Eight Ideas for a High-Performing Health Care System

ACP Medicine provides physicians and other clinicians with the information they need to practice evidence-based and state-of-the art medicine. Even if this information were used in each patient encounter and with adherence to the highest principles of professionalism, however, that would not be sufficient to create a high-performing health care system. More is needed; the systems in which we work must be robust and responsive, too.

A paper in the January 1, 2008 issue of Annals of Internal Medicine addresses problems in the United States health care system. The article describes current health care in the United States in terms of its costs and who pays for it, the physician workforce, and the availability and application of technology and innovations. It then describes a set of criteria and 37 indicators of high performance developed by the independent, nonprofit Commonwealth Foundation; those criteria and indicators are used to compare health care in the United States with that in twelve other highly industrialized countries. The scoring sheet includes measures of living longer and healthier; the quality, access, efficiency, and equity of health services; and the system's capacity for innovation and improvement.

The report indicates that although the United States has many fine physicians, medical services, and heath care facilities, its health care does not compare favorably with that in the other industrialized countries. The United States spends far more—per capita or as a percentage of the gross domestic product—on health services, administration, and regulation and scores lower on quality of care, safe care, coordinated care, and patient-centered care. Access, efficiency, equity, infant mortality, and longevity scores for the United States are all the lowest or next to lowest, compared with those of Australia, Canada, Germany, New Zealand, and the United Kingdom. The study clearly delineates major gaps in the United States system and many opportunities for improvement.

This analysis led the ACP, through its Health and Public Policy Committee and the Board of Regents, to formulate new College policy to improve health care in the United States and begin advocating for this policy as strongly as possible. The ACP made eight specific recommendations:

• Provide universal health insurance coverage through either a pluralistic or a single-payer system to ensure that all residents have equitable access to appropriate health care without unreasonable financial barriers. Health insurance coverage and benefits should be continuous and not dependent on place of residence or employment status.

• Create incentives to encourage patients to be prudent purchasers by having access to health information necessary for informed decision-making.

• Avert a collapse of primary care by developing a national workforce policy that ensures an adequate supply of physicians trained to manage care for the whole patient.

• Redirect federal health care policy toward supporting the “patient-centered medical home.” This is an innovative practice system proposed by the ACP to strengthen the physician-patient relationship by having a primary care physician coordinate a team of health care professionals as they address the full range of a patient's needs.

• Provide financial incentives for physicians to coordinate care, prevent disease, and achieve evidence-based performance standards.

• Reduce the costs of health care administration by creating a uniform billing system for all services.

• Support with federal funds an interoperable health information technology infrastructure.

• Encourage public and private investment in medical research and assessments of the comparative effectiveness of different medical treatments.

More information about ACP policies on access to health care is available at the ACP Web site ( www.acponline.org ), including questions and answers about the policy paper and a discussion area for ACP members ( http://www.acponline.org/auth-cgi/readnews.pl?g=lounge&a=1564&t=fetch ; password required). There is also a new nonpartisan ACP Web tool ( http://www.acponline.org/advocacy/election08/ ) that analyzes the health care reform proposals of the 2008 presidential candidates, drawing on the recommendations outlined in the College's new policy paper. The tool will be updated continually throughout the election cycle. I encourage you to check it often. We hope this tool will help you conduct a personal analysis of the 2008 presidential candidates with respect to the health care policies they espouse.

As the ACP Ethics Manual ( http://www.acponline.org/ethics/ethics_man.htm ) points out, “Physicians have an opportunity and duty to advocate for the needs of individual patients as well as society.” The Physician Charter on Professionalism ( http://www.annals.org/cgi/content/full/136/3/243 ) instructs physicians to “... strive to reduce barriers to equitable health care” through “the promotion of public health and preventive medicine, as well as public advocacy on the part of each physician, without concern for the self-interest of the physician or the profession.”

I strongly encourage all physicians to get involved in these issues. It is more important than ever for physicians to become engaged in systems issues as well as the scientific and clinical issues of patient care. We will all be better off—our patients and our profession—if we do.

