitro activity against VRE, but its clinical utility in treating VRE infections remains unclear. Both agents have extremely long half-lives of greater than 10 days, which allows for once-weekly intravenous administration. Dalbavancin and oritavancin have been approved for the treatment of skin and soft tissue infections. There are limited clinical data supporting the use of dalbavancin for


Pharmacology_Katzung

Pharmacology_Katzung. intravenous administration. Dalbavancin and oritavancin have been approved for the treatment of skin and soft tissue infections. There are limited clinical data supporting the use of dalbavancin for uncomplicated catheter-associated bloodstream infections, though it is not approved for use in this setting. Dalbavancin was originally approved as a two-dose, once-weekly intravenous regimen (1000 mg infused on day 1 and 500 mg infused on day 8), but a subsequent phase 3 study comparing the two-dose regimen with a single, 1500-mg intravenous dose showed that the single-dose regimen is noninferior. The results of this study allowed for updated labelling, making both dalbavancin and oritavancin appropriate for single-dose treatments for complicated skin and soft tissue infections. A practical difference between the two is the infusion time: dalbavancin can be administered over 30 minutes, while oritavancin must be infused over 3 hours. Neither requires dose adjustment in mild to moderate


Pharmacology_Katzung

Pharmacology_Katzung. difference between the two is the infusion time: dalbavancin can be administered over 30 minutes, while oritavancin must be infused over 3 hours. Neither requires dose adjustment in mild to moderate renal or hepatic impairment, and neither is removed by dialysis.


Pharmacology_Katzung

Pharmacology_Katzung. Daptomycin is a novel cyclic lipopeptide fermentation product of Streptomyces roseosporus (Figure 43–9). Its spectrum of activity is similar to that of vancomycin except that it may be active against vancomycin-resistant strains of enterococci and S aureus. In vitro, it has more rapid bactericidal activity than vancomycin. The precise mechanism of action is not fully understood, but it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail. This results in depolarization of the cell membrane with potassium efflux and rapid cell death (Figure 43–10). Daptomycin is cleared renally. The approved doses are 4 mg/kg/dose for treatment of skin and soft tissue infections and 6 mg/kg/dose for treatment of bacteremia and endocarditis once daily in patients with normal renal function and every other day in patients with creatinine clearance of less than 30 mL/min. For serious infections, many experts recommend using 8–10 mg/kg/dose. These higher doses appear to


Pharmacology_Katzung

Pharmacology_Katzung. renal function and every other day in patients with creatinine clearance of less than 30 mL/min. For serious infections, many experts recommend using 8–10 mg/kg/dose. These higher doses appear to be safe and well tolerated, although evidence supporting increased efficacy is lacking. In clinical trials, daptomycin was noninferior in efficacy to vancomycin. It can cause myopathy, and creatine phosphokinase levels should be monitored weekly. Pulmonary surfactant antagonizes daptomycin, and it should not be used to treat pneumonia. Daptomycin can also cause an allergic pneumonitis in patients receiving prolonged therapy (>2 weeks). Treatment failures have been reported in association with an increase in daptomycin MIC during therapy. Daptomycin is an effective alternative to vancomycin, and its role continues to unfold.


Pharmacology_Katzung

Pharmacology_Katzung. Fosfomycin trometamol, a stable salt of fosfomycin (phosphonomycin), inhibits a very early stage of bacterial cell wall synthesis. An analog of phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine. This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precursor of N-acetylmuramic acid, which is found only in bacterial cell walls. The drug is transported into the bacterial cell by glycerophosphate or glucose 6-phosphate transport systems. Resistance is due to inadequate transport of drug into the cell.


Pharmacology_Katzung

Pharmacology_Katzung. Fosfomycin is active against both Gram-positive and Gram-negative organisms at concentrations ≥ 125 mcg/mL. Susceptibility tests should be performed in growth medium supplemented with glucose 6-phosphate to minimize false-positive indications of resistance. In vitro synergism occurs when fosfomycin is combined with β-lactam antibiotics, aminoglycosides, or fluoroquinolones. Fosfomycin trometamol is available in both oral and parenteral formulations, although only the oral preparation is approved for use in the USA. Oral bioavailability is approximately 40%. Peak serum concentrations are 10 mcg/mL and 30 mcg/mL following a 2-g or 4-g oral dose, respectively. The half-life is approximately 4 hours. The active drug is excreted by the kidney, with urinary concentrations exceeding MICs for most urinary tract pathogens. FIGURE 43–9 Structure of daptomycin. (Kyn, deaminated tryptophan.)


