Marie A. Abate, BS PharmD

• Professor of Clinical Pharmacy
• Director, West Virginia Center for Drug and Health Information
• Director of Programmatic Assessment, West Virginia University School of Pharmacy, Morgantown, West Virginia

https://directory.hsc.wvu.edu/Individual/Index/28087

It is important to consider these nondrug factors in the differential diagnosis of drug-induced adverse fetal effects mental disorders 13 letters discount lyrica on line. For example mental therapy in cincinnati discount lyrica 150mg fast delivery, several drugs have been labeled "X" despite extensive opposite human safety data (eg mental disorders vs diseases purchase lyrica 75 mg on-line, oral contraceptives) list of mental disorders and their symptoms trusted lyrica 150mg. Diazepam and other benzodiazepines are labeled as "D" despite lack of positive evidence of human fetal risk biological mental disorders list buy lyrica with mastercard. Counseling women about teratogenic risk-Since the thalidomide disaster what mental conditions qualify for social security disability cheap 75 mg lyrica with amex, medicine has been practiced as if every drug were a potential human teratogen when, in fact, fewer than 30 such drugs have been identified, with hundreds of agents proved safe for the unborn. Owing to high levels of anxiety among pregnant women-and because half of the pregnancies in North America are unplanned-every year many thousands of women need counseling about fetal exposure to drugs, chemicals, and radiation. The ability of appropriate counseling to prevent unnecessary abortions has been documented. Clinicians who wish to provide such counsel to pregnant women must ensure that their information is up-to-date and evidence-based and that the woman understands that the baseline teratogenic risk in pregnancy (ie, the risk of a neonatal abnormality in the absence of any known teratogenic exposure) is about 3%. It is also critical to address the maternal-fetal risks of the untreated condition if a medication is avoided. Recent studies show serious morbidity in women who discontinued selective serotonin reuptake inhibitor therapy for depression in pregnancy. Pharmacodynamic differences between pediatric and other patients have not been explored in great detail but are probably important for those specific target tissues that mature at birth or immediately thereafter (eg, the ductus arteriosus). Drug Absorption Drug absorption in infants and children follows the same general principles as in adults. Unique factors that influence drug absorption include blood flow at the site of administration, as determined by the physiologic status of the infant or child; and, for orally administered drugs, gastrointestinal function, which changes rapidly during the first few days after birth. Blood Flow at the Site of Administration Absorption after intramuscular or subcutaneous injection depends mainly, in neonates as in adults, on the rate of blood flow to the muscle or subcutaneous area injected. Physiologic conditions that might reduce blood flow to these areas are cardiovascular shock, vasoconstriction due to sympathomimetic agents, and heart failure. However, sick preterm infants requiring intramuscular injections may have very little muscle mass. In such cases, absorption becomes irregular and difficult to predict, because the drug may remain in the muscle and be absorbed more slowly than expected. If perfusion suddenly improves, there can be a sudden and unpredictable increase in the amount of drug entering the circulation, resulting in high and potentially toxic concentrations of drug. Examples of drugs especially hazardous in such situations are cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants. Gastrointestinal Function Significant biochemical and physiologic changes occur in the neonatal gastrointestinal tract shortly after birth. In full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours. In preterm infants, the secretion of gastric acid occurs more slowly, with the highest concentrations appearing on the fourth day of life. Either animal-reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. C D X 1 this system has been changed as of 2014 by eliminating the A, B, C qualifications and replacing them with specific structured narratives for each drug. Gastric emptying time is prolonged (up to 6 or 8 hours) in the first day or so after delivery. Therefore, drugs that are absorbed primarily in the stomach may be absorbed more completely than anticipated. In the case of drugs absorbed in the small intestine, therapeutic effect may be delayed. The fraction of drug absorbed in the small intestine may therefore be unpredictable; more than the usual amount of drug may be absorbed if peristalsis is slowed, and this could result in toxicity from an otherwise standard dose. An increase in peristalsis, as in diarrheal conditions, tends to decrease the extent of absorption, because contact time with the large absorptive surface of the intestine is decreased. Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of -amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipidsoluble drugs. Drug Distribution As body composition changes with development, the distribution volumes of drugs are also changed. Differences can also be observed between the full-term neonate (70% of body weight as water) and the small preterm neonate (85% of body weight as water). Similarly, extracellular water is 40% of body weight in the neonate, compared with 20% in the adult. Since many drugs are distributed throughout the extracellular water space, the size (volume) of the extracellular water compartment may be important in determining the concentration of drug at receptor sites. This is especially important for water-soluble drugs (such as aminoglycosides) and less crucial for lipid-soluble agents. Total body fat in preterm infants is about 1% of total body weight, compared with 15% in full-term neonates. Therefore, organs that generally accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in less mature infants. Another major factor determining drug distribution is drug binding to plasma proteins. In general, protein binding of drugs is reduced in the neonate, as seen with local anesthetic drugs, diazepam, phenytoin, ampicillin, and phenobarbital. Therefore, the concentration of free (unbound) drug in plasma is increased initially. Because the free drug exerts the pharmacologic effect, this can result in greater drug effect or toxicity despite a normal or even low plasma concentration of total drug (bound plus unbound). As an example, consider a therapeutic dose of a drug (eg, diazepam) given to a patient. If the drug is 98% protein-bound in an older child or adult, then 6 mcg/L is the concentration of free