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By F. Osmund. Robert Morris College, Pittsburgh, PA. 2019.

For example purchase levitra super active 20 mg on-line, penicillins discount levitra super active line, which are cell wall is equal to the sum of the independent effects; synergistic synthesis inhibitors generic levitra super active 40mg online, often show additive or synergistic if the combined effect is greater than the sum of the inde- effects with aminoglycosides discount 20mg levitra super active with visa, which inhibit protein syn- pendent effects; and indifferent if the combined effect is thesis, against gram-negative bacilli such as P. Bactericidal tial steps in bacterial folate synthesis and have synergistic drugs are usually more effective against rapidly dividing activity against organisms that may be resistant to either bacteria, and their effect may be reduced if bacterial growth drug alone. As discussed in Chapter 41, tuberculosis is always treated If two bactericidal drugs that target different microbial with more than one drug. Comparison of several possible interactions of two 101 Drugs X and Y antimicrobial drugs combined in vitro. Curves show the results when Synergism cultures containing 105 bacteria per milliliter are incubated with no drug (control), with drug X alone, with drug Y alone, and with a 0 combination of drugs X and Y. In an antagonistic interaction, 0 3 6 9 12 the combined effect is less than the effect of either drug alone. In Hours an indifferent interaction, the combined effect is similar to the great- est effect produced by either drug alone. In a synergistic interaction, Drug(s) the combined effect is greater than the sum of the independent added effects. The invasive procedures or to prevent disease transmission to rate of mutation to a form that is resistant to two drugs is close contacts of infected persons. Recommendations for the product of the individual drug resistance rates, or about prophylaxis are summarized in Box 37-3. Because fewer than 10 organisms are usually present in a patient with tuberculosis, it is unlikely Prevention of Infection Caused that a resistant mutant will emerge during combination by Invasive Procedures therapy. These individuals are at The prevention of infections requires the sterilization of risk for developing acute bacterial endocarditis caused by diagnostic and surgical instruments, the use of disinfectants viridans streptococci and other streptococci that can be to reduce environmental pathogens in hospitals and clinics, acquired during dental, oral, or upper respiratory tract pro- and the disinfection of skin and mucous membranes before cedures and surgery. In some cases, antimicrobial drugs are drug of choice, but endocarditis can be prevented by using also administered prophylactically either to reduce the an alternative drug (e. Drugs are also used to prevent enterococci malaria in persons who are traveling to regions of the world • Aminoglycoside plus broad-spectrum penicillin against where malaria is endemic and to prevent infuenza type A gram-negative bacilli in populations at increased risk for these diseases. Prophy- • Aminoglycoside plus cephalosporin against gram-negative lactic drugs are discussed more thoroughly in subsequent bacilli chapters. Antimicrobial drugs include cell • Broad-spectrum penicillin plus chloramphenicol against wall synthesis inhibitors, protein synthesis inhibitors, Streptococcus pneumoniae metabolic and nucleic acid inhibitors, and cell mem- • Broad-spectrum penicillin plus imipenem against gram- brane inhibitors. The choice of antibiotic depends on • Combination drug therapy is generally used for the the most likely sources of bacterial pathogens during a par- treatment of mixed infections, the empiric treatment ticular procedure. The skin is the most common source of of serious infections, and the prevention of antibiotic pathogens, especially staphylococci, during most types of resistance. The gastrointestinal tract is also an important source synergistic drugs is used for the treatment of infections of pathogens when surgical procedures involve the gastroin- caused by a single microbial species. Surgery to repair contaminated wounds • Antibiotic prophylaxis is used to prevent infections (e. A cell membrane constituent that transports chemother- drugs out of mammalian and microbial cells. The continued suppression of bacterial growth after an has been removed from a bacterial culture or eliminated antibiotic has been eliminated from the body. A synergistic effect occurs (D) concentration-dependent killing when the combined effect of two drugs is greater than the (E) synergistic effect sum of their individual effects. The combined antibacterial effect of two drugs is greater nations show synergism against susceptible organisms, than the sum of their individual effects. Transferable drug resistance (B) indifference refers to the acquisition of genes conferring resistance (C) synergism from other bacteria. Most commonly this occurs by (D) supranormal bacterial conjugation and exchange of plasmids contain- (E) competition ing resistance factors. The most frequent mechanism of transferable drug are less-common mechanisms of transferring drug resistance. It is based on visualiza- (D) conjugation tion of the point of intersection between the zone of (E) mutation and selection bacterial growth inhibition and the concentration scale 5. The penicillins were the