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 43–9 Structure of daptomycin. (Kyn, deaminated tryptophan.) FIGURE 43–10 Proposed mechanism of action of daptomycin. Daptomycin first binds to the cytoplasmic membrane (step 1) and then forms complexes in a calcium-dependent manner (steps 2 and 3). Complex formation causes a rapid loss of cellular potassium, possibly by pore formation, and membrane depolarization. This is followed by arrest of DNA, RNA, and protein synthesis resulting in cell death. Cell lysis does not occur. Fosfomycin is approved for use as a single 3-g dose for treatment of uncomplicated lower urinary tract infections (UTI) in women. Limited data in case reports have suggested efficacy in males with UTI and prostatitis; in these cases, a 3-g dose has been given every 3 days for 9 days when treating UTI or 21 days for prostatitis. There are no supportive data for using fosfomycin to treat pyelonephritis. The drug appears to be safe for use in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Bacitracin is a cyclic peptide mixture first obtained from the Tracy strain of Bacillus subtilis in 1943. It is active against Gram-positive microorganisms. Bacitracin inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. There is no cross-resistance between bacitracin and other antimicrobial drugs. Bacitracin is highly nephrotoxic when administered systemically and is only used topically (Chapter 61). Bacitracin is poorly absorbed, and topical application results in local antibacterial activity. Bacitracin, 500 units/g in an ointment base (often combined with polymyxin or neomycin), is used for the treatment of infections due to mixed bacterial flora in surface lesions of the skin or on mucous membranes. Bacitracin is commonly associated with hypersensitivity and should not be applied to wounds for the purpose of preventing infection.


Pharmacology_Katzung

Pharmacology_Katzung. Cycloserine is an antibiotic produced by Streptomyces orchidaceous. It is water soluble and very unstable at acid pH. Cycloserine inhibits many Gram-positive and Gram-negative organisms, but it is used almost exclusively to treat tuberculosis caused by strains of Mycobacterium tuberculosis resistant to first-line agents. Cycloserine is a structural analog of d-alanine and inhibits the incorporation of d-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts l-alanine to d-alanine, and d-alanyl-d-alanine ligase. After ingestion of 0.25 g of cycloserine blood levels reach 20–30 mcg/mL—sufficient to inhibit many strains of mycobacteria and Gram-negative bacteria. The drug is widely distributed in tissues. Most of the drug is excreted in active form into the urine. The dosage for treating tuberculosis is 0.5 to 1 g/d in two or three divided doses.


Pharmacology_Katzung

Pharmacology_Katzung. Cycloserine causes serious, dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions. If oral dosages are maintained below 0.75 g/d, such effects can usually be avoided. • Penicillin G Prevents bacterial cell wall synthesis by binding to and inhibiting cell wall transpeptidases Penicillin V: Oral, low systemic levels limit widespread use Benzathine penicillin, procaine penicillin: Intramuscular, long-acting formulations Nafcillin, oxacillin: Intravenous, added stability to staphylococcal β-lactamase, biliary clearance Ampicillin, amoxicillin, piperacillin: Greater activity versus Gram-negative bacteria; addition of β-lactamase inhibitor restores activity against many β-lactamase-producing bacteria


Pharmacology_Katzung

Pharmacology_Katzung. Ampicillin, amoxicillin, piperacillin: Greater activity versus Gram-negative bacteria; addition of β-lactamase inhibitor restores activity against many β-lactamase-producing bacteria CEPHALOSPORINS •CefazolinPrevents bacterial cell wall synthesis by binding to and inhibiting cell wall transpeptidases Rapid bactericidal activity against susceptible bacteria Skin and soft tissue infections, urinary tract infections, surgical prophylaxis IV administration • renal clearance (half-life 1.5 h) • given every 8 h • poor penetration into the central nervous system (CNS) • Toxicity: Rash, drug fever Cephalexin: Oral, first-generation drug used for treating skin and soft tissue infections and urinary tract infections Cefuroxime: Oral and intravenous, second-generation drug, improved activity versus pneumococcus and Haemophilus influenzae Cefotetan, cefoxitin: Intravenous, second-generation drugs, activity versus Bacteroides fragilis allows for use in abdominal/pelvic infections