drug. Assume that this concentration of free drug produces the desired effect in the patient without producing toxicity. Although the higher free concentration may result in faster elimination (see Chapter 3), this concentration may be quite toxic initially. Because of the greater permeability of the neonatal blood-brain barrier, substantial amounts of bilirubin may enter the brain and cause kernicterus. This was in fact observed when sulfonamide antibiotics were given to preterm neonates as prophylaxis against sepsis. Conversely, as the serum bilirubin rises for physiologic reasons or because of a blood group incompatibility, bilirubin can displace a drug from albumin and substantially raise the free drug concentration. This may occur without altering the total drug concentration and would result in greater therapeutic effect or toxicity at normal concentrations, as has been shown with phenytoin. The process of maturation must be considered when administering drugs to this age group, especially in the case of drugs administered over long periods. Another consideration for the neonate is whether or not the mother was receiving drugs (eg, phenobarbital) that can induce early maturation of fetal hepatic enzymes. In this case, the ability of the neonate to metabolize certain drugs will be greater than expected, and one may see less therapeutic effect and lower plasma drug concentrations when the usual neonatal dose is given. Drug Excretion the glomerular filtration rate is much lower in newborns than in older infants, children, or adults, and this limitation persists during the first few days of life. The glomerular filtration rate is even lower in neonates born before 34 weeks of gestation. At the end of the first week, the glomerular filtration rate and renal plasma flow have increased 50% from the first day. Subsequently, during toddlerhood, it exceeds adult values, often necessitating larger doses per kilogram than in adults, as described previously for drug-metabolic rate. Therefore, drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life. Penicillins, for example, are cleared by preterm infants at 17% of the adult rate based on comparable surface area and 34% of the adult rate when adjusted for body weight. A decreased rate of renal elimination in the neonate has also been observed with aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, and streptomycin). The dosage of gentamicin for a neonate less than 7 days old is 5 mg/kg/d in two doses at 12-hour intervals. Total body clearance of digoxin is directly dependent upon adequate renal function, and accumulation of digoxin can occur when glomerular filtration is decreased. Since renal function in a sick infant may not improve at the predicted rate during the first weeks and months of life, appropriate adjustments in dosage and dosing schedules may be very difficult. In this situation, adjustments are best made on the basis of plasma drug concentrations determined at intervals throughout the course of therapy. Although great focus is naturally concentrated on the neonate, it is important to remember that toddlers may have shorter elimination half-lives of drugs than older children and adults, Drug Metabolism the metabolism of most drugs occurs in the liver (see Chapter 4). The point in development at which enzymatic activity reaches adult levels depends on the specific enzyme system in question. Glucuronide formation reaches adult values (per kilogram body weight) between the third and fourth years of life. If drug doses and dosing schedules are not altered appropriately, this immaturity predisposes the neonate to adverse effects from drugs that are metabolized by the liver. For example, the dose per kilogram of digoxin is much higher in toddlers than in adults. Special Pharmacodynamic Features in the Neonate the appropriate use of drugs has made possible the survival of neonates with severe abnormalities who would otherwise die within days or weeks after birth. For example, administration of indomethacin (see Chapter 36) causes the rapid closure of a patent ductus arteriosus, which would otherwise require surgical closure in an infant with a normal heart. Infusion of prostaglandin E1, on the other hand, causes the ductus to remain open, which can be lifesaving in an infant with transposition of the great vessels or tetralogy of Fallot (see Chapter 18). An unexpected effect of such infusion has been described when the drug caused antral hyperplasia with gastric outlet obstruction as a clinical manifestation in 6 of 74 infants who received it. Neonates are also more sensitive to the central depressant effects of opioids than are older children and adults, necessitating extra caution when they are exposed to some narcotics (eg, codeine) through breast milk. At birth, the function of drug transporters may be very low; for example, P-glycoprotein, which pumps morphine from the blood-brain barrier back to the systemic circulation. Low-level function of P-glycoprotein at birth can explain why neonates are substantially more sensitive than older children to the central nervous system depressant effects of morphine. Elixirs are alcoholic solutions in which the drug molecules are dissolved and evenly distributed. No shaking is required, and unless some of the vehicle has evaporated, the first dose from the bottle and the last dose should contain equivalent amounts of drug. Suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking. If shaking is not thorough each time a dose is given, the first doses from the bottle may contain less drug than the last doses, with the result that less than the expected plasma concentration or effect of the drug may be achieved early in the course of therapy. Conversely, toxicity may occur late in the course of therapy, when it is not expected. This uneven distribution is a potential cause of inefficacy or toxicity in children taking phenytoin suspensions. It is thus essential that the prescriber know the form in which the drug will be dispensed and provide proper instructions to the pharmacist and patient or parent. The parents should obtain a calibrated medicine spoon or syringe from the pharmacy as these devices improve the accuracy of dose measurements and simplify administration of drugs to children. When evaluating adherence, it is often helpful to ask if an attempt has been made to give a further dose after the child has spilled half of what was offered. The parents may not always be able to say with confidence how much of a dose the child actually received. The parents must be told whether or not to wake the infant for its every-6-hour dose day or night. These matters should be discussed and made clear, and no assumptions should be made about what the parents may or may not do.