frst antibiotics to be discov- • Penicillin G ered and isolated, and their development inaugurated the • Penicillin V modern era of antimicrobial chemotherapy in the 1940s. Penicillinase-Resistant Penicillins Despite the growing problem of microbial resistance to these • Dicloxacillin drugs, they have remained one of the most widely used • Nafcillin groups of antibiotics for over 60 years. This chapter describes • Oxacillin (Bactocill) the structure and function of the bacterial cell envelope and the pharmacologic properties and clinical use of the bacterial Extended-Spectrum Penicillins cell wall inhibitors. The cell wall is much • Clavulanate (with amoxicillin as Augmentin)a thicker in gram-positive bacteria than it is in gram-negative bacteria. The envelope of each gram-negative bacterium also First-Generation Cephalosporins has an outer membrane that is not found in other types of • Cefazolin bacteria. The cell envelope components are illustrated in • Cephalexin (Keflex) Figure 38-1. Second-Generation Cephalosporins Cytoplasmic and Outer Membranes • Cefprozil The cytoplasmic membrane is a trilaminar membrane. It • Cefaclor b contains various types of transport proteins, which facilitate • Cefuroxime (Ceftin, Zinacef) the uptake of a wide variety of substrates used by bacteria, Third-Generation Cephalosporins and it also contains several enzymes required for the synthe- c sis of the cell wall. The outer membrane of gram-negative bacteria is also a Fourth-Generation Cephalosporin trilaminar membrane. It contains species-specifc forms of a • Cefepime (Maxipime) complex lipopolysaccharide and various types of protein channels called porins. One portion of lipopolysaccharide Advanced-Generation Cephalosporin (the lipid A portion) is the endotoxin responsible for • Ceftaroline (Teflaro) gram-negative sepsis. This endotoxin activates immunologic Monobactam mechanisms that lead to fever, platelet aggregation, increased • Aztreonam (Azactam) vascular permeability, and other adverse effects on tissues. Porins allow ions and other small hydrophilic molecules to Carbapenems pass through the outer membrane, and they are responsible d • Imipenem (with cilastatin as Primaxin) for the entry of several types of antibiotics. Acquired altera- tions in porin structure can lead to microbial resistance to Other Bacterial Cell Wall antibiotics, as is the case with resistance to imipenem. Synthesis Inhibitors The bacterial cytoplasmic membrane is the target of two • Bacitracin peptide antibiotics, daptomycin and polymyxin. These • Fosfomycin (Monurol) drugs act directly on the cell membranes to increase mem- • Vancomycin brane permeability and thereby cause the cytoplasmic con- • Telavancin (Vibativ) tents to leak out of the cell. The properties and uses of these aAlso clavulanate with ticarcillin (Timentin), sulbactam with ampicillin antibiotics are discussed in Chapter 40. A, The gram-positive bacterium has a thick cell wall but does not have an outer membrane. It also has an outer membrane that contains lipopolysaccharide and protein channels called porins. Each disaccharide is attached to others and thereby inhibit the catalytic activity of these enzymes. During this reaction, the terminal This partly accounts for the variation in the sensitivity of d-alanine is removed. The cell wall maintains the shape of the bacterium and protects it from osmotic lysis if it is placed in a hypotonic Other Drugs medium. Bacitracin and fosfomycin inhibit cell wall peptidoglycan This is why inhibition of cell wall synthesis by antimicrobial synthesis by blocking specifc steps in the formation of drugs is usually bactericidal. As shown in higher organisms, antimicrobial drugs can inhibit its for- in Figure 38-2, bacitracin inhibits the dephosphorylation mation without harming host cells. The cell wall is synthe- of bactoprenol pyrophosphate, which is the carrier lipid sized during bacterial replication, and drugs that inhibit cell required for regeneration of bactoprenol phosphate, the wall synthesis are more active against rapidly dividing bac- active carrier of the disaccharide precursor. Fosfomycin teria than they are against bacteria in the resting or station- inhibits enolpyruvyl transferase, the enzyme that cata- ary phase. D-alanine portion of the peptidoglycan precursor and prevents bonding of the penultimate d-alanine to the pen- Sites of Drug Action taglycine peptide during cross-linking of peptidoglycan β-Lactam Drugs strands. Numbers indicate the steps involved in the synthesis of the cell wall of Staphylococcus aureus. In step 1, bactoprenol 5 pyrophosphate (bactoprenol-P-P) is dephosphorylated to regener- (Gly)5 ate the carrier molecule, bactoprenol phosphate (bactoprenol-P). In step 5, the disaccharide peptide is transferred to the peptidoglycan growth point. In this reaction a glycine of one strand forms a peptide bond with the penultimate d-alanine 6 of an adjacent strand, and the terminal d-alanine is released. Baci- (Gly)5 (Gly)5 tracin blocks step 1, and β-lactam antibiotics and vancomycin β-Lactam antibiotics and block step 6 by different mechanisms. Alexander Fleming is credited with the discovery of penicil- group that protects them from hydrolysis by staphylococcal lin, but he was unable to isolate the substance in suffcient penicillinase, a specifc type of bacterial β-lactamase. Florey, working in England, obtained enough penicil- Pharmacokinetics lin to establish its clinical effectiveness.

