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Phagocytic cells are in turn attracted to chronic arthritis in feet purchase 120 mg etoricoxib fast delivery these react against normal endogenous proteins and thereby sites arthritis in feet diet purchase cheap etoricoxib on-line, where they release enzymes that destroy sureffect a reaction against certain body tissues multiple levels of arthritis in neck buy genuine etoricoxib line. They are usually apparent at birth or develop Cranial arteritis shortly thereafter rheumatoid arthritis labs buy genuine etoricoxib online. For those with deficienWegener’s granulomatosis cies in humoral immunity, the only effective treatment available is antibody replacement. For those with deficiencies in cell-mediated immunity, there is no effective pharmacological treatment. In general, because suppressive therapy is commonly used can be found in of the role of antibodies in protection against bacterial Table 57. Since transplantation is usually perCandida albicans, cytomegalovirus, and Pneumocystis formed in patients with a poor prognosis for survival, carinii, since cell-mediated immune responses are the the use of immunosuppressive agents has potentially primary defenses against these types of infection. In the past, immunosuppression could be achieved only through the use of nonspecific cytotoxic drugs. Consequently, serious side effects, including bone consider three principles of immunosuppressive therapy. Therefore, components of concurrent use of corticosteroids with the immunosupthe primary phase of the immune response, such as propressants increased the risk of additional toxicity. With cessing, proliferation, and differentiation, will be the the development of the immunosuppressants cymost sensitive to drug action. Drugs that are effective in closporine and tacrolimus it is now possible to avoid suppressing an immune response in an unsensitized permuch of this toxicity. Because of their relatively low toxson generally will show much less effect, if any, in a senicity, these drugs have revolutionized the field of transsitized individual. It is now possible to successfully transplant has been established, immunosuppressive drugs show tissues to patients not previously considered as candilittle effectiveness. Cellular 57 Immunomodulating Drugs 659 and humoral immunity may be affected differentially. Peak plasma concentrations are reached in Additionally, the different classes of immune globulins 3 to 4 hours, and the plasma half-life is 10 to 27 hours. Metabolism results in inactivainflammatory properties of certain of these drugs may tion of the immunosuppressive activity. Agents that enbe valuable because inflammation often accompanies hance or inhibit the mixed-function oxidase enzymes the immune response. If only an inflammatory reaction will alter the therapeutic response to cyclosporine. Cyclosporine has been approved for use in allogeneic the focus in the next section is on immunosuppreskidney, liver, and heart transplant patients and is under sants that have been shown to be clinically useful. Cyclosporine Cyclosporine appears to have promise in the treatCyclosporine (Sandimmune) is a potent inhibitor of anment of autoimmune diseases. It has a beneficial effect tibodyand cell-mediated immune responses and is the on the course of rheumatoid arthritis, uveitis, insulinimmunosuppressant of choice for the prevention of dependent diabetes, systemic lupus erythematosus, and transplant rejection. The molecule is very lipophilic and essenare often required to suppress autoimmune disorders. Adverse Effects Compared with previously available therapy, the adverse Mechanism of Action effects associated with cyclosporine are much less severe Cyclosporine can bind to the cytosolic protein cybut still worthy of concern. This drug–protein complex inhibits calcur in up to 75% of patients, ranges from severe tubular cineurin phosphatase activity, which leads to a denecrosis to chronic interstitial nephropathy. This effect is creased synthesis and release of several cytokines, generally reversible with dosage reduction. Hypertension occurs in Cyclosporine exhibits a high degree of specificity in 25% of the patients and more frequently in patients with its actions on T cells without significantly impairing Bsome degree of renal dysfunction; the concomitant use of cell activity. It can inhibit the T cell–dependent limb of antihypertensive drugs may prove useful. Hyperglyantibody production by lymphocytes by preventing the cemia, hyperlipidemia, transient liver dysfunction, and differentiation of B cells into antibody-secreting plasma unwanted hair growth are also observed. However, the toxicity asAbsorption, Metabolism, and Excretion sociated with their use necessitates prudent administraAfter oral administration, cyclosporine is absorbed tion. Additional information on corticosteroids can be slowly and incompletely, with great variation among infound in Chapter 60. Virtually all phases of the inflammatory Mechanism of Action process are affected by these drugs. Corticosteroid therAzathioprine is a phase-specific drug that is toxic to apy alone is successful in only a limited number of aucells during nucleic acid synthesis. Phase-specific drugs toimmune diseases, such as idiopathic thrombocytopeare toxic during a specific phase of the mitotic cycle, nia, hemolytic anemia, and polymyalgia rheumatica. Azathioprine is converted in vivo to thioinosinic Tacrolimus (Prograf) is a second-generation immunoacid, which competitively inhibits the synthesis of insuppressive agent that has been approved for use in osinic acid, the precursor to adenylic acid and guanylic liver transplantation. This those of cyclosporine except that weight for weight it is effectively inhibits both humoral and cell-mediated im10 to 100 times more potent. Although the binding proteins (cytophilins) Azathioprine is well absorbed following oral adminisfor cyclosporine and tacrolimus are different, they share tration, with peak blood levels occurring within 1 to 2 similar functions in that the cytophilins are important hours. It is rapidly and extensively metabolized to 6for the intracellular folding of proteins. It is speculated mercaptopurine, which is further converted in the liver that these proteins are important in regulating gene exand erythrocytes to a variety of metabolites, including 6pression in T lymphocytes and that both drugs somethiouric acid. Although its beneficial effect in various condiSirolimus tions is principally attributable to its direct immunosuppressive action, the antiinflammatory properties of the Sirolimus (Rapamune) is structurally related to drug play an important role in its overall therapeutic eftacrolimus. This mechanism of action is different it is usually reserved for patients who do not respond to from those of tacrolimus and cyclosporine. It is as effective as cyclophosAzathioprine phamide in the treatment of Wegener’s granulomatosis. It has largely been replaced by cyclosporine in imAzathioprine (Imuran) is a cytotoxic agent that prefermunosuppressive therapy. Since imagents, the better oral absorption of azathioprine is the munologically competent cells are generally rapidly direason for its more widespread clinical use. Unfortunately, any cell that is Adverse Effects replicating is a target for this action. The therapeutic use of azathioprine has been limited by Azathioprine, in combination with corticosteroids, the number and severity of adverse effects associated has historically been used more widely than any other with its administration. It is classified as a sulting in leukopenia, thrombocytopenia, or both may 57 Immunomodulating Drugs 661 occur. Because of its immunosuppressive activity, been used successfully alone and in combination with azathioprine therapy can lead to serious infections. It azathioprine and corticosteroids to prevent renal allohas been shown to be mutagenic in animals and humans graft rejection. Mycophenolate Mofetil Antithymocyte globulin binds to circulating T lymphocytes in the blood, which are subsequently removed Mycophenolate mofetil (CellCept), in conjunction with from the circulation by the reticuloendothelial system. It is used steroids is a more effective regimen than azathioprine for the prevention of acute allograft rejection in kidin preventing the acute rejection of transplanted organs. It is also used to deplete T cells in marrow from donors before bone marrow transplantaOther Cytotoxic Drugs tion. See Chapter 56 for izing antibodies may develop over time and necessitate further details of these agents. Antibodies Antiserum can be raised against lymphocytes or thymoRho(D) Immune Globulin cytes by the repeated injection of human cells into an An Rh-negative mother can become sensitized to Rh appropriate recipient, usually a horse. This antiserum or the immune globulin fraction derived sensitization may lead to Rh hemolytic disease in future from it has been used to produce immunosuppression. Rho(D) graft systems, the responses are variable, particularly immune globulin functions to prevent the mother from from one batch of serum to another. It is generally given at 28 weeks of pregnancy Antithymocyte globulin (Atgam) is purified immune and within 72 hours after delivery. Rh incompatibility globulin obtained from hyperimmune serum of horses can be identified with routine blood tests. These conditions humoral immunodeficiency, congenital agammaglobuinclude immunodeficiency diseases, cancer, some types linemias, common variable immunodeficiency, severe of viral and fungal infections, and certain autoimmune combined immunodeficiency, idiopathic thrombocydisorders.