During pregnancy mental illness reading list lyrica 150 mg lowest price, a large amount of estrogen is synthesized by the fetoplacental unit-consisting of the fetal adrenal zone mental health jobs in north carolina order generic lyrica on-line, secreting androgen precursor mental disorders for children buy generic lyrica online, and the placenta mental health 72653 cheap lyrica 75mg line, which aromatizes it into estrogen mental treatment act 1945 cheap 150 mg lyrica visa. The estriol synthesized by the fetoplacental unit is released into the maternal circulation and excreted into the urine mental disorders like ocd purchase discount lyrica on line. Repeated assay of maternal urinary estriol excretion has been used in the assessment of fetal well-being. One of the most prolific natural sources of estrogenic substances is the stallion, which liberates more of these hormones than the pregnant mare or pregnant woman. The equine estrogens- equilenin and equilin-and their congeners are unsaturated in the B as well as the A ring and are excreted in large quantities in urine, from which they can be recovered and used for medicinal purposes. Synthetic Estrogens A variety of chemical alterations have been applied to the natural estrogens. The most important effect of these alterations has been to increase their oral effectiveness. In addition to the steroidal estrogens, a variety of nonsteroidal compounds with estrogenic activity have been synthesized and used clinically. These include dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol, methallenestril, and chlorotrianisene. Bound estrogen is relatively unavailable for diffusion into cells, and it is the free fraction that is physiologically active. Preparation Ethinyl estradiol Micronized estradiol Estradiol cypionate Estradiol valerate Estropipate Oral Injectable Transdermal Quinestrol Chlorotrianisene Methallenestril Average Replacement Dosage 0. Estrogens are also excreted in small amounts in the breast milk of nursing mothers. Because significant amounts of estrogens and their active metabolites are excreted in the bile and reabsorbed from the intestine, the resulting enterohepatic circulation ensures that orally administered estrogens will have a high ratio of hepatic to peripheral effects. As noted below, the hepatic effects are thought to be responsible for some undesirable actions such as synthesis of increased clotting factors and plasma renin substrate. The hepatic effects of estrogen can be minimized by routes that avoid first-pass liver exposure, ie, vaginal, transdermal, or by injection. The receptor may also bind to other transcription factors to influence the effects of these factors on their responsive genes. Some of the effects of estrogens are indirect, mediated by the autocrine and paracrine actions of autacoids such as growth factors, lipids, glycolipids, and cytokines produced by the target cells in response to estrogen. These appear to be mediated by nongenomic effects of the classic estrogen receptor-estrogen complex, influencing several intracellular signaling pathways. Recently, all steroid receptors except the mineralocorticoid receptors were shown to have palmitoylation motifs that allow enzymatic addition of palmitate and increased localization of the receptors in the vicinity of plasma membranes. Such receptors are available for direct interactions with, and effects on, various membrane-associated or cytoplasmic proteins without the need for entry into the nucleus and induction of transcriptional actions. Female Maturation Estrogens are required for the normal sexual maturation and growth of the female. They stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary sex characteristics. They stimulate stromal development and ductal growth in the breast and are responsible for the accelerated growth phase and the closing of the epiphyses of the long bones that occur at puberty. They contribute to the growth of axillary and pubic hair and alter the distribution of body fat to produce typical female body contours. Larger quantities also stimulate development of pigmentation in the skin, most prominent in the region of the nipples and areolae and in the genital region. Endometrial Effects In addition to its growth effects on uterine muscle, estrogen plays an important role in the development of the endometrial lining. When estrogen production is properly coordinated with the production of progesterone during the normal human menstrual cycle, regular periodic bleeding and shedding of the endometrial lining occur. Continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns. Metabolic and Cardiovascular Effects Estrogens have a number of important metabolic and cardiovascular effects. Two genes code for two estrogen receptor isoforms, and, which are members of the superfamily of steroid, sterol, retinoic acid, and thyroid receptors. Estrogens also decrease the rate of resorption of bone by promoting the apoptosis of osteoclasts and by antagonizing the osteoclastogenic and pro-osteoclastic effects of parathyroid hormone and interleukin 6. Estrogens also stimulate adipose tissue production of leptin and are in part responsible for the higher levels of this hormone in women than in men. In addition to stimulating the synthesis of enzymes and growth factors leading to uterine and breast growth and differentiation, estrogens alter the production and activity of many other proteins in the body. This leads to increased circulating levels of thyroxine, estrogen, testosterone, iron, copper, and other substances. Estrogens decrease hepatic oxidation of adipose tissue lipid to ketones and increase synthesis of triglycerides. Increased plasminogen levels and decreased platelet adhesiveness have also been found (see Hormonal Contraception, below). They are responsible for estrous behavior in animals and may influence behavior and libido in humans. Administration of estrogens stimulates central components of the stress system, including the production of corticotropin-releasing hormone and the activity of the sympathetic system, and promotes a sense of well-being when given to women who are estrogen-deficient. They also facilitate the loss of intravascular fluid into the extracellular space, producing edema. The resulting decrease in plasma volume causes a compensatory retention of sodium and water by the kidney. Estrogens also modulate sympathetic nervous system control of smooth muscle function. When growth is completed, chronic therapy consists mainly of the administration of adult doses of both estrogens and progestins, as described below. Postmenopausal Hormonal Therapy In addition to the signs and symptoms that follow closely upon the cessation of normal ovarian function-such as loss of menstrual periods, vasomotor symptoms, sleep disturbances, and genital atrophy-there are longer-lasting changes that influence the health and well-being of postmenopausal women. These include an acceleration of bone loss, which in susceptible women may lead to vertebral, hip, and wrist fractures; and lipid changes, which may contribute to the acceleration of atherosclerotic cardiovascular disease noted in postmenopausal women. The effects of estrogens on bone have been extensively studied, and the effects of hormone withdrawal have been well-characterized. However, the role of estrogens and progestins in the cause and prevention of cardiovascular disease, which is responsible for 350,000 deaths per year, and breast cancer, which causes 35,000 deaths per year, is less well understood. Very-low-density lipoprotein and triglyceride levels are also relatively unaffected. Estrogen replacement therapy has a beneficial effect on circulating lipids and lipoproteins, and this was earlier thought to be accompanied by a reduction in myocardial infarction by about 50% and of fatal strokes by as much as 40%. In fact, there may be a small increase in cardiovascular problems as well as breast cancer in women who received the replacement therapy. In any case, there is no increased risk for breast cancer if therapy is given immediately after menopause and for the first 7 years, while Clinical Uses* A. Primary Hypogonadism Estrogens have been used extensively for replacement therapy in estrogen-deficient patients. The estrogen deficiency may be due to primary failure of development