The fourth- and fifth-generation agents are effective against resistant organisms levitra super active 20 mg otc. First-Generation Cephalosporins When a cephalosporin is indicated for a gram-positive infection cheap levitra super active 20mg amex, a first- generation drug should be used; these agents are the most active of the cephalosporins against gram-positive organisms and are less expensive than other cephalosporins buy 40mg levitra super active overnight delivery. First-generation agents are frequently employed as alternatives to penicillins to treat infections caused by staphylococci or streptococci (except enterococci) in patients with penicillin allergy order levitra super active in united states online. However, it is important to note that cephalosporins should be given only to patients with a history of mild penicillin allergy—not to those who have experienced a severe, immediate hypersensitivity reaction. The first-generation agents have been employed widely for prophylaxis against infection in surgical patients. First-generation agents are preferred to second- or third-generation cephalosporins for surgical prophylaxis because they are as effective as the newer drugs, are less expensive, and have a more narrow antimicrobial spectrum. Second-Generation Cephalosporins Specific indications for second-generation cephalosporins are limited. Cefuroxime has been used with success against pneumonia caused by Haemophilus influenzae, Klebsiella species, pneumococci, and staphylococci. Oral cefuroxime is useful for otitis, sinusitis, and respiratory tract infections. Nosocomial infections caused by gram-negative bacilli, which are often resistant to first- and second- generation cephalosporins (and most other commonly used antibiotics), are appropriate indications for the third-generation drugs. Two third-generation agents—ceftriaxone and cefotaxime—are drugs of choice for infections caused by Neisseria gonorrhoeae (gonorrhea), H. Rather, they should be given only when conditions demand so as to delay emergence of resistance. Fourth-Generation Cephalosporins There are only two drugs in this category: cefepime [Maxipime] and ceftolozane/tazobactam [Zerbaxa]. Cefepime is commonly used to treat health care− and hospital-associated pneumonias, including those caused by the resistant organism Pseudomonas. Zerbaxa was approved in 2014 for the treatment of complicated intraabdominal and urinary tract infections. Drug Selection Nineteen cephalosporins are currently employed in the United States, and selection among them can be a challenge. Within each generation, the similarities among cephalosporins are more pronounced than the differences. Hence, aside from cost, there is frequently no rational basis for choosing one drug over another in the outpatient setting. However, there are some differences between cephalosporins, and these differences may render one agent preferable to another for treating a specific infection in a specific host. The differences that do exist can be grouped into three main categories: (1) antimicrobial spectrum, (2) adverse effects, and (3) pharmacokinetics (e. Antimicrobial Spectrum A prime rule of antimicrobial therapy is to match the drug with the bug: the drug should be active against known or suspected pathogens, but its spectrum should be no broader than required. When a cephalosporin is appropriate, we should select from among those drugs known to have good activity against the causative pathogen. The third- and fourth-generation agents, with their very broad antimicrobial spectra, should be avoided in situations in which a narrower spectrum, first- or second-generation drug would suffice. For some infections, one cephalosporin may be decidedly more effective than all others and should be selected on this basis. For example, ceftazidime (a third- generation drug) is the most effective of all cephalosporins against P. Adverse Effects Although most cephalosporins produce the same spectrum of adverse effects, a few can cause unique reactions. When an equally effective alternative is available, it would be prudent to avoid these drugs. Duration of Action In patients with normal renal function, the half-lives of the cephalosporins range from about 30 minutes to 9 hours (see Table 70. Because they require fewer doses per day, drugs with a long half-life are frequently preferred. Cephalosporins with the longest half-lives in each generation are as follows: first generation, cefazolin (1. Hence, for meningitis caused by susceptible organisms, these drugs are preferred over first- and second-generation agents. Route of Elimination Most cephalosporins are eliminated by the kidneys and, if dosage is not carefully adjusted, they may accumulate to toxic levels in patients with renal impairment. Only one agent—ceftriaxone—is eliminated primarily by nonrenal routes and hence can be used with relative safety in patients with kidney dysfunction. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment. Administration Oral If oral cephalosporins produce nausea, administration with food can reduce the response. Intramuscular injection of cephalosporins is frequently painful; the patient should be forewarned. The injection site should be checked for induration, tenderness, and redness, and the prescriber informed if these occur. To delay emergence of resistance, these drugs should be reserved for patients who cannot be treated with a more narrow- spectrum agent. Imipenem Imipenem [Primaxin], a beta-lactam antibiotic, has an extremely broad antimicrobial spectrum—broader, in fact, than nearly all other antimicrobial drugs. As a result, imipenem may be of special use for treating mixed infections in which anaerobes, S. Imipenem is supplied in fixed-dose combinations with cilastatin, a compound that inhibits destruction of imipenem by renal enzymes. Antimicrobial Spectrum Imipenem is active against most bacterial pathogens, including organisms resistant to other antibiotics. The drug is highly active against gram-positive cocci and most gram-negative cocci and bacilli. In addition, imipenem is the most effective beta-lactam antibiotic for use against anaerobic bacteria. When employed alone, imipenem is inactivated by dipeptidase, an enzyme present in the kidneys. To increase urinary concentrations, imipenem is administered in combination with cilastatin, a dipeptidase inhibitor. When the combination is used, about 70% of imipenem is excreted unchanged in the urine. Hypersensitivity reactions (rashes, pruritus, drug fever) have occurred, and patients allergic to other beta-lactam antibiotics may be cross-allergic with imipenem. Fortunately, the incidence of cross sensitivity with penicillins is low —only about 1%. Interaction With Valproate Imipenem can reduce blood levels of valproate, a drug used to control seizures (see Chapter 19). If no other antibiotic will suffice, supplemental antiseizure therapy should be considered. Therapeutic Use Because of its broad spectrum and low toxicity, imipenem is used widely. The drug is effective for serious infections caused by gram-positive cocci, gram- negative cocci, gram-negative bacilli, and anaerobic bacteria. This broad antimicrobial spectrum gives imipenem special utility for antimicrobial therapy of mixed infections (e. Consequently, imipenem should be combined with another antipseudomonal drug when used against this microbe. Children/adolescents Cephalosporins are commonly used to treat bacterial infections in children, including otitis media and gonococcal and pneumococcal infections. Pregnant women Administration of telavancin during pregnancy should be avoided because of risk for adverse developmental outcomes. Breastfeeding Cephalosporins are generally not expected to cause adverse effects in breastfed infants. Other Carbapenems Meropenem Actions and Uses Meropenem [Merrem] is a beta-lactam antibiotic similar in structure and actions to imipenem. Meropenem is active against most clinically important gram- positive and gram-negative aerobes and anaerobes. Approved indications are (1) bacterial meningitis in children age 3 months or older, (2) intraabdominal infections in children and adults, and (3) complicated skin and skin structure infections in children and adults.

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Hypothyroidism in Infants Clinical Presentation Hypothyroidism in newborns may be permanent or transient purchase generic levitra super active. In either case buy levitra super active overnight delivery, congenital hypothyroidism can cause delay in mental development and derangement of growth purchase generic levitra super active online. In the absence of thyroid hormones levitra super active 20 mg low cost, the child develops a large and protruding tongue, potbelly, and dwarfish stature. Causes Congenital hypothyroidism usually results from a failure in thyroid development. Therapeutic Strategy Hypothyroidism in newborns requires replacement therapy with thyroid hormones. If treatment is initiated within a few days of birth, physical and mental development will be normal. However, if therapy is delayed beyond 3 to 4 weeks, some permanent disability will be evident, although the physical effects of thyroid deficiency will reverse. In all children, replacement therapy should continue for 3 years, after which it should be stopped for 4 weeks. The objective is to determine whether thyroid deficiency is permanent or transient. Hyperthyroidism There are two major forms of hyperthyroidism: Graves disease and toxic nodular goiter (also known as Plummer disease). The principal difference is that Graves disease may cause exophthalmos, whereas toxic nodular goiter does not. Graves Disease Graves disease is the most common cause of excessive thyroid hormone secretion. Clinical Presentation Most clinical manifestations result from elevated levels of thyroid hormone. The central nervous system is stimulated, resulting in nervousness, insomnia, rapid thought flow, and rapid speech. Metabolic rate is raised, resulting in increased heat production, increased body temperature, intolerance to heat, and skin that is warm and moist. However, despite increased food consumption, weight loss occurs if caloric intake fails to match the increase in metabolic rate. In addition to thyrotoxicosis, patients with Graves disease often present with exophthalmos. The underlying cause is an immune-mediated infiltration