Pharmacology_Katzung

Pharmacology_Katzung. Cefotetan, cefoxitin: Intravenous, second-generation drugs, activity versus Bacteroides fragilis allows for use in abdominal/pelvic infections Ceftriaxone: Intravenous, third-generation drug, mixed clearance with long half-life (6 hours), good CNS penetration, many uses including pneumonia, meningitis, pyelonephritis, and gonorrhea Cefotaxime: Intravenous, third-generation, similar to ceftriaxone; however, clearance is renal and half-life is 1 hour Ceftazidime: Intravenous, third-generation drug, poor Gram-positive activity, good activity versus Pseudomonas aeruginosa Cefepime: Intravenous, fourth-generation drug, broad activity with improved stability to chromosomal β-lactamases Ceftaroline: Intravenous, active against methicillin-resistant staphylococci, broad Gram-negative activity not including Pseudomonas aeruginosa


Pharmacology_Katzung

Pharmacology_Katzung. Ceftaroline: Intravenous, active against methicillin-resistant staphylococci, broad Gram-negative activity not including Pseudomonas aeruginosa Ceftazidime-avibactam, ceftolozane-tazobactam: Intravenous, cephalosporin-β-lactamase inhibitor combination drugs, broad activity with improved stability to chromosomal β-lactamase and some extended-spectrum β-lactamases Meropenem, doripenem: Intravenous, similar activity to imipenem; stable to renal dehydropeptidase, lower incidence of seizures Ertapenem: Intravenous, longer half-life allows for once-daily dosing, lacks activity versus Pseudomonas aeruginosa and Acinetobacter •VancomycinInhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan Bactericidal activity against susceptible bacteria, slower kill than β-lactam antibiotics Infections caused by Gram-positive bacteria including sepsis, endocarditis, andmeningitis•C difficile colitis (oral formulation)


Pharmacology_Katzung

Pharmacology_Katzung. Teicoplanin: Intravenous, similar to vancomycin except that long half-life (45–70 h) permits once-daily dosing Dalbavancin: Intravenous, very long half-life (>10 days) permits once-weekly dosing Oritavancin: Intravenous, very long half-life (>10 days) permits once-weekly dosing Telavancin: Intravenous, once-daily dosing Oral, IV administration • renal clearance (half-life 6 h) • starting dose of 30 mg/kg/d in two or three divided doses in patients with normal renal function • trough concentrations of • Toxicity: “Red man” syndrome • nephrotoxicity


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS PENICILLINS Amoxicillin Generic, Amoxil, others Amoxicillin/potassium clavulanate *Generic, Augmentin Ampicillin Generic Ampicillin/sulbactam sodium† Generic, Unasyn Dicloxacillin Generic, Dynapen Nafcillin Generic, Nallpen Oxacillin Generic, Bactocill Penicillin G Generic, Pfizerpen Penicillin G benzathine Permapen, Bicillin L-A Penicillin G procaine Generic Penicillin V Generic, V-Cillin, Pen-Vee K, others Piperacillin and tazobactam sodium‡ Zosyn CEPHALOSPORINS & OTHER BETA-LACTAM DRUGS Narrow-spectrum (first-generation) cephalosporins Cefadroxil Generic Cefazolin Generic, Ancef, Kefzol Cephalexin Generic, Keflex, others Intermediate-spectrum (second-generation) cephalosporins Cefaclor Generic Cefotetan Generic, Cefotan Cefoxitin Generic Cefprozil Generic Cefuroxime Generic, Ceftin, Zinacef GENERIC NAME AVAILABLE AS Broad-spectrum (third& fourth-generation) cephalosporins Cefdinir Generic Cefditoren pivoxil Spectracef Cefepime Generic, Maxipime Cefixime


Pharmacology_Katzung

Pharmacology_Katzung. Generic, Ceftin, Zinacef GENERIC NAME AVAILABLE AS Broad-spectrum (third& fourth-generation) cephalosporins Cefdinir Generic Cefditoren pivoxil Spectracef Cefepime Generic, Maxipime Cefixime Suprax Cefotaxime Generic, Claforan Cefpodoxime proxetil Generic Ceftaroline fosamil Teflaro Ceftazidime Generic, Fortaz, Tazicef Ceftazidime/avibactam§ Avycaz Ceftibuten Generic, Cedax Ceftolozane/tazobactam|| Zerbaxa Ceftriaxone Generic, Rocephin Monobactam & Carbapenems Aztreonam Generic, Azactam, Cayston Doripenem Doribax Ertapenem Invanz Imipenem/cilastatin Generic, Primaxin IM, Primaxin IV Meropenem Generic, Merrem IV OTHER DRUGS DISCUSSED IN THIS CHAPTER Cycloserine Generic Dalbavancin Dalvance Daptomycin Cubicin Fosfomycin Monurol Oritavancin Orbactiv Telavancin Vibativ Vancomycin Generic, Vancocin PREP AR A TIONS A V AIL ABLE *Clavulanate content varies with the formulation; see package insert.