of the ovaries, premature menopause, castration, or menopause. Transdermal or vaginal administration of estrogen may be associated with decreased cardiovascular risk because it bypasses the liver circulation. However, one large study has shown that the addition of a progestin to estrogen replacement therapy does not influence the cardiovascular risk. Optimal management of the postmenopausal patient requires careful assessment of her symptoms as well as consideration of her age and the presence of (or risks for) cardiovascular disease, osteoporosis, breast cancer, and endometrial cancer. Bearing in mind the effects of the gonadal hormones on each of these disorders, the goals of therapy can then be defined and the risks of therapy assessed and discussed with the patient. If the main indication for therapy is hot flushes and sleep disturbances, therapy with the lowest dose of estrogen required for symptomatic relief is recommended. Treatment may be required for only a limited period of time and the possible increased risk for breast cancer avoided. In women who have undergone hysterectomy, estrogens alone can be given 5 days per week or continuously, since progestins are not required to reduce the risk for endometrial hyperplasia and cancer. Hot flushes, sweating, insomnia, and atrophic vaginitis are generally relieved by estrogens; many patients experience some increased sense of well-being; and climacteric depression and other psychopathologic states are improved. The role of estrogens in the prevention and treatment of osteoporosis has been carefully studied (see Chapter 42). The amount of bone present in the body is maximal in the young active adult in the third decade of life and begins to decline more rapidly in middle age in both men and women. The development of osteoporosis also depends on the amount of bone present at the start of this process, on vitamin D and calcium intake, and on the degree of physical activity. The risk of osteoporosis is highest in smokers who are thin, Caucasian, and inactive and have a low calcium intake and a strong family history of osteoporosis. Estrogens should be used in the smallest dosage consistent with relief of symptoms. Dosages in the middle of these ranges have been shown to be maximally effective in preventing the decrease in bone density occurring at menopause. From this point of view, it is important to begin therapy as soon as possible after the menopause for maximum effect. In these patients and others not taking estrogen, calcium supplements that bring the total daily calcium intake up to 1500 mg are useful. Patients at low risk of developing osteoporosis who manifest only mild atrophic vaginitis can be treated with topical preparations. The vaginal route of application is also useful in the treatment of urinary tract symptoms in these patients. It is important to realize, however, that although locally administered estrogens escape the first-pass effect (so that some undesirable hepatic effects are reduced), they are almost completely absorbed into the circulation, and these preparations should be given cyclically. As noted below, the administration of estrogen is associated with an increased risk of endometrial carcinoma. The administration of a progestational agent with the estrogen prevents endometrial hyperplasia and markedly reduces the risk of this cancer. On this regimen, some women will experience a return of symptoms during the period off estrogen administration. If the progestin produces sedation or other undesirable effects, its dose can be reduced to 2. Women who object to the cyclic bleeding associated with sequential therapy can also consider continuous therapy. About half of these patients experience breakthrough bleeding during the first few months of therapy. The main disadvantage of continuous therapy is the need for uterine biopsy if bleeding occurs after the first few months. When estrogens are given by these routes, the liver is bypassed on the first circulation, and the ratio of the liver effects to peripheral effects is reduced. In patients in whom estrogen replacement therapy is contraindicated, such as those with estrogen-sensitive tumors, relief of vasomotor symptoms may be obtained by the use of clonidine. Other Uses Estrogens combined with progestins can be used to suppress ovulation in patients with intractable dysmenorrhea or when suppression of ovarian function is used in the treatment of hirsutism and amenorrhea due to excessive secretion of androgens by the ovary. Adverse Effects Adverse effects of variable severity have been reported with the therapeutic use of estrogens. Uterine Bleeding Estrogen therapy is a major cause of postmenopausal uterine bleeding. Unfortunately, vaginal bleeding at this time of life may also be due to carcinoma of the endometrium. To avoid confusion, patients should be treated with the smallest amount of estrogen possible. It should be given cyclically so that bleeding, if it occurs, will be more likely to occur during the withdrawal period. As noted above, endometrial hyperplasia can be prevented by administration of a progestational agent with estrogen in each cycle. Cancer the relation of estrogen therapy to cancer continues to be the subject of active investigation. Although no adverse effect of shortterm estrogen therapy on the incidence of breast cancer has been demonstrated, a small increase in the incidence of this tumor may occur with prolonged therapy. Studies indicate that following unilateral excision of breast cancer, women receiving tamoxifen (an estrogen partial agonist, see below) show a 35% decrease in contralateral breast cancer compared with controls. These studies also demonstrate that tamoxifen is well tolerated by most patients, produces estrogenlike alterations in plasma lipid levels, and stabilizes bone mineral loss. Studies bearing on the possible efficacy of tamoxifen and raloxifene in postmenopausal women at high risk for breast cancer show decreases of risk for at least 5 years, but of unknown further duration. Another study showed that postmenopausal hormone replacement therapy with estrogens plus progestins was associated with greater breast epithelial cell proliferation and breast epithelial cell density than estrogens alone or no replacement therapy. Furthermore, with estrogens plus progestins, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the main site of development of breast cancer. Thus, further studies are needed to conclusively assess the possible association between progestins and breast cancer risk. Many studies show an increased risk of endometrial carcinoma in patients taking estrogens alone.

While the HbA1c target is appropriate for individuals treated with lifestyle interventions and euglycemic therapy mental disorders made easy buy generic lyrica pills, it may need to be modified for individuals treated with insulin or insulin secretagogues due to their increased risk of hypoglycemia mental illness and crime purchase lyrica 75mg fast delivery. Over the study period mental therapy hotline order discount lyrica on-line, which averaged 7 years mental disorders do have cheap lyrica 150 mg on-line, a reduction of approximately 60% in risk of diabetic retinopathy disorders of brain xray buy genuine lyrica on line, nephropathy mental illness timeline order lyrica with a mastercard, and neuropathy was noted in the tight control group compared with the standard control group. During a 6-year follow-up period, both the intensively and conventionally treated groups had similar levels of glycemic control, and both had progression of carotid intimal-medial thickness. However, the intensively treated cohort had significantly less progression of intimal thickness. A total of 3867 newly diagnosed type 2 diabetic patients were studied over 10 years. Patients were given dietary treatment alone or intensive therapy with insulin, chlorpropamide, glyburide, or glipizide. Tight control of blood pressure was added as a variable, with an angiotensin-converting enzyme inhibitor, a blocker, or in some cases, a calcium channel blocker available for this purpose. Cardiovascular complications were not noted for any particular therapy; metformin treatment alone reduced the risk of macrovascular disease (myocardial infarction, stroke). Epidemiologic analysis of the study suggested