1 Cardiovascular Medicine

V Supraventricular Tachycardia

Better Living with Electricity

The overall success rate for catheter ablation therapy is approximately 95% in patients with tachycardia from atrioventricular (AV) node reentry involving an accessory pathway. Current techniques allow for successful ablation of accessory pathways that traverse the AV annulus or the anterior or posteroseptal spaces. For pathways over the left AV groove, current ablation techniques involve use of either transseptal or retrograde aortic approaches. Recent advances in ablative techniques allow for ablation of anteroseptal accessory pathways that could not be ablated via a right- or left-sided approach. These pathways can be ablated from the noncoronary cusp of the aortic valve.¹ Other newer techniques involve navigational systems for precise mapping,² use of cryoablation for pathways close to the bundle of His,³ and epicardial approaches for ablation.⁴

1. Huang H, Wang X, Ouyang F, et al: Catheter ablation of anteroseptal accessory pathway in the non-coronary aortic sinus. Europace 8:1041, 2006 [PMID 17098777]

2. Davis DR, Tang AS, Birnie DH, et al: Successful ablation of a concealed parahisian accessory pathway using a remote magnetic navigation system following failure by conventional methods. J Interv Card Electrophysiol 16:149, 2006 [PMID 17109208]

3. Grossmann G, Stiller P, Hombach V, et al: Cryoablation of an anteroseptal accessory pathway. Clin Res Cardiol 96:56, 2007 [PMID 17146604]

4. Ho I, d'Avila A, Ruskin J, et al: Images in cardiovascular medicine: percutaneous epicardial mapping and ablation of a posteroseptal accessory pathway. Circulation 115:e418, 2007 [PMID 17452613]

The Skinny on FAT

Focal atrial tachycardias (FATs)—regular tachycardias emanating in an atrial area and showing a centripetal pattern of spread—are the least common cause of paroxysmal supraventricular tachycardia but nevertheless can cause significant morbidity. Recent advances in the diagnosis of FAT include the development of an algorithm for identification of the anatomic site of origin on the basis of P wave morphology.¹ A new technique that uses multielectrode surface mapping to detect atrial focus also appears promising.²

1. Kistler PM, Roberts-Thomson KC, Haqqani HM, et al: P-wave morphology in focal atrial tachycardia: development of an algorithm to predict the anatomic site of origin. J Am Coll Cardiol 48:1010, 2006 [PMID 16949495]

2. Wang Y, Cuculich PS, Woodard PK, et al: Focal atrial tachycardia after pulmonary vein isolation: noninvasive mapping with electrocardiographic imaging (ECGI). Heart Rhythm 4:1081, 2007 [PMID 17675084]

Better than Amiodarone?

Dronedarone is a new antiarrhythmic agent pharmacologically related to amiodarone but developed to reduce the risk of side effects. In two multicenter, double-blind, randomized trials of dronedarone in patients with either atrial fibrillation or atrial flutter, 828 patients received 400 mg of the drug twice daily and 409 patients received placebo.¹ Dronedarone proved significantly more effective than placebo in maintaining sinus rhythm and reducing ventricular rate during arrhythmia.

1. Singh BN, Connolly SJ, Crijns HJ, et al: Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. EURIDIS and ADONIS Investigators. N Engl J Med 357:987, 2007 [PMID 17804843]

Healing Flutter, Causing Fibrillation

A number of studies have focused on long-term follow-up of patients treated with radiofrequency ablation of the cavotricuspid isthmus for typical atrial flutter. In one retrospective study, 50% of the patients with no history of atrial fibrillation developed atrial fibrillation after a mean follow-up of 29.6 months¹; another study found a 59.1% recurrence rate of atrial fibrillation after a mean follow-up of 3 years.² Despite the high rate of progression to atrial fibrillation, the authors concluded that there was a significant symptomatic benefit and that the need for hospitalization was reduced.²

1. Chinitz JS, Gerstenfeld EP, Marchlinski FE, et al: Atrial fibrillation is common after ablation of isolated atrial flutter during long-term follow-up. Heart Rhythm 4:1029, 2007 [PMID 17675077]

2. Meissner A, Christ M, Maagh P, et al: Quality of life and occurrence of atrial fibrillation in long-term follow-up of common type atrial flutter ablation: ablation with irrigated 5 mm tip and conventional 8 mm tip electrodes. Clin Res Cardiol 96:794, 2007 [PMID 17721735]

Clinical Essentials

III Reducing Risk of Injury and Disease

On the Cusp of Quitting?