Pharmacology_Katzung

Pharmacology_Katzung. †Sulbactam content is half the ampicillin content. ‡Tazobactam content is 12.5% of the piperacillin content. §Avibactam content is 25% of the ceftazidime content. ||Tazobactam content is half the ceftolozane content. Biek D et al: Ceftaroline fosamil: A novel broad-spectrum cephalosporin with expanded Gram-positive activity. J Antimicrob Chemother 2010;65(Suppl 4):iv9. Billeter M et al: Dalbavancin: A novel once-weekly lipoglycopeptide antibiotic. Clin Infect Dis 2008;46:577. Boucher HW et al: Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014;370:2169. Carpenter CF, Chambers HF: Daptomycin: Another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis 2004;38:994. Centers for Disease Control and Prevention (CDC): Antibiotic resistance threats in the United States, 2013. Available at: www.cdc.gov/drugresistance/ threat-report-2013/.


Pharmacology_Katzung

Pharmacology_Katzung. Centers for Disease Control and Prevention (CDC): Antibiotic resistance threats in the United States, 2013. Available at: www.cdc.gov/drugresistance/ threat-report-2013/. Chang C et al: Overview of penicillin allergy. Clinic Rev Allerg Immunol 2012;43:84. Chovel-Sella A et al: The incidence of rash after amoxicillin treatment in children Corey GR et al: Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: The SOLO II noninferiority study. Clin Infect Dis 2015;60:254. DePestel DD et al: Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc 2008;48:530. Fowler VG et al: Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653. Jacoby GA, Munoz-Price LS: The new beta-lactamases. N Engl J Med 2005;352:380.


Pharmacology_Katzung

Pharmacology_Katzung. Jacoby GA, Munoz-Price LS: The new beta-lactamases. N Engl J Med 2005;352:380. Keating GM, Perry CM: Ertapenem: A review of its use in the treatment of bacterial infections. Drugs 2005;65:2151. Kerneis S et al: Cefoxitin as a carbapenem-sparing antibiotic for infections caused by extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae. Infect Dis 2015;47:789. Lee SH et al: TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci. Sci Transl Med 2016;8:329. with infectious mononucleosis. Pediatrics 2013;131:1424. Leonard SN, Rybak MJ: Telavancin: An antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infections. Pharmacotherapy 2008;28:458. Mandell L: Doripenem: A new carbapenem in the treatment of nosocomial infections. Clin Infect Dis 2009;49(Suppl 1):S1. Marston HD et al: Antimicrobial resistance. JAMA 2016;316:1193.


Pharmacology_Katzung

Pharmacology_Katzung. Mandell L: Doripenem: A new carbapenem in the treatment of nosocomial infections. Clin Infect Dis 2009;49(Suppl 1):S1. Marston HD et al: Antimicrobial resistance. JAMA 2016;316:1193. Noskin GA et al: National trends in Staphylococcus aureus infection rates: Impact on economic burden and mortality over a 6-year period. Clin Infect Dis 2007;45:1132. Rybak M et al: Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66:82. Sievart DM et al: Vancomycin-resistant Staphylococcus aureus in the United States, 2002-2006. Clin Infect Dis 2008;46:668. Tamma PD et al: The use of cefepime for treating AmpC β-lactamase-producing enterobacteriaceae. Clin Infect Dis 2013;57:781.


Pharmacology_Katzung

Pharmacology_Katzung. Tamma PD et al: The use of cefepime for treating AmpC β-lactamase-producing enterobacteriaceae. Clin Infect Dis 2013;57:781. Van Duin D and Bonomo RA: Ceftazidime/avibactam and ceftolozane/tazobactam: Second-generation β-lactam/β-lactamase combinations. Clin Infect Dis 2016;63;234. Zar FA et al: A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 2007;45:302.


Pharmacology_Katzung

Pharmacology_Katzung. An intravenous third-generation cephalosporin (ceftriaxone or cefotaxime) with adequate penetration into inflamed meninges that is active against the common bacteria that cause community-acquired pneumonia and meningitis (pneumococcus, meningococcus, Haemophilus) should be ordered. Vancomycin also should be administered until culture and sensitivity results are available in case the patient is infected with a resistant pneumococcus. Although the patient has a history of rash to amoxicillin, the presentation was not consistent with an anaphylactic reaction. The ami-nopenicillins are frequently associated with rashes that are not caused by Type I hypersensitivity. In this instance, cross-reactivity with a cephalosporin is unlikely—particularly with a third-generation drug—and the patient presents with life-threatening illness necessitating appropriate and proven antibiotic coverage. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones