By I. Ortega. Loyola College, Baltimore. 2019.

No intracardiac injections should be given during cardiopulmonary resuscitation because they can render the heart unsuitable for transplantation buy depakote 500mg mastercard. Respiratory and Acid–Base Maintenance Use of endotracheal suctioning is usually minimized during the treatment of cerebral edema to avoid any unnecessary stimulation that would increase intracranial pressure discount depakote 250 mg. In contrast order depakote 250mg online, after brain death is declared buy depakote 500mg amex, vigorous tracheobronchial toilet is important, with frequent suctioning using sterile precautions. Even if the lungs are unsuitable for donation, it is important to minimize the risk of atelectasis and infection. Steroids administered to some patients as part of the treatment for increased intracranial pressure predispose to pulmonary infectious complications. The presence of pneumonia can preclude donation of the lungs as well as other organs, depending on its severity and association with systemic sepsis. The etiology of pulmonary edema in organ donors can be cardiogenic, neurogenic, aspiration induced, a result of trauma or fluid overload, or a combination of these factors. Neurogenic pulmonary edema can preclude lung or combined heart–lung donation, but not donation of other organs (e. Fluids must be administered carefully to maintain organ perfusion while avoiding exacerbation of the edema. In potential lung donors, the endotracheal tube should not be advanced more than several centimeters into the trachea, to prevent damage to areas that may become part of an anastomosis. A sample of sputum should be obtained for Gram’s stain and cultures to exclude the presence of infection. The samples can be obtained using bronchoscopy, a procedure that is often routinely performed before lung donation. In a randomized trial, the number of transplanted lungs doubled when a lung-protective strategy was pursued [102]. Aggressive living donor management protocols aimed at improving alveolar recruitment and oxygenation have proven successful with high rates of conversion from unacceptable to acceptable PaO /FiO ratios [2 2 102]. For potential lung donors, the lowest FiO that is capable of maintaining a2 PaO of greater than 100 mm Hg should be selected. To date, there is no evidence that such a conservative fluid management approach in donors adversely impacts the function of kidney grafts obtained from the same donor [130]. Excessive use of crystalloid fluids during the initial resuscitation after brain death is declared can render the lungs unsuitable for transplantation. If relatively large amounts of fluid are required for resuscitation and hemodynamic stabilization, colloids (i. Respiratory alkalosis can develop in brain-dead organ donors secondary to mechanical hyperventilation as part of the treatment protocol for elevated intracranial pressure. After brain death, the arterial pH should be adjusted to normal values because alkalosis has many undesirable side effects, such as increased cardiac output, systemic vasoconstriction, bronchospasm, and a shift to the left of the oxyhemoglobin dissociation curve. The latter decreases oxygen unloading in the tissues and impairs oxygen delivery, thereby diminishing tissue oxygenation and metabolism. Lactic metabolic acidosis is frequent in brain-dead donors; it should be treated by compensation with a slight respiratory alkalosis until the underlying abnormality has been corrected (e. Administration of sodium bicarbonate should be contemplated only if the increased minute ventilation necessary to induce respiratory alkalosis leads to a decrease in cardiac output. In either situation, the most important aspect of managing metabolic acidosis is to treat the underlying cause. In selected patients this may require pulmonary artery catheterization to assess the adequacy of hydration, cardiac output, and tissue oxygen delivery. Renal Function and Fluid and Electrolyte Management Maintaining adequate systemic perfusion pressure while minimizing the use of vasopressors contributes to good renal allograft function and reduces the rate of acute tubular necrosis after transplantation. Cephalosporins, monobactams, carbapenems, and quinolones are examples of less nephrotoxic but effective antibiotics that can be used if infection occurs. It can be due to diabetes insipidus, osmotic diuresis (induced by mannitol administered to decrease elevated intracranial pressures or hyperglycemia), physiologic diuresis due to previous massive fluid administration during resuscitation after the original injury with return of third-space fluid into the intravascular space, or hypothermia. Found in up to 80% of all brain-dead bodies [81], it is related to insufficient blood levels of antidiuretic hormone (vasopressin), resulting in the production of large quantities of dilute urine. Diabetes insipidus should be suspected when urine volumes exceed 300 mL per hour (or 7 mL/kg/h) in conjunction with hypernatremia (serum sodium greater than 150 mEq per dL), elevated serum osmolality (greater than 310 mOsm per L) and a low urinary sodium concentration. In