that every 1% decrease in the HbA1c achieved an estimated risk reduction of 37% for microvascular complications, 21% for any diabetes-related end point and death related to diabetes, and 14% for myocardial infarction. Tight control of hypertension also had a surprisingly significant effect on microvascular disease (as well as more conventional hypertension-related sequelae) in these diabetic patients. Epidemiologic analysis of the results suggested that every 10-mmHg decrease in the systolic pressure achieved an estimated risk reduction of 13% for diabetic microvascular complications, 12% for any diabetes-related complication, 15% for death related to diabetes, and 11% for myocardial infarction. These studies show that tight glycemic control benefits both type 1 and type 2 patients. Increased insulin requirements typically occur with obesity, during adolescence, and during the latter trimesters of pregnancy. If the patient is on an insulin pump, he or she may require about a basal infusion rate of 0. The ratios might be one unit for 12 grams carbohydrate plus one unit for 50 mg/dL (2. Type 2 Diabetes Normalization of glucose levels can occur with weight loss and improved insulin sensitivity in the obese patient with type 2 diabetes. A combination of caloric restriction and increased exercise is necessary if a weight reduction program is to be successful. Understanding the long-term consequences of poorly controlled diabetes may motivate some patients to lose weight. Orlistat, phentermine/ topiramate, lorcaserin, naltrexone plus extended release bupropion, and high-dose liraglutide are approved weight loss medications for use in combination with diet and exercise. Bariatric surgery (Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diversion/duodenal switch) typically result in significant weight loss and can result in remission of the diabetes. There is less emphasis on weight loss in such patients, but exercise is important. Unless there is a contraindication, medical therapy should be initiated with intensive lifestyle interventions (diet and exercise), diabetes selfmanagement education, and metformin. In the choice of the second agent, consideration should be given to efficacy of the agent, hypoglycemic risk, effect on weight, adverse effects, and cost. If two agents are inadequate a third agent is added, although data regarding efficacy of such combined therapy are limited. Simply adding nighttime intermediate- or long-acting insulin to the oral regimen may lead to improved fasting glucose levels and adequate control during the day. If daytime glucose levels are problematic, premixed insulins before breakfast and dinner may help. If such a regimen does not achieve adequate control or leads to unacceptable rates of hypoglycemia, a more intensive basal bolus insulin regimen (long-acting basal insulin) combined with rapid-acting analog before meals can be instituted. Metformin has been shown to be effective when combined with insulin therapy and should be continued. Pioglitazone can be used with insulin, but this combination is associated with more weight gain and peripheral and macular edema. Cost, complexity, and risk for adverse events should be considered when deciding which drugs to continue once the patient starts on insulin therapy. To expedite absorption, simple sugar or glucose should be given, preferably in liquid form. To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given. If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is 1 mg of glucagon injected either subcutaneously or intramuscularly. Emergency medical services should be called in the event of loss of consciousness. It typically occurs in newly diagnosed type 1 patients or in those who have experienced interrupted insulin replacement, and rarely in people with type 2 diabetes who have concurrent unusually stressful conditions such as sepsis or pancreatitis or are on highdose steroid therapy. Signs and symptoms include nausea, vomiting, abdominal pain, deep slow (Kussmaul) breathing, change in mental status (including coma), elevated blood and urinary ketones and glucose, an arterial blood pH lower than 7. Close attention must be given to hydration and renal status, sodium and potassium levels, and the rate of correction of plasma glucose and plasma osmolality. Regular human insulin should be used for intravenous therapy with a usual starting dosage of about 0. It is associated with inadequate oral hydration, especially in elderly patients; with other illnesses; with the use of medication that elevates the blood sugar or causes dehydration, such as phenytoin, steroids, diuretics, and calcium channel blockers; and with peritoneal dialysis and hemodialysis. The diagnostic hallmarks are declining mental status and even seizures, a plasma glucose >600 mg/dL, and a calculated serum osmolality >320 mmol/L. Hypoglycemia Hypoglycemic reactions are the most common complication of insulin therapy. It can also occur in any patient taking oral agents that stimulate insulin secretion (eg, sulfonylureas, meglitinide, d-phenylalanine analogs), particularly if the patient is elderly, has renal or liver disease, or is taking certain other medications that alter metabolism of the sulfonylureas (eg, phenylbutazone, sulfonamides, warfarin). Rapid development of hypoglycemia in persons with intact hypoglycemic awareness causes signs of autonomic hyperactivity- both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger)-and may progress to convulsions and coma if untreated. In persons exposed to frequent hypoglycemic episodes during tight glycemic control, autonomic warning signals of hypoglycemia are less common or even absent. When patients lack the early warning signs of low blood glucose, they may not take corrective measures in time. In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop- confusion, weakness, bizarre behavior, coma, seizures-at which point they may not be able to procure or safely swallow glucosecontaining foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes. Chronic Complications of Diabetes Late clinical manifestations of diabetes mellitus include a number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the lens of the eye. These lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of the diabetic state subsequent to the onset of puberty and glycemic control. In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death, whereas patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Guo S: Insulin signaling, resistance, and the metabolic syndrome: Insights from mouse models to disease mechanisms. Karagiannis T et al: Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: Systematic review and meta-analysis. Kitabchi A et al: Thirty years of personal experience in hyperglycemic crises: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Lefebvre P et al: Role of bile acids and bile acid receptors in metabolic regulation. Levin D et al: Pioglitazone and bladder cancer risk: A multipopulation pooled, cumulative exposure analysis. Nauck M: Incretin therapies: Highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Standl E, Schnell O: Alpha-glucosidase inhibitors 2012-cardiovascular considerations and trial evaluation. Tuccori M et al: Pioglitazone use and risk of bladder cancer: population based cohort study. The patient underwent multifactorial intervention targeting his weight, glucose levels, and blood pressure. He attended structured diabetes classes and received individualized instruction from a diabetes educator and a dietitian. The patient lost about 8 kg in weight over the next 3 years and was able to stop his insulin. His antihypertensive therapy was optimized and his urine albumin excretion declined to 1569 mg/g creatinine. This case illustrates the importance of weight loss in controlling glucose levels in the obese patient with type 2 diabetes. Combining metformin with other oral agents and non-insulin injectables may be a better option. X-rays of the spine showed some degenerative changes in the lumbar spine plus several wedge deformities in the thoracic spine. The patient is a long-time smoker (up to two packs per day) and has two to four glasses of wine with dinner, more on the weekends. He has chronic bronchitis, presumably from smoking, and has been treated on numerous occasions with oral prednisone