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Mitotane is capable of inducing remission of Because of its effectiveness in blocking C17-20 lyase Cushing’s disease arthritis pain prescriptions buy cheap etoricoxib 90mg line, but only after several weeks of theractivities arthritis medication kidney cheap 90 mg etoricoxib amex, ketoconazole does not enhance existing hirapy and at the price of severe gastrointestinal distress arthritis relief drink buy cheap etoricoxib online. On the other hand arthritis medication wikipedia 90mg etoricoxib otc, Moreover, more than half of patients relapse following the antiandrogenic effects of ketoconazole may prove cessation of therapy. Hypoadrenalism, nausea, and drowsiness have been reported during prolonged adMifepristone is a progesterone receptor antagonist that ministration of mifepristone. This drug has recently been approved for Dexamethasone use in the United States for the treatment of hypercortisolism. At high doses, mifepristone blocks negative Cushing’s disease is defined as hypercortisolism due to feedback of the hypothalamic–pituitary axis, thereby inchronic overproduction of corticotrophin by a corticreasing endogenous corticotrophin and cortisol levels. Cortisol’s lack of suppressibility durBecause mifepristone exerts its effects at the receptor ing the administration of low doses of dexamethasone level and not by altering glucocorticoid production, elebut suppressibility during high-dose dexamethasone is vated serum cortisol and corticotrophin levels may not the key diagnostic finding in 99% of the patients with accurately reflect the effectiveness of the therapeutic Cushing’s disease. Mifepristone does not inhibit cortisol binding corticoid suppressibility typically found in patients with to the mineralocorticoid receptor, so that the resulting corticotrophin-independent hypercortisolism (Cushing’s corticotrophin disinhibition may cause potassium desyndrome). Thus, administration of a mineralocorticoid remay be necessary to obtain an accurate diagnosis in paceptor antagonist such as spironolactone may be inditients with Cushing’s syndrome. The addition of a fluoride group on ring C of cortiglucocorticoid therapy sol to give 9-fluorocortisol (A) Prompt recovery of the hypothalamic– (A) Will shorten its half-life pituitary–adrenal axis results in restoration of en(B) Will increase both glucocorticoid and minerdogenous corticotrophin release. Dexamethasone uted to steroid withdrawal may be difficult to distin(A) Is adequate replacement therapy in an adrenaguish from reactivation of rheumatic disease. Which one of the following enzymes is required for (B) Has a half-life equivalent to that of cortisol cortisol biosynthesis? Recovery from prolonged steroid therapy is thesis, ketoconazole is frequently used as an antislow, and the withdrawal may be unpleasant. Its action is readily reversible and is patient may be reluctant to reduce the dose of used principally for interim management of steroid because of its salutary effects on the psyche. Tapering the dose of steroid is important in steroid Ketoconazole preferentially blocks the C17,20 lyase withdrawal; however, the patient may temporarily reaction that is involved in the synthesis of sex require a dose increase during periods of heightsteroids. Molecular mechanisms of glucocorticoid hydroxysteroid dehydrogenase-2 acts as a reducactions. Efficacy of inhaled corticosteroids in ative cortisone, whereas 18-hydroxylase is required asthma. J Allergy Clin Immunol hypothalamic–pituitary–adrenal axis is an unwanted 1998;102:S5–S16. Management of bone disease in patients ment of a sense of well-being may be attributed to on long term glucocorticoid therapy. Rheumatol Dis Clin cortisol to give 9-fluorocortisol greatly increases North Am 2000;26:859–880. Assessment of adrenal glucocorticoid funcagent with potent glucocorticoid and mineralocortition. Glucocorticoid-induced ostended action, fluorocortisol will have a greater tenteoporosis. Medical therapy for While devoid of salt-retaining activity in therapeutic Cushing’s disease. Endocrinol Metab Clin North doses, this glucocorticoid does possess most of the Am 1999;28:211–222. Because it lacks mineralocorticoid activity, dexamethasone is not used in replacement therapy. Inferior petrosal sinus sampling proJwas admitted to the emergency department in vided a final confirmation of the diagnosis. A previous physical examination tient was prescribed metyrapone 2 g/day and showed hypertension and diabetes mellitus type 2. Hyponatremia and the patient’s present medications include enalapril hyperkalemia required the concomitant administra40 mg, nifedipine 60 mg, and 100 U insulin. A physition of a mineralocorticoid, fludrocortisone acetate cal examination