addition to hypernatremia, other electrolyte abnormalities frequently observed during diabetes insipidus include hypokalemia, hypocalcemia, and hypomagnesemia. The appropriate replacement of these electrolyte losses can be guided by urinary electrolyte determinations, which easily allow calculation of the amount of the electrolyte to be replaced. Because diabetes insipidus is so common, mannitol administration should be discontinued after brain death is declared. Other supportive care of patients with diabetes insipidus includes replacing urine output milliliter for milliliter with free water (e. Once urine output due to diabetes insipidus exceeds 300 mL per hour, desmopressin (desamino-8-D-arginine vasopressin), a synthetic analog of vasopressin (or arginine vasopressin), should be administered. Desmopressin has a long duration of action (6 to 20 hours) and a high antidiuretic-to-pressor ratio, without any undesirable splanchnic vasoconstrictive effects that can occur with administration of normal- and high-dose arginine vasopressin [18,25,131]. For example, doses of 1 to 2 μg desmopressin are administered intravenously every 8 to 12 hours to achieve a urine output less than 300 mL per hour [18,25,131]. Compared to desmopressin, arginine vasopressin is easily titrated and adds beneficial hemodynamic effects. The choice of the resuscitation fluid depends on the clinical circumstances and the donor’s electrolyte, osmolar, and acid–base state. If the serum sodium concentration exceeds 150 mEq per dL, the maintenance fluid should consist of 5% dextrose solution with 20 mEq potassium added to each liter. Should the hourly fluid administration rate exceed 500 mL per hour, the dextrose concentration of the maintenance fluid should be decreased to 1% to avoid excessive hyperglycemia. Diabetes insipidus develops in approximately 80% of brain-dead donors as a result of low or absent blood levels of vasopressin [80]. These findings are a direct consequence of brain death, which abolishes vasopressin production in the hypothalamic nuclei (supraoptic and paraventricular nuclei) and vasopressin storage and release in the posterior pituitary. In contrast, near-normal levels of anterior pituitary hormones, such as thyroid- stimulating hormone, adrenocorticotropic hormone, and growth hormone, have been documented after brain death in some studies [133–136]. Their persistence is probably due to the preservation of small subcapsular areas in the anterior pituitary, the blood supply of which is derived from small branches of the inferior hypophyseal artery. The latter arises from the extradural internal carotid artery, which is relatively protected from increases in intracranial pressure [137]. Clinical evidence, however, suggests deficient adrenal cortisol secretion after dynamic stimulation in brain-dead donors, irrespective of the level of pituitary dysfunction [138]. The principle of pharmacologic replacement therapy for deficient posterior pituitary vasopressin after brain death is well established [18,19,25,111]. Low-dose vasopressin has been shown to exert beneficial hemodynamic effect in brain-dead donors (Table 56. In contrast, controversy still exists regarding the benefits of supplementation with triiodothyronine [T3] and thyroxine [T4], which are synthesized under anterior pituitary control (Table 56. Initially, the presence of low T3 blood levels was demonstrated after brain death in animal experiments [149]. Administration of exogenous T3 to donor animals improved a variety of metabolic parameters before and after organ preservation [150–152], as well as organ function after transplantation [153]. A limited number of uncontrolled clinical trials suggested favorable influences of donor pretreatment with thyroid hormone on hemodynamic and metabolic parameters during the donor maintenance phase [84,154,155] and on outcome after heart transplantation [156–158]. But a number of other investigators failed to observe a significant benefit of thyroid hormone administration on biochemical and hemodynamic donor parameters and on posttransplant outcomes (Table 56. The latter outcomes could be explained at least in part by the findings of some studies which have suggested that the low T3 levels in human donors do not correlate with the presence of hemodynamic stability [161,162] or outcome after transplantation [163–166] to begin with. The typical thyroidal hormonal pattern after brain death consists of decreased T3, normal or decreased thyroxine, and normal thyroid-stimulating hormone. This pattern is not consistent with acute insufficiency of the hypothalamic–pituitary–thyroid axis or clinically overt hypothyroidism, but is similar to changes (sick euthyroid syndrome) observed in other groups of critically ill individuals. Thyroid hormone administration to such patients may not only be ineffective but may theoretically even be detrimental in some cases [145,146]. In summary, there is no conclusive evidence to date that supplementation of organ donors with thyroid hormone alone yields a significant clinical benefit. As per a consensus recommendation by leading North American critical care medicine societies and the U.

An ideal antiarrhythmic agent would discount depakote 500 mg free shipping, therefore buy depakote line, accelerate conduction and prolong refractoriness within the substrate for reentry cheap 500 mg depakote fast delivery. Many antiarrhythmic agents prolong refractory periods in myocardium buy depakote 250mg mastercard, but none accelerates conduction at therapeutic concentrations. This combination of decreasing conduction and refractory period prolongation can be either proarrhythmic or antiarrhythmic. A complete conduction block through an ischemic segment of a reentrant circuit may be the mechanism of arrhythmia termination; this could occur without slowing conduction in healthy myocardium. Lengthening of refractoriness should be proarrhythmic, but if conduction is slowed simultaneously, the net effect on the reentrant circuit determines the outcome. If voltage conditions are appropriate, prolonged depolarization may trigger a series of automatic action potentials. The upstrokes of these action potentials are due to inward current flow through the normal calcium channels that had been inactivated, had recovered from inactivation, and had found the membrane potential still within their activation range. Increased intracellular calcium concentrations activate calcium-sensitive potassium channels and accelerate repolarization. This process can occur as a single event or as an oscillatory series of action potentials, depending on the prevailing conditions of voltage and calcium levels [5]. Symptoms following acute overdose usually begin within 4 hours and can occur at any time during chronic therapy. Drug absorption may continue for many hours following the ingestion of large doses, sustained-release preparations, or agents with anticholinergic effects, resulting in delayed or progressive toxicity. Respiratory depression and hypotension produce acidosis and myocardial ischemia that further aggravate depressed conduction. Manifestations of acute toxicity may also include dizziness, visual disturbances, psychosis, anticholinergic symptoms, hypoglycemia, hyperglycemia, and hypokalemia. The differential diagnosis of bradyarrhythmias includes β-blocker, calcium channel blocker, cholinergic agent (carbamate and organophosphate insecticides), clonidine, cyclic antidepressant, and digitalis poisoning. Hypoglycemia, hypoxia, and metabolic disturbances should be considered in the differential diagnosis of patients with neurologic symptoms. Patients with hypotension and hypoxemia should have arterial blood gas and serum lactate measurements. Care of the antiarrhythmic poisoned patient centers on general supportive and critical care principles. All patients suspected of ingesting an overdose of an antiarrhythmic agent should receive oral activated charcoal. Patients with complications of therapeutic dosing may also benefit from oral activated charcoal to reduce absorption of a recently administered drug dose. The greatest amount of absorption to charcoal will occur when it is given within 1 to 2 hours of the ingestion. Phenytoin should never be used to treat seizures secondary to drug toxicity because of the risk of increased mortality. If hemodynamic improvement is noted, the loading dose should be followed by a continuous infusion at a rate of 0. Because poisoned patients are infrequently hypovolemic, fluid administration should be monitored closely. In general, if a response in blood pressure is not seen with 2 L of intravenous fluids, pressors such as norepinephrine should be administered. Early consideration should be given to providing a circulatory assist device for patients with cardiogenic shock. Intra-aortic balloon pump counterpulsation has been used successfully to treat patients with severe quinidine or disopyramide toxicity, and partial cardiac bypass has been used to maintain circulation during massive lidocaine or flecainide toxicity [9]. Common practice is to administer intravenous boluses of sodium bicarbonate (50 mEq of 1 mEq per mL solution) as needed to increase and maintain blood pH between 7. As an alternative, a continuous infusion of 1,000 mL of 5% dextrose in water containing 2 to 3 ampoules of sodium bicarbonate and potassium chloride is an option. For the most severely poisoned patients, however, alkalinization may be ineffective, especially if there is persistent metabolic acidosis. In a series of patients with class I antiarrhythmic drug overdose requiring cardiopulmonary resuscitation, only 2 of 29 survived despite the use of hypertonic sodium bicarbonate [13]. Hypertonic sodium chloride has proven effective for animals and, anecdotally, in humans, but sodium bicarbonate is generally preferable because increasing pH is equally or more important in some models [14] (see Chapter 97 for more detail). The treatment of recalcitrant ventricular tachycardia typically consists of repeated cardioversions, cardiopulmonary resuscitation, vasopressor support, and mechanical ventilation. Suppression of ventricular tachycardia and hemodynamic improvement has been anecdotally described with sodium bicarbonate [10,11]. The treatment of torsade de pointes should include 1 to 2 g of a 25% solution of intravenous magnesium sulfate. Direct-current cardioversion is often effective in terminating torsade de pointes, but it frequently recurs. Increasing the ventricular rate to greater than 90 to 110 beats per minute by an infusion of isoproterenol or ventricular pacing may also be effective [16]. Magnesium therapy should also be considered for patients at increased risk for this arrhythmia (see above); it has been found to prevent occurrence of torsade in a dog model (dose of 30 to 60 mg per kg) [19]. Although most antiarrhythmic drugs are weak bases, urine acidification is contraindicated because systemic acidosis may aggravate cardiotoxicity; treatment with hypertonic alkaline solution to reduce cardiotoxicity is likely to be of greater benefit. Hemodialysis is of limited benefit for antiarrhythmic toxicity because drug clearance is limited by protein binding and high lipid solubility [20]. Hemoperfusion using charcoal resin is more effective for removing drugs with