Research has shown that a strong message from a personal physician is the most important factor in successfully quitting smoking. The elements of successful quitting are consistent, repeated, and strong advice to stop smoking; setting a specific quit date; and follow-up visits to reinforce behavior. However, not all physicians counsel smokers to quit. In one study, less than 50% of cigarette smokers reported that their physician had advised them to quit.¹

A current theory in behavioral psychology suggests that changes in behavior reflect predictable stages in the readiness to change, ranging from no intention to change, to definite plans to change in the near future, to active attempts at change. A stage of readiness to change is predictive of quitting, and this behavioral model may help clinicians shape smoking-cessation efforts to the patient's readiness to quit [see Table].

1. Cokkinides VE, Ward E, Jemal A, et al: Under-use of smoking-cessation treatments: results from the National Health Interview Survey, 2000. Am J Prev Med 28:119, 2005 [PMID 15626567]

Smoke and Mirrors

Weight gain is a common occurrence in patients who have stopped smoking. The average weight gain in a national sample of adults who had stopped smoking was 4.4 kg for men and 5.0 kg for women. Younger age, lower socioeconomic status, and heavier smoking are predictors of higher weight gain. According to surveys, women smokers who are concerned about weight are especially unlikely to seek treatment or to attempt quitting on their own.

Mechanisms for weight gain after smoking cessation include increased energy intake, decreased resting metabolic rate, decreased physical activity, and increased lipoprotein lipase activity. Weight gain also appears to be related to increases in food reward, which is partly determined by genetic factors and can be attenuated with bupropion. Smoking can impair glucose tolerance and insulin sensitivity, and smoking cessation seems to improve insulin sensitivity, despite weight gain.

The Newest Aid to Smoking Cessation

The newest approach to smoking cessation is the use of nicotinic receptor antagonists to block the response to nicotine in cigarette smoke. The partial nicotinic receptor agonist varenicline has been shown to increase the odds of successful long-term smoking cessation approximately threefold compared with pharmacologically unassisted attempts at quitting.^1,2 In trials reported so far, more participants quit successfully with varenicline than with bupropion.

The Food and Drug Administration approved the use of varenicline for smoking cessation in May 2006. The dosage for the first 3 days is 0.5 mg once a day, followed by 0.5 mg twice a day for the next 4 days, then 1 mg twice a day for the remainder of the 12-week treatment period. Patients who are able to quit smoking with varenicline may continue the drug for an additional 12 weeks of treatment; this further increases the likelihood of long-term success.

As of November 2007, the FDA began recommending that clinicians monitor patients who are taking varenicline for behavior and mood changes.³ In addition, because the use of varenicline has been associated with drowsiness, patients should use caution when driving or operating machinery until they know how varenicline may affect them. The most common side effect of varenicline is nausea.

1. Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev (1):CD006103, 2007 [PMID 17253581]

2. Gonzales D, Rennard SI, Nides M, et al: Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. Varenicline Phase 3 Study Group. JAMA 296:47, 2006 [PMID 16820546]

3. Early communication about an ongoing safety review: varenicline (marketed as Chantix). U.S. Food and Drug Administration, November 20, 2007 http://www.fda.gov/cder/drug/early_comm/varenicline.htm

Swift Solutions for Problem Drinkers

Problem drinkers often respond to brief office interventions (as short as 10 or 15 minutes), which use motivational techniques such as goal setting, contracts, and enhancing self-efficacy. In most instances, the goal is usually controlled moderate drinking rather than abstinence. The first step toward successful counseling is to get the patient to recognize that their drinking is a problem. It is important to help the patient see a relationship between drinking and current medical or psychosocial problems. Strong advice to reduce consumption is also important.