revealed prominent ankle edema, a 0. Chest radiogratient’s overall appearance and the clinical findings phy revealed diffuse cardiac enlargement and left began to improve slowly. Based upon the history better controlled, congestive failure showed imand clinical findings, what is your diagnosis and provement, insulin resistance diminished, and bone what treatment do you recommend? This study illustrates the important mg/dL) suggest hypercortisolism (Cushing’s synprinciple that clinical acumen and judicious use of drome). This tentative diagnosis was supported by a drugs in diagnosis and treatment can lead to the low-dose (1 mg) dexamethasone overnight suppresdramatic reversal of the metabolic and cardiovascusion test demonstrating unsuppressed serum cortilar abnormalities in a patient with severe Cushing’s sol (1409 nM). Progesterone is Biologically important natural estrogens and progestins secreted in small amounts by the testes and adrenal include estradiol, estrone, estriol, and progesterone. The combined estrogen and progestin production Estradiol-17 is the most potent estrogen that is found by all of these peripheral sites amounts to 10% or less naturally in women. Estrone is one-tenth as biologically of ovarian synthesis in normal premenopausal women. Estriol is synthesized by the placenta and is exdeclines and peripheral estrogen biosynthesis accounts creted at high levels in the urine of pregnant women. The naturally occurring estrogens and progestins the ovary is the major site of estrogen and progestin are not orally active because they are rapidly metabolibiosynthesis in nonpregnant premenopausal women. The major site of estrogen and progpregnant women, the fetoplacental unit is the major estin metabolism is the liver. Estrogens and progestins are primarily example of a nongenomic estrogen action that is mediated creted in the urine. This enzyme produces nitric oxconjugates are the most abundant estrogen urinary ide. Progesterone, on the Plasma proteins bind estrogens and modulate estroother hand, appears to limit tissue responses to estrogen genic activity. It is this cyclical release of Estrogens and progestins exert their effects in target tisestrogen and progesterone that determines the regular sues by a combination of cellular mechanisms. Highhormonal changes in the uterus, vagina, and cervix asaffinity estrogen and progestin receptors are found in tarsociated with the menstrual cycle. Gene activation is mediated cycle, estradiol blood levels rise slowly and then fall by the ability of steroid hormone receptor complexes to quite rapidly. Estradiol blood levels peak around midrecruit nuclear coactivator proteins to the transcription cycle (days 12–14). As a consequence, during the An additional mode of estrogen and progesterone luteal phase, estrogen production is reduced and androaction is classified as nongenomic effects. In the event that pregnancy occurs, human chorionic goGrowth and Development nadotropin secretion by the embryo maintains the corpus luteum through stimulation of progesterone and esEstrogens cause the growth of the uterus, fallopian trogen synthesis. Stimulation of proliferation of the vaginal epithelium is checked by the cyclical exposure to progesterone during the luteal phase in the mature Control of Pregnancy female. Estrogens also are responsible for the expresOvulation sion of female secondary sex characteristics during puDuring the follicular phase of the menstrual cycle, one berty. These include breast enlargement, the distribuor more follicles are prepared for ovulation. This has led to the idea that progesterone, as well as estrogens, exerts mitotic effects in adult human breast tissue. The effects of Implantation estrogens and progesterone on breast development are the lining of the uterus, that is, the endometrium, is critmost noticeable during puberty and pregnancy. The enEstrogens can stimulate the release of growth hordometrium consists of a layer of epithelial cells overlymone and exert a positive effect on nitrogen balance. Under the these effects contribute to the growth spurt during puinfluence of estrogen and progesterone, the endomeberty. Closure of the bone epiphyses signaling the end trium undergoes cyclical changes that prepare it for the of long bone growth is also estrogen mediated. Estrogens induce endometrial cell division and tivity of other bone cells, called osteoclasts. Estrogens to high concentrations of progesterone and moderate maintain bone mass by inhibiting bone resorption by estradiol levels, the mitotic activity in the endometrial the osteoclasts. The action of progesterone on the tokines by peripheral blood cells and the osteoblasts endometrium converts it from a proliferative state to a that stimulate osteoclast activity.