for exacerbations of bronchitis. Examination shows kyphosis of the thoracic spine, with some tenderness to fist percussion over the thoracic spine. This reservoir is dynamic, with constant remodeling of bone and ready exchange of bone mineral with that in the extracellular fluid. Bone also serves as the principal structural support for the body and provides the space for hematopoiesis. This relationship is more than fortuitous, as elements of the bone marrow affect skeletal processes just as skeletal elements affect hematopoietic processes. During aging and in nutritional diseases such as anorexia nervosa and obesity, fat accumulates in the marrow, suggesting a dynamic interaction between marrow fat and bone. Furthermore, bone has 772 been implicated as an endocrine tissue with release of osteocalcin, which in its uncarboxylated form stimulates insulin secretion and testicular function. Abnormalities in bone mineral homeostasis can lead to a wide variety of cellular dysfunctions (eg, tetany, coma, muscle weakness), disturbances in structural support of the body (eg, osteoporosis with fractures), and loss of hematopoietic capacity (eg, infantile osteopetrosis). This amount represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The quantity of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excretion of calcium and phosphate balances intestinal absorption. The movement of calcium and phosphate across the intestinal and renal epithelia is closely regulated. Dysfunction of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) can disrupt bone mineral homeostasis. The term vitamin D, when used without a subscript, refers to both vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). The initial product, pre-vitamin D3, undergoes a temperature-sensitive isomerization to vitamin D3. Vitamin D2 thus comes only from the diet, whereas vitamin D3 comes from the skin or the diet, or both. Other hormones-calcitonin, prolactin, growth hormone, insulin, insulin-like growth factors, thyroid hormone, glucocorticoids, and sex steroids-influence calcium and phosphate homeostasis under certain physiologic circumstances and can be considered secondary regulators. However, certain of these secondary regulators-especially calcitonin, glucocorticoids, and estrogens-are useful therapeutically and discussed in subsequent sections. In addition to these hormonal regulators, calcium and phosphate themselves, other ions such as sodium and fluoride, and a variety of drugs (bisphosphonates, anticonvulsants, and diuretics) also alter calcium and phosphate homeostasis. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell. It is produced in the parathyroid gland in a precursor form of 115 amino acids, the excess 31 amino terminal amino acids being cleaved off before secretion. Loss of the first two amino terminal amino acids eliminates most biologic activity. The inactive carboxyl terminal fragments produced by metabolism of the intact hormone have a much lower clearance, especially in renal failure. This action increases bone remodeling, a specific sequence of cellular events initiated by osteoclastic bone resorption and followed by osteoblastic bone formation.

Finally mental conditions treatment order lyrica, the patient should be made aware that abrupt cessation of these medications may precipitate an acute flare of hepatitis mental treatment 4 ringworm discount lyrica online master card. C Miscellaneous Antimicrobial Agents; Disinfectants mental hygiene therapy aide order genuine lyrica, Antiseptics mental disorder color test cheap 150mg lyrica mastercard, & Sterilants Camille E mental disorders negative thinking order generic lyrica. He receives ceftriaxone and azithromycin upon admission mental disorders in the bible buy cheap lyrica online, rapidly improves, and is transferred to a semiprivate ward room. On day 7 of his hospitalization, he develops copious diarrhea with eight bowel movements but is otherwise clinically stable. Metronidazole is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up by anaerobes, it is nonenzymatically reduced by reacting with reduced ferredoxin. This action occurs only when metronidazole is partially reduced, and, because this reduction usually happens only in anaerobic cells, it has relatively little effect on human cells or aerobic bacteria. The drug penetrates well into the cerebrospinal fluid and brain, reaching levels similar to those in serum. Metronidazole is metabolized in the liver and may accumulate in hepatic insufficiency. Metronidazole is indicated for treatment of anaerobic or mixed intra-abdominal infections (in combination with other agents with activity against aerobic organisms), vaginitis (trichomonas infection, bacterial vaginosis), Clostridium difficile infection, and brain abscess. Adverse effects include nausea, diarrhea, stomatitis, and peripheral neuropathy with prolonged use. Metronidazole has a disulfiram-like effect, and patients should be instructed to avoid alcohol. Although teratogenic in some animals, metronidazole has not been associated with this effect in humans. A structurally similar agent, tinidazole, is a once-daily drug approved for treatment of trichomonas infection, giardiasis, amebiasis, and bacterial vaginosis. When administered orally, systemic absorption is negligible but fecal concentrations are high. It is as effective as oral vancomycin and may be associated with lower rates of relapsing disease. Strains with high-level resistance have caused hospitalassociated outbreaks of staphylococcal infection and colonization. Although higher rates of resistance are encountered with extensive use of mupirocin, most staphylococcal isolates are still susceptible. Mupirocin is indicated for topical treatment of minor skin infections, such as impetigo (see Chapter 61). Topical application over large open areas, such as pressure ulcers or surgical wounds, is an important factor leading to emergence of mupirocin-resistant strains and is not recommended. Mupirocin temporarily eliminates S aureus nasal carriage by patients or health care workers, but results are mixed with respect to its ability to prevent subsequent staphylococcal infection. Patients most likely to benefit from decolonization are those undergoing orthopedic or cardiothoracic procedures. Owing to their significant toxicity with systemic administration (especially nephrotoxicity), polymyxins were, until recently, largely restricted to topical use. Ointments containing polymyxin B, 5000 units/g, in mixtures with bacitracin or neomycin (or both) are commonly applied to infected superficial skin lesions. Emergence of strains of Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae that are resistant to all other agents has renewed interest in polymyxins as parenteral agents for salvage therapy of infections caused by these organisms. Typical doses of rifaximin range from 200 mg to 550 mg administered orally twice to three times daily depending on the indication. Unlike other rifamycins, rifaximin is not thought to be associated with cytochrome-P450-mediated drug interactions due to its limited absorption. Mupirocin is active against Gram-positive cocci, including methicillin-susceptible and methicillin-resistant strains of Nitrofurantoin At therapeutic doses, nitrofurantoin is bactericidal for many Gram-positive and Gram-negative bacteria; however, P aeruginosa and many strains of Proteus are inherently resistant. Antibacterial activity appears to correlate with rapid intracellular conversion of nitrofurantoin to highly reactive intermediates by bacterial reductases. It is not known which of the multiple actions of nitrofurantoin is primarily responsible for its bactericidal activity. There is no cross-resistance between nitrofurantoin and other antimicrobial agents, and resistance emerges slowly. As resistance to trimethoprim-sulfamethoxazole and fluoroquinolones has become more common in Escherichia coli, nitrofurantoin has become an important alternative oral agent for treatment of uncomplicated urinary tract infection. It is metabolized and excreted so rapidly that no systemic antibacterial action is achieved. The drug is excreted into the urine by both glomerular filtration and tubular secretion. In renal failure, urine levels are insufficient for antibacterial action, but high blood levels may