of the extraocular muscles and orbital fat by lymphocytes, macrophages, plasma cells, mast cells, and mucopolysaccharides. Treatment Treatment for Graves disease is directed at decreasing the production of thyroid hormones. Three modalities are employed: (1) surgical removal of thyroid tissue, (2) destruction of thyroid tissue with radioactive iodine, and (3) suppression of thyroid hormone synthesis with an antithyroid drug (methimazole or propylthiouracil). Radiation is the preferred treatment for adults, whereas antithyroid drugs are preferred for younger patients. Because exophthalmos is not the result of hyperthyroidism per se, this condition is not improved by lowering thyroid hormone production. If exophthalmos is severe, it can be treated with surgery or with high doses of oral glucocorticoids. Toxic Nodular Goiter (Plummer Disease) Toxic nodular goiter is the result of a thyroid adenoma. Clinical manifestations are much like those of Graves disease, except exophthalmos is absent. Toxic nodular goiter is a persistent condition that rarely undergoes spontaneous remission. However, if an antithyroid drug is used, symptoms return rapidly when the drug is withdrawn. Accordingly, surgery and radiation, which provide long-term control, are often preferred. Thyrotoxic Crisis (Thyroid Storm) Thyrotoxic crisis can occur in patients with severe thyrotoxicosis when they undergo major surgery or develop a severe intercurrent illness (e. The syndrome is characterized by profound hyperthermia (105° F or even higher), severe tachycardia, restlessness, agitation, and tremor. High doses of potassium iodide or strong iodine solution are given to suppress thyroid hormone release. Thyroid Hormone Preparations for Hypothyroidism Thyroid hormones are available as pure, synthetic compounds and as extracts of animal thyroid glands. The synthetic preparations are more stable and better standardized than the animal gland extracts. Levothyroxine is the drug of choice for most patients who require thyroid hormone replacement. Consequently, levothyroxine will serve as our prototype for the thyroid hormone preparations. P ro t o t y p e D r u g s Drugs for Thyroid Disorders Drugs for Hypothyroidism Levothyroxine (T )4 Drugs for Hyperthyroidism Methimazole (a thionamide) Pharmacokinetics Absorption Absorption of oral levothyroxine is reduced by food. Accordingly, to minimize variability in blood levels, levothyroxine should be taken on an empty stomach in the morning, at least 30 to 60 minutes before breakfast. Conversion to T3 Much of an administered dose of levothyroxine is converted to T in the body. The good news is that hormone levels remain fairly steady, even with once-a-day dosing, which makes levothyroxine well suited for lifelong therapy. The bad news is that it takes about 1 month (four half-lives) for plasma levels of levothyroxine to reach plateau (steady state). Therapeutic Uses Levothyroxine is indicated for all forms of hypothyroidism, regardless of cause. The drug is used for congenital hypothyroidism, myxedema coma, simple goiter, and primary hypothyroidism in adults and children. In addition, levothyroxine is used to maintain proper levels of thyroid hormones after thyroid surgery, irradiation, and treatment with antithyroid drugs. Adverse Effects When administered in appropriate dosage, levothyroxine rarely causes adverse effects. Signs and symptoms include tachycardia, angina, tremor, nervousness, insomnia, hyperthermia, heat intolerance, and sweating. The patient should be informed about these signs and instructed to notify the prescriber if they develop. Chronic overdosage is associated with accelerated bone loss and increased risk for atrial fibrillation, especially in older adults. Drug Interactions Drugs That Reduce Levothyroxine Absorption Absorption of levothyroxine can be reduced by the following drugs: • Histamine (H ) receptor blockers (e. Drugs That Accelerate Levothyroxine Metabolism Several drugs can accelerate the metabolism of levothyroxine. Among these are phenytoin [Dilantin], carbamazepine [Tegretol, Carbatrol], rifampin [Rifadin], sertraline [Zoloft], and phenobarbital. Accordingly, to maintain adequate levothyroxine levels, patients taking these drugs may need to increase their levothyroxine dosage. Levothyroxine accelerates the degradation of vitamin K–dependent clotting factors. If thyroid hormone replacement therapy is started in a patient taking warfarin, the dosage of warfarin may need to be reduced. Thyroid hormones increase cardiac responsiveness to catecholamines, thereby increasing the risk for catecholamine-induced dysrhythmias. Caution must be exercised when administering catecholamines to patients receiving levothyroxine and other thyroid preparations. Other Interactions Levothyroxine can increase requirements for insulin and digoxin. When converting patients from a hypothyroid to a euthyroid state, dosages of insulin and digoxin may need to be increased. Levothyroxine has a narrow therapeutic range, so tight control of plasma drug levels is important. To maintain good control, all pills a patient takes must produce the same levothyroxine levels.

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