high protein binding and high lipid solubility; however, this modality is rarely available. The usual dose of immediate-release quinidine sulfate is 200 to 400 mg, 4 times per day, with gluconate doses being approximately 30% higher. Bioavailability is approximately 70% for both forms; peak plasma levels are reached earlier for the sulfate (60 to 90 minutes) than for the gluconate. Torsade de pointes is an adverse effect of therapeutic doses of quinidine (also known as quinidine syncope). Risk factors for this arrhythmia are recent initiation of quinidine therapy, concurrent digoxin therapy, female gender, structural heart disease, hypokalemia, and hypomagnesemia. At therapeutic doses, sustained-release quinidine formulations produce therapeutic plasma concentrations for up to 8 hours for most patients. In overdose, however, saturation of enzymes that metabolize the drug may dramatically prolong serum concentrations. Mild quinidine overdose presents as cinchonism (headache, tinnitus, deafness, diplopia, confusion), vertigo, visual disturbances (blurred vision, photophobia, scotomata, contracted visual fields, yellow vision), or delirium. Initial therapy for acute quinidine overdose should include gastric decontamination with activated charcoal. When pacing is indicated for bradycardia, failure to capture is common in the face of drug-induced myocardial depression. Hypotension may result from vasodilation from β- adrenergic blockade, impaired contractility from sodium channel blockade, or arrhythmias. Vasodilation may be treated with fluid administration and β-acting vasopressors such as norepinephrine; large doses may be required. Refractory hypotension has been successfully treated with an intra-aortic balloon pump and partial circulatory bypass. The cardiovascular side effects of procainamide are very similar to those of quinidine except that the drug has no α-adrenergic antagonist activity. Inappropriate drug dosing in renal insufficiency or before achieving steady-state concentrations is the most common cause of procainamide toxicity. Approximately 40% of patients receiving long-term oral therapy with procainamide develop a syndrome resembling systemic lupus erythematosus that usually resolves after drug withdrawal [28]. Disopyramide Disopyramide, unlike most other antiarrhythmic drugs, has protein binding that shows nonlinear, saturable characteristics [29]. This is clinically important because small increases in total plasma level within the therapeutic range (see Table 101. When administered intravenously, disopyramide produces hypotension less frequently than does quinidine or procainamide. Data regarding management are limited, but an approach similar to that for quinidine toxicity is appropriate. Hypotension refractory to intravenous fluids and vasopressors has been treated with an intra-aortic balloon pump. Because of its relatively small volume of distribution, disopyramide clearance is substantially increased by hemoperfusion [21]. The maintenance infusion rate of lidocaine must be reduced for patients with cardiac failure or hepatic dysfunction and among the elderly.

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Fungal infections carry the highest morbidity and mortality rates of all infections after transplantation; mortality rates can range from 40% to 70% purchase 250 mg depakote mastercard. Aspergillus can invade blood vessels and may appear as an infarct on chest imaging or present with hemoptysis purchase depakote 250 mg free shipping. The radiographic findings of pulmonary aspergillosis include focal lower-lobe infiltrates purchase depakote cheap online, patchy bronchopneumonic infiltrates purchase depakote in united states online, single or multiple nodules with or without cavitation, thin-wall cavities, and opacification of the entire lung graft. Other manifestations of Aspergillus infection include pseudomembranous tracheobronchitis, often at and distal to the site of the anastomosis. These organisms can appear as septate hyphae that branch at acute angles and can be detected on hematoxylin-eosin and methenamine silver stains. Survival rates for patients with Aspergillus infection have been improved by the early initiation of broad-spectrum azoles (such as voriconazole or itraconazole, and more recently posaconazole), sometimes with the addition of an echinocandin, and a reduction in immunosuppressive therapy [96]. In patients with airway involvement with Aspergillus and for short-term prophylaxis following transplantation, inhaled amphotericin may be used. It is now rare to require systemic amphotericin or the less nephrotoxic liposomal formulation of amphotericin B. Prophylaxis with the azoles (voriconazole or itraconazole) for 3 to 6 months, and/or with aerosolized amphotericin, has shown promise for decreasing the incidence of Aspergillus infection after transplantation. Candidal infections may occur during the early postoperative period but usually do not cause invasive disease. Fluconazole and caspofungin have emerged as effective alternatives for treating infections caused by Candida albicans. Less common causes of fungal infections among lung transplant recipients include Cryptococcus neoformans and the dimorphic fungi (Coccidioides, Histoplasma, and Blastomyces). The broad-spectrum azole agents are the initial therapeutic choices for treating serious infections with the invasive mycoses. A minority of transplantation programs completely discontinue the administration of prednisone approximately 1 year after transplantation. It is recommended that sirolimus not be used in the early perioperative period (<10 to 12 weeks) due to impaired wound healing. Physicians caring for transplant recipients must be aware of the numerous drugs that can interact with tacrolimus and cyclosporine. For example, the azoles cause a significant increase in the serum concentrations of tacrolimus and cyclosporine. Likewise, discontinuing azole agents without increasing the dose of tacrolimus or cyclosporine can cause an acute and life-threatening decrease in the therapeutic concentrations of these drugs. Interactions with macrolide