cause toxicity. Nitrofurantoin is contraindicated in patients with significant renal insufficiency. Traditional recommendations are to avoid use in patients with creatinine clearance <60 mL/min; however, some data suggest short-term nitrofurantoin treatment is acceptable in patients with creatinine clearance >30 mL/min. The dosage for urinary tract infection in adults is 100 mg orally taken four times daily. Macrocrystalline nitrofurantoin, which has slower dissolution and absorption than nitrofurantoin monohydrate, constitutes 25%. The remaining 75% is nitrofurantoin monohydrate contained in a powder blend, which, upon exposure to gastric and intestinal fluids, forms a gel matrix that releases nitrofurantoin over time. A single daily dose of nitrofurantoin, 100 mg, can prevent recurrent urinary tract infections in some women. Neuropathies and pulmonary toxicities may occur, particularly with prolonged use or in patients with renal impairment. Hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase deficiency. Rashes, pulmonary infiltration and fibrosis, and other hypersensitivity reactions have been reported. Methenamine mandelate, 1 g four times daily, or methenamine hippurate, 1 g twice daily by mouth (in children age 6 to 12 years, 500 mg four times daily or twice daily, respectively), is used only as a urinary antiseptic to prevent, not treat, symptomatic urinary tract infection. Sulfonamides should not be given at the same time because they may form an insoluble compound with the formaldehyde released by methenamine. Persons taking methenamine mandelate may exhibit falsely elevated tests for catecholamine metabolites. Antiseptics are disinfecting chemical agents with sufficiently low toxicity for host cells that they can be used directly on skin, mucous membranes, or wounds. Sterilants kill both vegetative cells and spores when applied to materials for appropriate times and temperatures. Disinfection prevents infection by reducing the number of potentially infective organisms by killing, removing, or diluting them. Often a combination of agents is used, eg, water and moderate heat over time (pasteurization); ethylene oxide and moist heat (a sterilant); or addition of disinfectant to a detergent. Prevention of infection also can be achieved by washing, which dilutes the potentially infectious organism. Hand hygiene is probably the most important means of preventing transmission of infectious agents from person to person or from regions of high microbial load, eg, mouth, nose, or gut, to potential sites of infection. Evaluation of effectiveness of antiseptics, disinfectants, and sterilants, although seemingly simple in principle, is very complex. Factors in any evaluation include the intrinsic resistance of the microorganism, the number of microorganisms present, mixed populations of organisms, amount of organic material present (eg, blood, feces, tissue), concentration and stability of disinfectant or sterilant, time and temperature of exposure, pH, and hydration and binding of the agent to surfaces. Users of antiseptics, disinfectants, and sterilants need to consider their short-term and long-term toxicity because they may have general biocidal activity and may accumulate in the Methenamine Mandelate & Methenamine Hippurate Methenamine mandelate is the salt of mandelic acid and methenamine and possesses properties of both of these urinary antiseptics. Oral mandelic acid or hippuric acid is absorbed and excreted unchanged in the urine. Disinfectants and antiseptics may also become contaminated by resistant microorganisms-eg, spores, P aeruginosa, or Serratia marcescens-and actually transmit infection. Cleansing of wounds with soap and water may be less damaging than the application of antiseptics. Some of the chemical classes of antiseptics, disinfectants, and sterilants are described briefly in the text that follows. The reader is referred to the general references for descriptions of physical disinfection and sterilization methods. They are not used as sterilants because they are not sporicidal, do not penetrate protein-containing organic material, and may not be active against hydrophilic viruses. Their skin-drying effect can be alleviated by addition of emollients to the formulation. Alcohol-based hand rubs are ineffective against spores of C difficile, and handwashing with soap and water is required for decontamination after caring for a patient with infection from this organism. They must be allowed to evaporate before cautery, electrosurgery, or laser surgery. Therefore, instruments such as tonometers that have been disinfected in alcohol should be rinsed with sterile water, or the alcohol should be allowed to evaporate before they are used. Water-soluble chlorhexidine digluconate is used in waterbased formulations as an antiseptic. It is active against vegetative bacteria and mycobacteria and has variable activity against fungi and viruses. It strongly adsorbs to bacterial membranes, causing leakage of small molecules and precipitation of cytoplasmic proteins. Chlorhexidine gluconate is slower in its action than alcohols, but, because of its persistence, it has residual activity, producing bactericidal action equivalent to alcohols. Chlorhexidine digluconate is resistant to inhibition by blood and organic materials. However, anionic and nonionic agents in moisturizers, neutral soaps, and surfactants may neutralize its action. Chlorhexidine digluconate formulations of 4% concentration have slightly greater antibacterial activity than newer 2% formulations. The advantage of this combination over povidone-iodine may derive from its more rapid action after application, its retained activity after exposure to body fluids, and its persistent activity on the skin. Chlorhexidine must not be used during surgery on the middle ear because it causes sensorineural deafness. One hundred ppm kills vegetative fungal cells in 1 hour, but fungal spores require 500 ppm. Because chlorine is inactivated by blood, serum, feces, and protein-containing materials, surfaces should be cleaned before chlorine disinfectant is applied. When hypochlorite solutions contact formaldehyde, the carcinogen bischloromethyl is formed. Rapid evolution of irritating chlorine gas occurs when hypochlorite solutions are mixed with acid and urine. Alternative chlorine-releasing compounds include chlorine dioxide and chloramine-T. It is not commonly used due to serious hypersensitivity reactions and staining of clothing and dressings. These adverse actions are diminished by forming derivatives in which a functional group replaces a hydrogen atom in the aromatic ring. The phenolic agents most commonly used are o-phenylphenol, o-benzyl-p-chlorophenol, and p-tertiary amylphenol. Skin absorption and skin irritation still occur with these derivatives, and appropriate care is necessary in their use. Detergents are often added to formulations to clean and remove organic material that may decrease the activity of a phenolic compound. Phenolic compounds disrupt cell walls and membranes, precipitate proteins, and inactivate enzymes. They are bactericidal (including mycobacteria) and fungicidal and are capable of inactivating lipophilic viruses. Dilution and time of exposure recommendations of the manufacturer must be followed. Phenolic disinfectants are used for hard surface decontamination in hospitals and laboratories, eg, floors, beds, and counter or bench tops. They are not recommended for use in nurseries and especially near infants, where their use has been associated with hyperbilirubinemia. Use of hexachlorophene as a skin disinfectant has caused cerebral edema and seizures in premature infants and, occasionally, in adults. Iodophors can be used as antiseptics or disinfectants, the latter containing more iodine. Iodophors are less irritating and less likely to produce skin hypersensitivity than tincture of iodine. They require drying time on skin before becoming active, which can be a disadvantage. Although iodophors have a somewhat broader spectrum of activity than chlorhexidine, including sporicidal action, they lack its persistent activity on skin. Chlorine Chlorine is a strong oxidizing agent and universal disinfectant that is commonly provided as a 5. Because formulations may vary, the exact concentration should be verified on the label.