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Licensed psychologists: Psychopharmacology trainother meta-analyses of the same drugs: Systematic review rheumatoid arthritis diet mayo clinic order etoricoxib 60mg with visa. PsyBoard of Educational Affairs Working Group on Psychopharmacology chopharmacology Bulletin rheumatoid arthritis early signs discount generic etoricoxib canada, 27 arthritis pain tylenol or advil etoricoxib 90mg online, 417–426 rheumatoid arthritis hip purchase etoricoxib 90 mg on line. Pharmafor mental disorders: A guide to psychological and pharmacological ceutical industry sponsorship and research outcome and quality: Sysinterventions. Culture and psychopharin the use of antidepressant pharmacotherapy and diagnosis of depresmacology. Journal of Psychopharmacology, 8, differences in the pharmacogenetics of psychotropics (pp. Professional Psychology: Research and Practice, 35, Hoc Task Force on Psychopharmacology of the American Psycholog158–163. A 14-month randomized clinical trial of nation for adolescents with depression: Treatment for Adolescents treatment strategies for attention deficit hyperactivity disorder. Selective publication of antidepressant trials and its influence of antidepressant treatment for adults with depression in the United on apparent efficacy. Industry sponsorship and financial conflict of interest in in the prescribing of psychotropic medication really a new activity? One size fits some: the impact of patient pharmaceutical advertisements in medical journals. Pharmaceutical submitted to the Food and Drug Administration: Review of publication and advertisements in leading medical journals: Experts’ assessments. Journal of Child and Adolescent Psychopharmacology, 8, Nidotherapy and a clinical vignette from Oman. This antibiotic is rapidly bactericidal as it inhibits bacterial cell protein synthesis. Bacterial killing is concentration dependent: the higher the concentration, the greater the rate of bacterial killing. Dosing recommendations are based on: (1) higher gentamicin peak concentrations, (2) post-antibiotic efect on bacterial killing, especially when treating concurrently with a β-lactam antibiotic, and (3) less toxicity with less frequent gentamicin dosing, due to low renal gentamicin accumulation. When gentamicin trough concentration is > 2 µg/ml, intervals among gentamicin doses should be extended to yield gentamicin trough concentration < 2 µg/ml. Once-daily gentamicin dosing is preferred than twiceor thrice-daily gentamicin administration. Once-daily gentamicin dosing yields lower trough and higher peak gentamicin concentrations. The recommended peak and trough gentamicin serum concentrations range from 5 to 12 µg/ml, and from 0. In small-for-gestational age infants, with an age ≤ 7 days of life, gentamicin half-life is longer, and clearance is lower than in infants appropriate-for-gestational age. The aim of this study is to review the published data on efects, pharmacokinetics, and bacterial-resistance of gentamicin in infants and children. Gram-negative organisms stop Gentamicin is widely used to treat gram-negative bacterial taking up the drug after an hour and only do so again 2-10 infection, but it is of variable efcacy for known staphylococcal hours later ( adaptive resistance); therefore, repeat treatment sepsis. Serious toxicity is predominantly Gentamicin crosses the placenta, producing foetal levels seen with treatment longer than 7-10 days where there are that are about half of the maternal levels, but it has never sustained high trough serum levels and/or co-exposure to been known to have caused ototoxicity in utero. In children with normal renal function, from the gut it is too limited to disallow maternal use during treatment is optimized, and adverse efects are minimized, by lactation. Gentamicin is passive fltered unchanged by the following a once a day ( high peak low trough) policy. In healthy neonates increasing number of studies have now suggested that this the half-life decreases by more than 50% in the frst 7-10 days is the right strategy to adopt in infants and children. Renal tubular damage is progressive with time and aminoglycosides are given more than once a day in children, can even produce a Bartter-like syndrome (see reference 38). Gentamicin is frequently used in infants deafness, and these can become permanent if early symptoms undergoing therapeutic hypothermia. Blood levels should always