antibiotics, calcium-channel blockers, and gastric motility drugs have also been reported. A unique toxicity of the calcineuerin agents particularly when used with sirolimus include thrombotic microangiopathy [99]. One of the early clues to this diagnosis is radiographic evidence of a hemothorax or what appears to be a retained clot, or a large volume of blood draining from the thoracostomy tubes. This complication may occur more frequently among patients who require cardiopulmonary bypass with its attendant requirement for anticoagulation or among patients with pleural adhesions from previous procedures such as pleurodesis or diagnostic or therapeutic lung surgery. In addition to the bronchial anastomotic complications discussed earlier, vascular anastomotic complications can occur. A stenosis at the arterial anastomosis is suggested by unexplained gas exchange abnormalities and pulmonary hypertension [100]. An inability to wean the patient from mechanical ventilation may indicate phrenic nerve dysfunction; the diagnosis can be confirmed by phrenic nerve conduction studies. For patients who do not require ventilation, the diagnosis of phrenic nerve dysfunction can be made with a fluoroscopic “sniff test,” and more recently with the use of bedside ultrasound. If the injury is the result of stretching of the phrenic nerve or trauma to the nerve during the surgical procedure but the nerve is not completely transected, a slow recovery can be anticipated. The characteristics of these effusions are usually lymphocyte-predominant exudates and can be associated early on with severing of the lymphatics (i. A single-center study of a large number of lung transplant patients found that 27% of pleural effusions in these patients required drainage. Of the effusions, 96% was exudates, and 27% of patient had infected pleural effusions with organisms such as fungal pathogens (specifically Candida most commonly), followed by bacterial etiologies. These infected effusions were characterized by high lactate dehydrogenase levels and neutrophilia [102]. Lung transplant recipients also experience gastroparesis, severe gastroesophageal reflux resulting in aspiration pneumonia, and an increased incidence of gastrointestinal emergencies. This complication results from a combination of infections leading to sepsis and acute tubular necrosis, or from medication-related renal toxicity. Another study reported an incidence of acute renal failure postoperatively in 39% of patients and identified the use of aprotinin and bilateral lung procedures as risk factors. Acute renal failure was not predictive of late renal dysfunction or decreased long- term survival [104]. Cardiac arrhythmias, especially atrial arrhythmias such as atrial fibrillation, commonly develop in the perioperative period with an incidence of 25% in one study with resulting increase in length of hospital stay and increased 1-year mortality. Risk factors for their development included older age, diagnosis of pulmonary fibrosis, right ventricular dysfunction, right ventricle enlargement and elevated right atrial pressure, left atrial enlargement diastolic dysfunction, and history of coronary artery disease [105]. In one series of lung transplant recipients, the incidence of deep venous thrombosis and pulmonary embolism was reported to be 8. This complication was believed to be related to alterations in coagulability leading to a hypercoagulable state or hypercoagulability due to their underlying disease [107,108]. However, despite these improvements, numerous complications, many of which are managed by critical care professionals, can arise in this group of patients, and the unique aspects of their care are important. Chiumello D, Coppola S, Froio S, et al: Extracorporeal life support as bridge to lung transplantation: a systematic review. Javidfar J, Brodie D, Iribarne A, et al: Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery. Horai T, Shigemura N, Gries C, et al: Lung transplantation for patients with high lung allocation score: single-center experience. Sommer W, Kuhn C, Tudorache I, et al: Extended criteria donor lungs and clinical outcome: results of an alternative allocation algorithm. Minambres E, Coll E, Duerto J, et al: Effect of an intensive lung donor- management protocol on lung transplantation outcomes. Boffini M, Ricci D, Bonato R, et al: Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion. Perrin G, Roch A, Michelet P, et al: Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: a randomized clinical study. Ardehali A, Laks H, Levine M, et al: A prospective trial of inhaled nitric oxide in clinical lung transplantation. Struber M, Fischer S, Niedermeyer J, et al: Effects of exogenous surfactant instillation in clinical lung transplantation: a prospective, randomized trial. Cohen J, Singer P, Raviv Y, et al: Outcome of lung transplant recipients requiring readmission to the intensive care unit. Riera J, Baldirà J, Ramirez S, et al: Gastroparesis following lung transplantation: risk factor for pneumonia. Ferdinande P, Bruyninckx F, Van Raemdonck D, et al; Leuven Lung Transplant Group: Phrenic nerve dysfunction after heart–lung and lung transplantation. Jacques F, El-Hamamsy I, Fortier A, et al: Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences. Raghavan D, Gao A, Ahn C, et al: Contemporary analysis of incidence of post-operative atrial fibrillation, its predictors, and association with clinical outcomes in lung transplantation. Fourteen years passed before the first successful heart–lung transplant was performed on March 9, 1981. Heart–lung transplantation established the potential for lung transplantation as a viable therapeutic option, and the first successful single-lung transplant was performed in 1983 [1]. The waiting list for heart transplant has steadily grown because more patients are added than removed every year. Subsequently, the number of heart transplants has been increasing since 2004, with roughly 2,500 performed annually in the United States. It could also be an individual who has a mechanical assist device in place and either right or left ventricular support that is beginning to malfunction.