A meta-analysis of 21 randomized, controlled trials in 7,286 participants showed that participants receiving brief intervention reduced their alcohol consumption compared with the control group (mean difference: -41 g/week, 95% confidence interval: -57 to -25 g), although there was substantial heterogeneity between trials.¹ Subgroup analysis of eight studies that separated data by gender showed that the effect of brief intervention was clear in men at 1 year of follow-up, but unproven in women. Compared with brief intervention, extended intervention appeared to offer little additional effect.

1. Kaner EF, Beyer F, Dickinson HO, et al: Effectiveness of brief alcohol interventions in primary care populations. Cochrane Database Syst Rev (2):CD004148, 2007 [PMID 17443541]

9 Metabolism

I Type 1 Diabetes Mellitus

Measuring the Odds of Diabetes

In relatives of patients with type 1 diabetes, the risk of developing the disease can be stratified through measurement of islet autoantibodies. The number of antibodies present, as well as their characteristics (e.g., titer, subclass, and epitope), indicate the degree of risk. Autoantibody characteristics—and, therefore, degree of risk—may change over time, especially in young persons.¹

1. Achenbach P, Warncke K, Reiter J, et al: Type 1 diabetes risk assessment: improvement by follow-up measurements in young islet autoantibody-positive relatives. Diabetologia 49:2969, 2006 [PMID 17019596]

Viral Diabetes?

Because only 30% to 50% of unaffected identical twins of patients with type 1 diabetes mellitus will eventually develop the disease, it is likely that an environmental factor may be required to trigger the autoimmune destructive process.¹ In addition, individuals with genotypes that place them at high risk for diabetes make up a lower percentage of the diabetic population than in the past—a fact that suggests an environmental cause for the increasing incidence of type 1 diabetes.

A number of viral candidates have been proposed.¹ The only certain association is that the offspring of women who are infected with rubella during pregnancy are at increased risk for type 1 diabetes mellitus. In addition, some indirect evidence associates coxsackievirus B, enteroviruses, rotavirus, parvovirus, and cytomegalovirus with type 1 diabetes mellitus.² Toxins in the environment or diet might also initiate the destruction of genetically vulnerable beta cells.

1. Peng H, Hagopian W: Environmental factors in the development of type 1 diabetes. Rev Endocr Metab Disord 7:149, 2006 [PMID 17203405]

2. van der Werf N, Kroese FG, Rozing J, et al: Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev 23:169, 2007 [PMID 17103489]

Can Type 1 Be Prevented?

A trial sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases unfortunately found no evidence that type 1 diabetes mellitus can be prevented by inducing immune tolerance to exogenous human insulin given subcutaneously or orally to relatives of patients with high titers of islet autoantibodies. A hypothesis-generating analysis suggested, however, that study patients with high levels of insulin autoantibodies who received oral insulin may have experienced a delay and perhaps a reduction in the incidence of type 1 diabetes.¹ This hypothesis is being tested in a study launched by the Type 1 Diabetes TrialNet ( http://www.diabetestrialnet.org ), which is a clinical trials network created by the National Institutes of Health to conduct studies in patients with new-onset type 1 diabetes and in relatives at risk for the disease.

Current Type 1 Diabetes TrialNet studies are investigating the treatment of patients who have newly diagnosed type 1 diabetes, using tailored and humanized antagonists to molecules in lymphocytes that are important to their activation in the immune responses. These include rituximab, which is approved for the treatment of selected lymphomas and rheumatoid arthritis, and the combination of mycophenolate mofetil and daclizumab (an interleukin-2 receptor inhibitor), which are approved for the prevention of rejection after organ transplantation.