be measured in order to minimize these risks where facilities exist. It is at least as important to avoid simultaneous treatments with furosemide and to try to stop treatment after 7-10 days [1]. Correspondence to: Gian Maria Pacifci, Associate Professor of Pharmacology, via Saint Andrea 32, 56127 Pisa, Italy, Tel: 3388250108; Email: pacifci44@ Aminoglycosides are only efective against many bacteria tiscali. A 4 mg/kg dose and a 36 hourly regimen are reported temperature for several hours before the assay is performed. Transient and reversible tubular dysfunction may occur, resulting in increased urinary losses of sodium, calcium, and magnesium. Gentamicin is an important agent for the treatment of Vestibular and auditory ototoxicity medications. Increased aminoglycoside of frst choice because of its lower cost neuromuscular blockade. Gentamicin preparations are available or other neuromuscular blocking agents and in children with for parenteral, ophthalmic, and topical administration. Gentamicin is incompatible with amphotericin typical recommended intramuscular or intravenous dose of B, ampicillin, azithromycin, furosemide, imipenem-cilastatin, gentamicin sulphate, when used for the treatment of known heparin, (concentrations > 1 unit/ml), indomethacin, mezlocillin, or suspected gram-negative organisms, as a single agent or in nafcillin, oxacillin, propofol, and ticarcillin-clavulanate [3]. For patient’s recommended therapeutic serum concentrations of gentamicin renal dysfunction, the interval may be extended. Trough concentrations infants: 3 mg/kg once-daily for preterm newborns < 35 weeks should range 0. Peak plasma concentrations range from 4 database as search engine, the cut-of point was April 2019. It should be children efects, gentamicin infants metabolism, gentamicin emphasized that the recommended doses of gentamicin do not children metabolism, gentamicin infants pharmacokinetics, always yield desired concentrations. Periodic determination gentamicin children pharmacokinetics, gentamicin infants of the plasma concentration of gentamicin is recommended resistance, and gentamicin children resistance were used. When gentamicin is applied to large areas of denuded by Young and Mangum [3] were consulted. The manuscript was body surface, as may be the case in burn patients, plasma prepared according to the Instructions for Authors. Results Gentamicin is used in the treatment of infections caused by Mechanism of action of gentamicin aerobic gram-negative bacilli. Pseudomonas, Klebsiella, Gentamicin is rapidly bactericidal as it inhibits bacterial and Escherichia coli). Dosing recommendations are based on: dependent: the higher the concentration, the greater the rate higher peak concentrations. There may be less toxicity with less frequent the inhibitory action of gentamicin persists after the serum dosing, due to less renal drug accumulation. Serum half-life is prolonged in premature and account for the efcacy of high-dose, extended-interval asphyxiated newborns. Aminoglycosides, and thus gentamicin, containing compounds appears to be a time, temperature-, and difuse through aqueous channels formed by porin proteins concentration dependent process. This is probably clinically in the outer membrane of gram-negative bacteria to enter signifcant only when penicillin-containing compounds are periplasmic space. Transport of aminoglycosides across the Table 1: Doses and intervals among doses of gentamicin in infants of various postmenstrual and postnatal ages, by Young and Mangum [3] Postmenstrual age (weeks) Postnatal age (days) Dose (mg/kg) Intervals among doses (hours) 0 to 7 5 48 ≤ 29* 8 to 28 4 36 ≥ 29 4 24 0 to 7 4. The peak electrical gradient coupled to an electric transport to drive levels in neonates and infants were 5. The trough levels of gentamicin in is rate limiting and can be locked or inhibited by divalent the corresponding groups were 1. A signifcantly of aminoglycosides is reduced markedly in the anaerobic (P-value < 0. Once inside the cell, aminoglycosides, and thus gentamicin, the intravenous or intramuscular gentamicin route had any bind to polysomes and interfere with protein synthesis by efect on the peak and trough levels of gentamicin. At least three concentration was > 5 µg/ml in only 6% of neonates receiving of these ribosomal proteins and perhaps the 16S ribosomal 2. Thus, the standard of abnormal initiation complexes; aminoglycosides also can treatment of 2.