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Nordmann P discount 250mg depakote fast delivery, Cuzon G cheap depakote online visa, Naas T: the real threat of Klebsiella pneumoniae carbapenemase-producing bacteria purchase discount depakote online. Camus C purchase 250mg depakote with visa, Bellissant E, Sebille V, et al: Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Some semisynthetic penicillins, particularly nafcillin and oxacillin, are metabolized to a large extent by the liver; therefore, adjustment in dosage is not required in patients with renal insufficiency; for piperacillin, dosing adjustment is necessary only in severe renal insufficiency. For most other penicillins, moderate adjustments should be made in dosage for patients with severe renal insufficiency (Table 73. Penicillins are relatively nontoxic at usual doses, and side effects most commonly involve hypersensitivity reactions. Bone marrow and hepatic toxicity caused by semisynthetic penicillins have been described, with neutropenia more commonly seen with nafcillin and hepatitis more likely to occur with oxacillin. Because of the prevalence of penicillin-resistant pneumococci, life-threatening infections (especially meningitis) due to these organisms should be treated initially with ceftriaxone, cefotaxime, or vancomycin [2]. Although aspiration pneumonia commonly involves mouth anaerobes that are susceptible to penicillin G, penicillin-resistant anaerobes can be found in putrid, cavitary pneumonia and empyema, and clindamycin with or without a third-generation cephalosporin (or an extended-spectrum β-lactam plus metronidazole) is the preferred regimen [3,4]. Therapy for penicillin-susceptible Enterococcus spp causing endocarditis is penicillin G or ampicillin plus an aminoglycoside, generally gentamicin [5]. Staphylococcus aureus should be presumed to be resistant to penicillin, ampicillin, and piperacillin, as most strains produce a penicillinase. Both are sufficiently metabolized by the hepatic route such that no adjustment in dose is necessary for patients with renal insufficiency. For patients with Pseudomonas aeruginosa infections, the intensivist should consider using higher dosages or continuous infusions of piperacillin/tazobactam or piperacillin, with or without an aminoglycoside. The addition of the aminoglycoside to extended- spectrum penicillins is controversial [10] but has been shown to provide broader Gram-negative coverage and synergistic killing against P. Thus, the combination of one of these β-lactamase inhibitors with ampicillin or piperacillin results in a drug combination that is active against β-lactamase–producing strains of S. However, chromosomally mediated β-lactamases of other Gram-negative bacilli are unaffected by these β-lactamase inhibitors, and therefore these combinations are ineffective against many isolates of P. Formulations of β-lactamase combinations available parenterally include ampicillin/sulbactam and piperacillin/tazobactam. Piperacillin/tazobactam can be effective in the treatment of mixed infections, such as nosocomial pneumonia, intra-abdominal infections, and synergistic skin soft tissue infections. The pharmacology of the β-lactamase inhibitors is similar to that for other β-lactams: Clearance is by renal mechanisms, and dosage adjustments must be made with these combinations in the setting of renal impairment. Many strains of Enterobacter possess an inducible chromosomal β-lactamase and may become resistant during therapy. Nosocomial isolates of Enterobacteriaceae usually are resistant to first-generation cephalosporins, as are Pseudomonas and Acinetobacter spp. A number of these agents, particularly ceftazidime, are less active than first-generation cephalosporins against Gram-positive cocci. If a third-generation cephalosporin is used as a single agent, gaps in coverage may occur, including: (a) enterococcal superinfection; (b) P. Newer Cephalosporins Cefepime, a fourth-generation cephalosporin [14], has activity against Gram-positive organisms similar to that of cefotaxime and ceftriaxone and activity against Pseudomonas similar to that of ceftazidime. Compared with third-generation cephalosporins, cefepime has a lower affinity for β-lactamases and is not an inducer of chromosomal β- lactamases. Ceftaroline is indicated for treatment of acute bacterial skin and skin structure infections caused by susceptible isolates of the following Gram- positive and Gram-negative microorganisms: S. It is also approved for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates of S. The most commonly noted adverse effects are hypersensitivity reactions, including rashes, fever, interstitial nephritis, and anaphylaxis. In patients with documented penicillin allergy, the risk of cross-reactive allergic reactions to the cephalosporins is cited as 5% to 10%, and generally it is felt that cephalosporins should be avoided for patients with a history of documented anaphylaxis or immediate hypersensitivity (urticaria) reaction to the penicillins, but can be given to patients with a history of other types of reactions to penicillins, including morbilliform rash and fever. Enterococcal superinfections occur with any of the extended- spectrum cephalosporins because none of these agents has significant activity against enterococci [16]. In patients with severe impairment of renal function, dosages of all cephalosporins except ceftriaxone must be adjusted to avoid accumulation. Cephalosporins with β-Lactamase Inhibitor Activity Ceftazidime/avibactam is a combination of a third generation cephalosporin with a novel non-β-lactam β-lactamase inhibitor (avibactam) [17]. In a phase 2 clinical trial in patients with complicated intraabdominal infections, ceftazidime/avibactam at a dose 2. Since ceftazidime/avibactam is excreted primarily by the kidney, renal dose adjustment is required in patients with renal impairment (Table 73. Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. Ceftolozane/tazobactam is approved for treatment of complicated intraabdominal infections at a dose of 1. In a phase 3 clinical trial for treatment of complicated intraabdominal infection ceftolozane/tazobactam 1. Ceftolozane/tazobactam is excreted primarily by the kidney, with ceftozolane being eliminated unchanged and tazobactam being hydrolyzed to inactive metabolite. Imipenem is administered in combination with cilastatin, an enzymatic inhibitor of a renal dehydropeptidase, which inhibits metabolism of imipenem by the kidney, increasing the t½ and decreasing the nephrotoxicity of imipenem. Imipenem exhibits activity against Gram-negative bacilli at least equal to that of the third-generation cephalosporins (including anti-Pseudomonas potency equal to that of ceftazidime); against Gram-positive cocci similar to that of oxacillin, nafcillin, and cefazolin; and against anaerobic bacteria equal to metronidazole and clindamycin. Enterococcus faecalis appears susceptible in vitro, but Enterococcus faecium usually is resistant, and imipenem should not be regarded as effective therapy for serious infections caused by enterococci. The usual dosage of imipenem/cilastatin is 2 g per day in four divided doses, with up to 4 g per day in life-threatening infections by less susceptible organisms (e. The frequency of cross-reactivity with other classes of β-lactams is estimated to be approximately that observed with penicillins and cephalosporins. Meropenem is more active against Gram-negative rods, including Pseudomonas spp, and slightly less active against Gram-positive cocci, including S. Meropenem and ertapenem are excreted via the kidney but, in contrast to imipenem, their renal metabolism is negligible and cilastatin is not coadministered. Doripenem is a novel carbapenem with a broad spectrum of activity against Gram-positive pathogens, anaerobes, and Gram-negative bacteria, including P. Although skin rashes occur occasionally with this drug, aztreonam has been given safely to patients with immediate hypersensitivity-type reactions (anaphylaxis, urticaria) to penicillins or cephalosporins. Against most facultative aerobic Gram-negative bacilli, aztreonam exhibits a spectrum and potency much like that of third-generation cephalosporins, including activity against some strains of Pseudomonas spp. Aminoglycosides in common clinical use for the critically ill patient include gentamicin, tobramycin, and amikacin. Spectrum of Action and Indications for Therapy the primary clinical indication for aminoglycoside therapy is serious infection caused by Gram-negative bacilli. Aminoglycosides also are used in combination with a cell wall agent for therapy of enterococcal endocarditis. Although more toxic than penicillins and cephalosporins, aminoglycosides provide the broadest range of potent, bactericidal antibiotic activity against Gram-negative bacilli, particularly when multiply-resistant enteric Gram-negative bacilli (e. However, resistance to aminoglycosides has increased dramatically among Enterococcus spp, and currently in many hospitals, up to one fourth of isolates are gentamicin-resistant [23]. In addition, gentamicin in combination with ampicillin, penicillin, or vancomycin is indicated for treatment of endocarditis due to enterococci or viridans group streptococci and can be used with vancomycin and rifampin for treatment of prosthetic valve endocarditis caused by coagulase-negative staphylococci. In addition, tobramycin is less active than gentamicin against some organisms, such as Serratia spp and Acinetobacter spp. Amikacin Amikacin is the semisynthetic aminoglycoside most resistant to aminoglycoside-inactivating enzymes. Adverse Reactions Unlike β-lactam antibiotics, aminoglycosides are characterized by a narrow therapeutic–toxic ratio, and therapy with these agents can be associated with considerable toxicity. Hypersensitivity reactions such as fever and rash are uncommon and anaphylaxis has been observed rarely. Neuromuscular blockade has been described uncommonly and appears to be of concern only in patients with myasthenia gravis or severe hypocalcemia or those who are receiving neuromuscular blocking agents. Ototoxicity appears to occur with equal frequency (up to 10% of patients) among the modern aminoglycosides.

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Which antibiotic regimens are recommended for empiric therapy of community-acquired pneumonia and why? Estimates suggest that pneumonia is responsible for more than 10 million physician visits depakote 250mg otc, 500 order 250mg depakote mastercard,000 hospitalizations purchase genuine depakote on line, and 45 purchase depakote american express,000 deaths annually. Overall, 258 people per 100,000 population require hospitalization for pneumonia, and that number rises to 962 per 100,000 among or nearly 1/100 for those over the age of 65 years. It is estimated that, annually, 1 in 50 people over 65 years of age and 1 in 20 over 85 years will develop a pneumonia. Causes Improved diagnostic techniques have shown that the number of pathogens that cause acute pneumonia is ever expanding (Table 4. Mycoplasma and Chlamydophila pneumoniae also account for a significant percentage of acute pneumonias. Legionella species vary in importance, depending on the season and geographic area. Anaerobes such as anaerobic streptococci and bacteroides can cause acute pneumonia following aspiration of mouth contents. Common viral pathogens include influenza, parainfluenza, and respiratory syncytial virus. Pathogenesis and Pathology Under normal conditions, the tracheobronchial tree is sterile. The respiratory tract has a series of protective mechanisms that prevent pathogens from gaining entry [ure 4. The epiglottis covers the trachea and prevents secretions or food from entering the trachea. Mucin contains a number of antibacterial compounds including immunoglobulin A antibodies, defensins, lysozymes, and lactoferrin. Mucin also is sticky, and it traps bacteria or other foreign particles that manage to pass the epiglottis. Cilia lining the inner walls of the trachea and bronchi beat rapidly, acting as a conveyer belt to move mucin out of the tracheobronchial tree to the larynx. When significant volumes of fluid or large