1. Skyler JS, Krischer JP, Wolfsdorf J, et al: Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial-Type 1. Diabetes Care 28:1068, 2005 [PMID 15855569]

A New Way to Monitor Postprandial Glucose

Measurement of 1,5-anhydroglucitol (1,5-AG) levels in serum can be used to monitor postprandial glycemic control in patients with moderately well-controlled diabetes. 1,5-AG is the 1-deoxy form of glucose. In normal persons, the balance between a small oral intake and urinary excretion of 1,5-AG, as well as a large pool size of 1,5-AG, results in a constant blood level. When blood glucose levels exceed the renal threshold of 150 mg/dl, however, glucose competitively inhibits the reabsorption of 1,5-AG by the renal tubules. As a result, urinary excretion of 1,5-AG increases and serum levels fall. Measurement of 1,5-AG levels has been used clinically in Japan for over a decade; in the United States, the FDA has approved the use of a 1,5-AG serum assay (GlycoMark) for measuring postprandial glucose levels over 1 to 2 weeks.¹

1. Dungan KM, Buse JB, Largay J, et al: 1,5-Anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care 29:1214, 2006 [PMID 16731998]

Inhaled Insulin Stumbles

Inhaled insulin, produced by one pharmaceutical firm, was approved by the FDA in January 2006. Use of inhaled insulin has been associated with improved patient satisfaction and quality of life, presumably because of the reduced number of injections. Nevertheless, because of the disappointing level of adoption of the single FDA-approved formulation of inhaled insulin and its delivery device by physicians and patients, the manufacturer removed it from the market in 2007. At least two other formulations of inhaled insulin and their delivery systems are under development, however.

Pumps at Present

Current models of external pumps approach, but do not achieve, the ideal of completely closed-loop insulin delivery, in which blood glucose levels are monitored continuously and the results automatically drive insulin delivery rates. Some pumps have a separate glucose sensor that can be worn for up to 3 days at a time and that communicates wirelessly with the pump, providing continuous readings and warning of high and low levels. Patients can use these to adjust insulin delivery as necessary.

7 Infectious Disease

XXXIV Protozoan Infections

A New Drug for Severe Malaria

Artesunate, which is derived from the sweet wormwood plant (Artemisia annua), has been in worldwide use for the treatment of severe malaria for many years and became available in the United States in June 2007 under a Food and Drug Administration investigational new drug (IND) protocol.¹ Studies comparing quinine with artesunate have demonstrated better outcomes in the artesunate-treated groups,² perhaps because of the very rapid clearance of parasites after artesunate therapy. The Centers for Disease Control and Prevention now has artesunate stockpiled for release for treatment of severe malaria. Physicians can enroll patients in the artesunate IND protocol by calling the CDC Malaria Hotline (770-488-7788, Monday through Friday, 8 A.M. to 4:30 P.M. Eastern time; 770-488-7100 after hours) and asking to speak with a CDC Malaria Branch clinician. To minimize delay in antiparasitic therapy, physicians should give immediate quinidine therapy while requesting artesunate. Artesunate therapy must be followed with a course of another antimalarial agent; the CDC recommends atovaquone-proguanil (Malarone), doxycycline (clindamycin in pregnant women), or mefloquine for this purpose.

1. Artesunate now available to treat severe malaria in US. Centers for Disease Control and Prevention, Atlanta, July 30, 2007 http://www.cdc.gov/malaria/features/artesunate_now_available.htm

2. Checkley AM, Whitty CJ: Artesunate, artemether, or quinine in severe Plasmodium falciparum malaria? Expert Rev Anti Infect Ther 5:199, 2007 [PMID 17402835]

Alternatives for Giardiasis

Tinidazole, given as a single 2 g oral dose, is highly effective for the treatment of giardiasis. Nitazoxanide is also effective; it is given for 3 days (in adults, 500 mg b.i.d.; in children 4 to 11 years of age, 250 mg b.i.d; and in children 1 to 3 years of age, 150 mg b.i.d.). A randomized trial showed that for the treatment of symptomatic giardiasis in children, the efficacy of nitazoxanide is comparable to that of metronidazole. An alternative agent for children is furazolidone, which is available as a suspension; it is effective and well tolerated.¹

Both tinidazole and nitazoxanide are approved by the FDA for the treatment of giardiasis. Metronidazole, although not approved for the treatment of giardiasis, has been the principal agent used to treat this infection¹ because quinacrine, the first effective drug for giardiasis, is no longer distributed in the United States. The usual dosage of metronidazole is 250 mg orally three times a day for 5 days, though this may lead to recurrences in up to 40% of cases, or 500 to 750 mg orally three times a day for 10 days, which is effective in 60% to 95% of cases.