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Avoiding the unnecessary use of antibiotics is easier in theory than in practice arthritis back pain natural remedies 120mg etoricoxib visa, since clinical urgency often forbids waiting for conclusive and specific evidence of an infection rheumatoid arthritis medication new cheap etoricoxib 60 mg without prescription. In combination therapy arthritis pain keeps me awake at night discount 90 mg etoricoxib otc, the idea is to arthritis pain medication for dogs order 120 mg etoricoxib free shipping deny the microbe the benefit of acquiring resistance against a single antibiotic by simultaneously applying a second one that remains effective. The significance of hygiene is highlighted by the fact that most infections with highly resistant bacteria are acquired in hospitals. Most of these cases are contracted in regular wards and intensive care units rather than operation theaters. The mostly successful avoidance of infection in operation theaters illustrates both the power of hygiene and the discipline and drudgery required to make it work. Antibiotics are isolated from both prokaryotic and eukaryotic soil microorganisms, which use them as chemical weapons in their struggle against one another for the same ecological niche. Most antibiotics are toxic for both bacterial and eukaryotic cells, including human ones. Some of these, such as doxorubicin or streptozotocin, are actually used as cytotoxic agents in cancer chemotherapy (see Chapter 12). However, a still sizable number of antibiotics are indeed selectively toxic for prokaryotes and accordingly useful in the therapy of bacterial infections. These resistance mechanisms are genetically encoded and, like any other gene, potentially subject to genetic transfer. Indeed, the emergence of resistance to antibiotics in pathogenic 1 Some antibiotics are selective for eukaryotic cells. Antibacterial drugs are among the most frequently prescribed medicines; they probably also are the most frequently misused ones. While all bacteria are prokaryotes, they differ with respect to cell structure, life cycle, and genetic equipment for resistance to antimicrobial agents. It is therefore important to isolate and characterize the bacterium responsible for a given case of infection and to use such information to guide the selection of proper chemotherapy. On the other hand, the very short generation time and the existence of numerous mechanisms of genetic transfer are responsible for the rapid emergence and spreading of bacterial resistance to antibiotics. On the one hand, it contains multiple drug targets, since it has no counterpart in mammalian cells; on the other hand, the cell wall restricts access of drugs to intracellular targets. The innermost layer of the bacterial cell wall is the cytoplasmic membrane, which in many ways resembles that of mammalian cells. With most bacteria, the cytoplasmic membrane is covered by one or more additional layered structures. The composition of these structures is a major distinguishing feature between different classes of bacteria, and it also strongly influences their susceptibility to chemotherapy. The major variations in cell wall structure are schematically depicted in Figure 11. In Gram-positive bacteria, the cytoplasmic membrane is covered by a thick layer of murein, which is the intensely crosslinked, sturdy peptidoglycan unique to bacteria. Other types of polysaccharides and proteins are attached to its outer surface, but there is no protective membrane around the murein layer itself. Gram-positives are therefore often quite susceptible to antibiotics that inhibit murein synthesis. Examples of Gram-positive pathogens are Staphylococcus aureus and Listeria monocytogenes. However, the entire cell is wrapped by an outer membrane, which in many cases restricts the access of drugs to the interior layers and the cytosol. In those cases, one should secure samples before therapy is begun, base selection of initial therapy on educated guesses, and adapt therapy when laboratory results become available. Gram-negative bacteria have a comparatively thin murein layer that is surrounded by an outer membrane. In mycobacteria, the murein layer is surrounded by arabinogalactan polysaccharide, to which branched, long-chain fatty acids (mycolic acids) are attached; these, in turn, connect to a relatively thick outer membrane. Important Gram-negative pathogens are gonococci and meningococci, Salmonella species and Escherichia coli, and Pseudomonas aeruginosa. A thick outer membrane [238] is supported by a layer containing mycolic acids; together, these two form a thick, wax-like outer layer that efficiently excludes a wide range of antimicrobial drugs. Kinetic aspects of transport-mediated drug resistance Cell membranes pose barriers to drug penetration into the cytosol and, in case of Gramnegative bacteria, into the periplasmic space. However, while the rate of penetration of a drug may be low, it will be finite, so if no other mechanism of drug detoxification exists, any concentration gradient