As with first-generation agents mental health treatment veterans cheap lyrica uk, no member of this group is active against enterococci or P aeruginosa mental illness killers order lyrica 150mg with visa. Compared with other cephalosporins mental disorders symptoms list buy discount lyrica 150 mg line, cefoxitin shows improved stability in the presence of extended-spectrum -lactamases produced by E coli and Klebsiella sp mental illness treatment timeline order lyrica pills in toronto. Clinical data are limited mental disorders night terrors buy cheap lyrica 75 mg, but it may offer an alternative to carbapenems in treating certain infections due to these organisms disorders of brain knowledge purchase 75mg lyrica visa. Secondgeneration cephalosporins may exhibit in vitro activity against Enterobacter sp, but resistant mutants that constitutively express a chromosomal -lactamase that hydrolyzes these compounds (and third-generation cephalosporins) are readily selected, and they should not be used to treat Enterobacter infections. Antimicrobial Activity 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 -lactamase-producing strains of Haemophilus and Neisseria. Like the second-generation drugs, third-generation cephalosporins are hydrolyzed by constitutively produced AmpC -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. It is more resistant to hydrolysis by chromosomal -lactamases (eg, those produced by Enterobacter). However, like the thirdgeneration compounds, it is hydrolyzed by extended-spectrum -lactamases. Cefepime has good activity against P aeruginosa, Enterobacteriaceae, methicillin-susceptible S aureus, and S pneumoniae. 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. Because of its broad-spectrum activity, cefepime is commonly used empirically in patients presenting with febrile neutropenia, in combination with other agents. Third-generation cephalosporins penetrate body fluids and tissues well and intravenous cephalosporins achieve levels in the cerebrospinal fluid sufficient to inhibit most susceptible pathogens. 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. 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. 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. Cephalosporins Active against MethicillinResistant Staphylococci Beta-lactam antibiotics with activity against methicillin-resistant staphylococci are currently under development. 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. 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 hours. Clinical Uses Third-generation cephalosporins are used to treat a wide variety of serious infections caused by organisms that are resistant to most other drugs. 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. 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. Cephalosporins Combined with a-lactamase Inhibitors Novel cephalosporin-lactamase inhibitor combinations have been developed to combat resistant Gram-negative infections; see the subsequent section for more information on -lactamase inhibitors. While neither agent is active against organisms producing metallo-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 are primarily renally excreted and require dose adjustment in patients with impaired renal clearance. Their spectrum of activity is limited to aerobic Gram-negative organisms (including P aeruginosa). Unlike other -lactam antibiotics, they have no activity against Gram-positive bacteria or anaerobes. It has structural similarities to ceftazidime, and its Gram-negative spectrum is similar to that of the thirdgeneration cephalosporins. It is stable to many -lactamases with notable exceptions being AmpC -lactamases and extendedspectrum -lactamases. 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. Allergy 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 first- or second-generation cephalosporins, while thirdand fourth-generation cephalosporins should be administered with caution, preferably in a monitored setting. 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. Oral administration of vitamin K, 10 mg twice weekly, can prevent this uncommon problem. They are potent inhibitors of many but not all bacterial -lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. They are not good inhibitors of class C -lactamases, which typically are chromosomally encoded and inducible, produced by Enterobacter sp, Citrobacter sp, S marcescens, and P aeruginosa, but they do inhibit chromosomal -lactamases of B fragilis and M catarrhalis. The novel non-lactam -lactamase inhibitor avibactam is active against Ambler class A -lactamases but also active against Ambler class C and some Ambler class D -lactamases. Beta-lactamase inhibitors are available only in fixed combinations with specific penicillins and cephalosporins. Thus, ampicillin-sulbactam is active against -lactamase-producing S aureus and H influenzae but not against Serratia, which produces a -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 -lactamase produced by P aeruginosa. 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. 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 -lactamase produced by these organisms. Clinical experience suggests that carbapenems are also the treatment of choice for serious infections caused by extendedspectrum -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. 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. 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%. 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 -lactamases but not carbapenemases or metallo-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 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. 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. 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. This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. 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 highaffinity binding of vancomycin to its target and loss of activity. Vancomycin binds the d-Alanine d-Alanine (d-Ala d-Ala) terminus of the amino acid peptide, inhibiting cross-linkage of the cell wall. 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. 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. Pharmacokinetics Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of colitis caused by C difficile. Ninety percent of the drug is excreted Antibacterial Activity Vancomycin is bactericidal for Gram-positive bacteria in concentrations of 0. Most pathogenic staphylococci, including those producing -lactamase and those resistant to nafcillin and methicillin, are killed by 2 mcg/mL or less.

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