1. Drugs for parasitic infections. Med Lett Drugs Ther 49(suppl):1, 2007

Treatment Considerations in Cryptosporidiosis

In immunocompetent patients, cryptosporidiosis is a self-limited illness and usually requires only supportive therapy. Chemotherapy would be valuable in immunocompromised patients, but an effective regimen for cryptosporidiosis has not been established. If the patient is receiving immunosuppressive drugs, cessation of these agents may lead to resolution of the diarrhea. Similarly, improvement of CD4⁺ T cell levels in HIV-infected patients by highly active antiretroviral therapy has led to the cessation of life-threatening cryptosporidial diarrhea.

For some HIV-infected patients, paromomycin may be at least partially beneficial in treating cryptosporidiosis, although small controlled trials were unable to show a difference between paromomycin and placebo. Perhaps a better alternative is nitazoxanide (in adults, 500 mg b.i.d.; in children 4 to 11 years of age, 250 mg b.i.d; in children 1 to 3 years of age, 150 mg b.i.d.); however, nitazoxanide is approved by the FDA for the treatment of cryptosporidiosis in children only. One randomized trial has shown efficacy in cryptosporidiosis in immunocompent patients, but a meta-analysis of nitazoxanide therapy failed to show its utility for immunocompromised patients.¹

1. Abubakar I, Aliyu SH, Arumugam C, et al: Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol 63:387, 2007 [PMID 17335543]

Chagas Disease in the North

Only rare autochthonous cases of Trypanosoma cruzi infection (American trypanosomiasis, or Chagas disease) have been reported in the United States.¹ In rural areas of Central and South America, however, human infections are common where conditions favor access of infected bugs to persons.² In addition, infections may be transmitted by blood transfusions, across the placenta, to laboratory workers, and, in rare instances, by ingestion of foodstuffs contaminated with the excreta of infected reduviid bugs.

Increasingly, clinicians are asked to consult on patients found to be seropositive for T. cruzi antigens after donating blood. The clinician should verify that the blood bank did both the screening and confirmatory radioimmunoprecipitation assay for diagnosis and that the patient is from an endemic area (this includes the southeastern United States); the clinician should then speak with the CDC'S Division of Parasitic Diseases (770-488-7775; email ncidpdbpi@cdc.gov ) about the advisability of therapy. More information is available at the CDC'S Chagas disease Web page, http://www.cdc.gov/chagas/hcp.html .

1. Dorn PL, Perniciaro L, Yabsley MJ, et al: Autochthonous transmission of Trypanosoma cruzi, Louisiana. Emerg Infect Dis 13:605, 2007 [PMID 17553277]

2. Bern C, Montgomery SP, Herwaldt BL, et al: Evaluation and treatment of chagas disease in the United States: a systematic review. JAMA 298:2171, 2007 [PMID 18000201]

7 Infectious Disease

XXXVIII Mycotic Infections in the Compromised Host

New Triazoles

In the first years of the 21st century, several new antifungal agents gained important roles in the treatment of candidiasis and other fungal infections. Voriconazole, a new triazole with wide-spectrum antifungal activity and high bioavailability, proved effective as empirical antifungal therapy in patients with neutropenia and persistent fever. Another new triazole, posaconazole, proved more effective than fluconazole or itraconazole for prevention of invasive fungal infections in patients who had neutropenia from chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome, although perhaps at the price of a higher incidence of serious adverse events.¹

1. Cornely OA, Maertens J, Winston DJ, et al: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356:348, 2007 [PMID 17251531]

Enter the Echinocandins

The echinocandins are a new class of intravenous antifungal agents. They work by inhibiting synthesis of an integral component of the fungal cell wall, b-(1,3)-D-glucan.¹ Three echinocandins are approved by the Food and Drug Administration: caspofungin, micafungin, and anidulafungin.