particles gain access to the trachea, the cough reflex is activated, and the unwanted contents are quickly forced out of the tracheobronchial tree. If pathogens are able to bypass all of the above protective mechanisms and gain entry into the alveoli, they encounter a space that, under normal circumstances, is dry and relatively inhospitable. The presence of an invading pathogen induces the entry of neutrophils and alveolar macrophages that ingest and kill infecting organisms. The lymphatic channels adjacent to the alveoli serve to drain this space and transport fluid, macrophages, and lymphocytes to the mediastinal lymph nodes. Bacterial pathogens usually gain entry into the lung by aspiration of mouth flora or by inhalation of small aerosolized droplets (<3 μm in diameter) that can be transported by airflow to the alveoli. The nasal turbinates trap foreign particles, and the epiglottis covers the trachea. First, an outpouring of edema fluid into the alveoli occurs, serving as an excellent culture media for further bacterial growth. As fluid accumulates, it spills over to adjacent alveoli through the pores of Kohn and the terminal bronchioles, resulting in a centrifugal spread of infection. Bacterial invasion of the alveoli induces a) edema fluid that spreads to other alveoli through the pores of Kohn, and b) infiltration by polymorphonuclear leukocytes and red blood cells, followed by macrophages. Infection spreads centrifugally: a) Newer regions in the periphery appear red (“red hepatization”). On lower power microscopy, this region has an appearance similar to the architecture of the liver—an effect termed “red hepatization. Gram-negative rods and anaerobic bacteria also cause permanent tissue destruction. Predisposing Factors Most bacterial pneumonias are preceded by a viral upper respiratory infection [ure 4. Viral infections of the upper respiratory tract can damage the bronchial epithelium and cilia. Virus-mediated cell damage also results in the production of serous fluid that can pool in the pulmonary alveoli, serving as an excellent culture media for bacteria. The low viscosity of this fluid, combined with depressed ciliary motility, enables the viral exudate to carry nasopharyngeal bacteria past the epiglottis into the lungs. Smoking also damages the bronchial epithelial cells and impairs mucociliary function. Congenital defects in ciliary function (such as Kartagener syndrome) and diseases resulting in highly viscous mucous (such as cystic fibrosis) predispose patients to recurrent pneumonia. An active cough and normal epiglottal function usually prevent nasopharyngeal contents from gaining access to the tracheobronchial tree. However, drugs such as alcohol, sedatives, and anesthetics can depress the level of consciousness and impair these functions, predisposing the patient to pneumonia. Elderly individuals, particularly after a cerebrovascular accident, often develop impairments in swallowing that predispose them to aspiration. In addition, elderly people demonstrate reduced humoral and cell-mediated immunity, rendering them more susceptible to viral and bacterial pneumonia. Patients with impairments in immunoglobulin production, T- and B-cell function, and neutrophil and macrophage function are also at greater risk of developing pneumonia. Chronic diseases, including multiple myeloma, diabetes, chronic renal failure, and sickle cell disease, have been associated with an increased risk of pneumonia. Viral infections damage cilia and produce serous exudate that can transport nasopharyngeal bacteria into the alveoli. Elderly patients have reduced humoral and cell-mediated immunity, and may have impaired swallowing because of stroke. Cold weather dries the mucous membranes and increases person-to- person spread of infection. Cold, dry weather can alter the viscosity of mucous and impair bacterial clearance. Cold weather also encourages people to remain indoors, a situation that enhances person-to-person spread of respiratory infections. She also noted diffuse severe muscle aches and joint pains and a generalized headache. In her epidemiologic history, she noted that she had recently seen her grandchildren, who all had high fevers and were complaining of muscle aches. Physical examination showed these positive findings: temperature, 39°C; throat, erythematous; nasal discharge, clear; muscles, diffusely tender. Three days into the clinical course of her illness, the patient noted some improvement in her cough, muscle aches, and joint pains; however, on the fourth day, she developed a high fever (40°C) preceded by a teeth-chattering chill. That day, her cough became productive of rusty-colored opaque sputum, and she began feeling short of breath. Lungs were mildly dull to percussion, with E-to-A changes, and rales and rhonchi localized to the right middle lobe area. A number of viruses can explain these symptoms, including influenza, parainfluenza, adenovirus, respiratory syncytial virus (more common in children, but also found in elderly individuals and transplant patients), rhinoviruses (usually less severe), and enteroviruses. Subsequently, within a 24-hour period, this patient experienced the abrupt onset of a new constellation of symptoms. Symptoms that develop over 3 days to 1 week are generally classified as subacute, and symptoms that progress more slowly (over 3 weeks to several months) are classified as chronic. In generating a potential list of causative agents, the infectious disease specialist frequently uses the pace of the illness to narrow the possibilities. Most bacterial and viral pneumonias develop quickly; fungal and mycobacterial pulmonary infections tend to develop at a slower pace. Finally, pulmonary infections are separated into community-acquired or nosocomial. Generation of a logical differential list of potential pathogens guides the choice of diagnostic tests and narrows the possible treatment regimens. Environment in which the pneumonia was acquired: a) Community acquired—patient not recently (>14 days) in a hospital or chronic care facility.

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