across the membrane will eventually vanish. The rate of equilibration will be proportional to the ratio of surface to volume of the enclosed compartment, which is inversely related to cell size. Therefore, in order to sustain a low intracellular or periplasmic drug concentration, a membrane barrier must be complemented by an additional detoxifi1 Imipemem, a carbapenem antibiotic, is active on some mycobacterial species, as is cycloserine, which is not a β-lactam but inhibits murein precursor synthesis. Some of these are structurally related to the P-glycoprotein found in mammalian cells (see Figure 3. In Gram-negative bacteria, the requirement for complementary drug efflux or metabolic inactivation also applies to the outer membrane and the compartment enclosed by it, that is, the periplasmic space. Many drugs will therefore more readily penetrate the outer than the inner membrane. It is accomplished by multicomponent efflux systems that span the entire cell wall (see Figure 11. The cytoplasmic membrane component harnesses intracellular energy to capture, in cooperation with the periplasmic component, drug molecules from the periplasm, which are then channeled out of the cell across the outer membrane component. Periplasmic substrate capture by the multicomponent system protects against antibiotics acting in the periplasm. In addition, it amplifies the resistance afforded by efflux pumps that extrude drugs from the cytosol into the periplasm in a multiplicative manner [239, 240]. The cell wall in mycobacteria has two membranes, and therefore the same considerations just outlined for the Gram-negative cell wall should apply here as well. Drug efflux across the mycobacterial outer membrane has not been experimentally characterized, however [241]. Bacterial metabolism and chemotherapy Apart from the cell wall, there are other metabolic distinctions between bacterial and mammalian cells that can provide targets for chemotherapy. For example, Escherichia coli can thrive on a minimal growth medium that contains no organic compound other than glucose, indicating that the bacterium can synthesize all those molecu1 In rapidly proliferating bacterial cultures, we must also consider dilution, since the increase in cellular volume due to cell division counteracts the penetration of polar drug molecules. Biosynthetic enzymes exclusive to bacteria are potential drug targets, provided that the bacterial cell lacks the ability to acquire the product from the environment instead. An example is dihydropteroate synthase, which functions in the bacterial synthesis of folic acid; this enzyme is inhibited by sulfonamides (see Section 1. Another interesting and practically important class of drugs that exploit metabolic diversity are nitroimidazole derivatives such as metronidazole (see Figure 11. These are selectively toxic for bacteria and also some eukaryotic parasites that are anaerobic, meaning that they thrive only in the absence of oxygen. Aerobic human or bacterial cells are not affected because they don’t contain sufficiently strong reducing agents. Inside the mycobacterial cell, it is first activated to a reactive radical by a bifunctional catalase/peroxidase enzyme, KatG. The latter participates in the synthesis of mycolic acids, the long chain fatty acids that occur in the mycobacterial cell wall (Figure 11. Its toxicity for humans is tolerable and caused by metabolism in the liver (see Section 4. Many plasmids encode an elaborate apparatus of multiple proteins that enables their own transfer from one bacterial cell to another, often crossing species boundaries in the process. Through successive transposition events, resistance genes from multiple sources can be collected on a single plasmid molecule. Such plasmids, sometimes referred to as R factors, will greatly aid the survival of bacterial hosts exposed to multiple antibiotics and therefore be effectively selected for in a hospital environment. This became manifest only a few years after the introduction of antibiotic therapy, when bacterial species that had originally been susceptible began to acquire resistance to multiple antibiotics, often including ones that had not even been used on the individual patients from whom the resistant bacteria were isolated. While Mycobacterium tuberculosis actually propagates rather slowly, it is killed by antibiotics even more slowly, meaning that multiple successive generations of bacteria are exposed to them and have a chance to develop resistance. When a manifest case of tuberculosis is treated with a single antibiotic only, the emergence of resistant mutants is almost certain. Assuming that each of these drugs by itself is lethal, a bacterial cell would have to develop resistance to all of them at the same time to actually survive. With mutation rates on the order of 10-6 per drug and bacterial generation, 1 Plasmids may also encode enzymes that mediate resistance to heavy metal ions; mercury, for example, is disposed of by reduction to its volatile elemental form.

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