Caspofungin is approved for the treatment of candidemia, esophageal candidiasis, and other Candida infections (e.g., intra-abdominal abscesses, peritonitis, and pleural space infections). A comparison study found caspofungin to be at least as effective as amphotericin B for the treatment of invasive candidiasis and, more specifically, candidemia. Caspofungin is also approved by the FDA for the empirical treatment of presumed fungal infection in febrile neutropenic patients, and it appears to be as effective as, as well as generally better tolerated than, liposomal amphotericin B when used for this purpose.

Micafungin, the second echinocandin to become clinically available, is approved by the FDA for intravenous treatment of esophageal candidiasis; it is the only echnocandin approved for Candida prophylaxis in hematopoietic stem cell transplant recipients. Micafungin has been found to be equivalent to caspofungin for the treatment of candidemia and other forms of invasive candidiasis.²

Anidulafungin, the newest echinocandin, is FDA approved for the treatment of esophageal candidiasis, candidemia, and other forms of Candida infection, including abdominal abscesses and peritonitis.³ Anidulafungin was shown not to be inferior to fluconazole in the treatment of invasive candidiasis.⁴

1. Kim R, Khachikian D, Reboli AC: A comparative evaluation of properties and clinical efficacy of the echinocandins. Expert Opin Pharmacother 8:1479, 2007 [PMID 17661730]

2. Pappas PG, Rotstein CM, Betts RF, et al: Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 45:883, 2007 [PMID 17806055]

3. de la Torre P, Reboli AC: Anidulafungin: a new echinocandin for candidal infections. Expert Rev Anti Infect Ther 5:45, 2007 [PMID 17266452]

4. Reboli AC, Rotstein C, Pappas PG, et al: Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 356:2472, 2007 [PMID 17568028]

An ELISA for Aspergillus

An enzyme-linked immunosorbent assay (ELISA) for the detection of Aspergillus galactomannan antigen in serum is commercially available and has become an important tool for the early diagnosis of invasive aspergillosis.¹ In patients undergoing chemotherapy or hematopoietic stem cell transplantation, regular (e.g., biweekly) use of serum galactomannan ELISA may be valuable for early diagnosis of invasive aspergillosis.² Concomitant use of antifungal agents may cause false negative testing.²

The assay is increasingly being used on specimens of body fluids other than serum, including urine, bronchoalveolar lavage fluid, and cerebrospinal fluid. Preemptive antifungal treatment, given on the basis of galactomann ELISA and high-resolution computed tomography results, may provide effective control of invasive aspergillosis while reducing exposure to antifungal drugs (which are expensive and potentially toxic) for those with negative test results.³

The accuracy of galactomannan ELISA has been questioned, however; in one study, the test had a sensitivity of 75% and a specificity of 100%, but other studies have noted low sensitivity and a high frequency of false negative results. In addition, galactomannan is found in the cell walls of some Penicillium species, and false positive results have been reported in patients who had been taking piperacillin-tazobactam, even as long as 5 days after stopping the antibiotic.⁴

1. Maertens J, Theunissen K, Deeren D, et al: Defining a case of invasive aspergillosis by serum galactomannan. Med Mycol 44(suppl):173, 2006 http://www.aspergillus.org.uk/secure/articles/pdfs/MM44supplement1/17050436.pdf

2. Foy PC, van Burik JA, Weisdorf DJ: Galactomannan antigen enzyme-linked immunosorbent assay for diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13:440, 2007 [PMID 17287156]

3. Maertens J, Theunissen K, Verhoef G, et al: Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 41:1242, 2005 [PMID 16206097]

4. Aubry A, Porcher R, Bottero J, et al: Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with beta-lactam antibiotics in patients with hematological disorders. J Clin Microbiol 44:389, 2006 [PMID 16455889]

Two Sides of Aspergillus Treatment

Inhaled spores of Aspergillus can cause a localized infection that may result in allergic or invasive disease. Allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis are the two major clinical variants. ABPA is treated with systemic corticosteroids supplemented with oral itraconazole [see Table]. Itraconazole reduces the burden of colonizing fungal organisms, thereby decreasing chronic antigen stimulation, permitting a lower corticosteroid dose, and decreasing future recurrences of ABPA. The newer azoles are likely of clinical benefit but have not been systematically studied in the same fashion as itraconazole.¹

The recommended agent for treatment of invasive aspergillosis is voriconazole.² An alternative regimen is amphotericin B, either conventional or lipid formulations, in dosages equivalent to 1 mg/kg/day of standard amphotericin B. Caspofungin is approved by the FDA for patients who fail to tolerate or fail to improve with standard therapy (salvage treatment). Micafungin (either alone or in combination with other antifungal agents) has been found to be effective both for primary and for salvage therapy,³ but it is not approved for either purpose. Posaconazole is an effective alternative for salvage treatment⁴ [see Table, below].

1. Erwin GE, Fitzgerald JE: Case report: allergic bronchopulmonary aspergillosis and allergic fungal sinusitis successfully treated with voriconazole. J Asthma 44:891, 2007 [PMID 18097869]

2. Mouas H, Lutsar I, Dupont B, et al: Voriconazole for invasive bone aspergillosis: a woldwide experience of 20 cases. Voriconazole/Bone Invasive Aspergillosis Study Group. Clin Infect Dis 40:1141, 2005 [PMID 15791514]

3. Denning DW, Marr KA, Lau WM, et al: Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 53:337, 2006 [PMID 16678903]

4. Walsh TJ, Raad I, Patterson TF, et al: Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 44:2, 2007 [PMID 17143808]

5 Hematology

V The Polycythemias

Genetic Testing for Polycythemia

The initial evaluation of a patient suspected of having polycythemia should include genetic testing. A peripheral blood sample should be sent for polymerase chain reaction testing for the JAK2 V617F point mutation, which is associated with polycythemia vera and other myeloproliferative disorders.¹ If the JAK2 V617F mutation is found in a patient with polycythemia, the diagnosis of polycythemia vera is made. Although the JAK2 V617F mutation is found in 90% of patients with polycythemia vera, it is not detected in patients with autosomal dominant familial polycythemia.²

1. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355:2452, 2006 [PMID 17151367]

2. Rives S, Heike L, Pahl LF, et al: Molecular genetic analyses in familial and sporadic congenital primary erythrocytosis. Haematologica 92:674, 2007 [PMID 17488692]

The following is selected from the FDA'S list of recently approved products. Complete, updated information on FDA approvals and notifications is available on the FDA Web site ( http://www.fda.gov ).

New Beta Blocker for Treating Hypertension

The FDA has approved the beta blocker nebivolol for the treatment of high blood pressure. The safety and efficacy of nebivolol in lowering blood pressure was assessed in three randomized, double-blind, multicenter, placebo-controlled clinical trials that ran for up to 3 months. A fourth placebo-controlled clinical trial demonstrated additional blood pressure-lowering effects when nebivolol was given with up to two other antihypertensive medications in patients with inadequate blood pressure control. In total, more than 2,000 people received nebivolol trials. Its efficacy during the trials was similar to that of other FDA-approved beta blockers.

The most common side effects reported by patients taking nebivolol in clinical trials were headache, fatigue, dizziness and diarrhea.

Generic Name: Nebivolol

Brand Name: Bystolic

Distributor: Forest Laboratories, Inc., New York, New York

FDA Approves New Beta Blocker to Treat High Blood Pressure. FDA News. U.S. Food and Drug Administration, December 17, 2007
( http://www.fda.gov/bbs/topics/NEWS/2007/NEW01757.html )