August 2011 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • AUGUST 2011

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A FORUM FOR NURSE PRACTITIONERS AUGUST 2011

NEWSLINE

■ HbA1c spots prediabetes ■ Dietary sodium and CVD ■ ACOG endorses IUDs ADVISOR FORUM

■ Causes of delirium ■ Extended use of PPIs ■ Intertriginous warts

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■ Dermatology Clinic

CLEAR BULLAE ON THE HANDS PAGE 79

VOLUME 14, NUMBER 8

■ Dermatologic Look-Alikes

FLESH NUBBINS ON BOTH PINKIES PAGE 111 Expanded job listings! www.ClinicalAdvisor.com/Jobs

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CE: MANAGING BACTERIAL

CONJUNCTIVITIS Red swollen conjunctiva (shown here) are a hallmark of conjunctivitis.

Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Philip R. Cohen, MD; Peter F. Cohn, MD; JoAnn Deasy, PA-C, MPH; Melody French, PhD, PA, FNP; Virginia H. Joslin, PA-C, MPH; Norma M. Keller, MD; Debra August King, PhD, PA; Ann W. Latner, JD; Cheryl F. MacDonald, MSN, MPH, CRNP; Malka G. Messner, RPA-C, MPAS; Daniel R. Mishell Jr, MD; Claire B. O’Connell, MPH, PA-C; Patrick G. O’Connor, MD, MPH; Michael E. Ryan, DO; Sherril Sego, FNP, DNP; Lisa Stern, APRN; Karen T. Vujevich, RN-C, MSN, CRNP; Julee B. Waldrop, MS, PNP; Reuben W. Zimmerman, PA-C; Michael E. Zychowicz, RN, MS, NP-C Group art director, Haymarket Medical Jennifer Dvoretz Assistant art director Natasha Marcano-Dillon Production director Leslie Carsman Circulation manager Paul Silver Assistant circulation manager Monica Bond Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 thennessy@cortgroup.com Editorial director Tanya Gregory Chief executive officer Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6075. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7371), Volume 14, Number 8, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.clinicaladvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to: The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2011.

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CONTENTS AUGUST 2011

NEWS AND COMMENT

FEATURES

CME/CE Therapeutic strategies for bacterial conjunctivitis Resistance has made ophthalmic antibiotics less effective, but new topical treatments are available.

New data on managing atrial fibrillation Revised guidelines look at strict vs. lenient rate control and combining antiplatelet and anticoagulant therapy.

Raising awareness of HIV drug interactions Antiretrovirals can cause alterations in the liver enzymes responsible for metabolizing a number of medications.

Newsline ■ HbA1c can diagnose diabetes, prediabetes ■ Detecting gynecologic cancer recurrence ■ The role of salt in CVD is not clear-cut ■ IUDs fi nally endorsed by ACOG ■ Vitamin D screening guidelines ■ CT deemed best test for adult appendicitis ■ Anticholinergics may hasten mental decline ■ Errors seen in 12% of computerized prescriptions ■ And more

Use HbA1c to identify prediabetes 15

Drug Update ■ COPD therapy now available in pill form ■ Bactericide fights Clostridium diffi cile infection

DEPARTMENTS 78

Derm Dx Challenge Read the clinical descriptions, view the images, and then make your diagnosis at ClinicalAdvisor.com.

CME/CE Dermatology Clinic

122 Commentary

Drug-drug interactions with HIV meds 50

■ An older man experienced discomfort after several blisters on his stomach and hands ruptured and became itchy. ■ An asymptomatic nodule on a man’s neck became tender after he tried to squeeze out its contents at home.

Continues on page 10

“You need to learn to balance between work and even more work.”

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CONTENTS DEPARTMENTS, cont’d 87

119 Evidence-Based Medicine ■ Injections of dextranomer gel in stabilized hyaluronic acid reduce fecal incontinence ■ Prunes may be more effective than psyllium for constipation ■ Hydroxyurea reduces pain events in very young children with sickle-cell disease ■ And more

Clinical Challenge ■ A woman continued to feel a rocking sensation after a trip on the water. ■ A man with a skin condition rarely

seen in his adopted home of Iowa. 102 Stat Consult Find out the most recent information on breastfeeding. 108 Legal Advisor Inadequate documentation affects a busy clinician’s ability to remember a patient’s treatment.

ADVISOR FORUM The lingering effects of a vacation at sea 87

Consultations ■ Causes of delirium ■ What to do with an elevated

homocysteine level ■ Is simultaneous vaccination

111 CME/CE Dermatologic Look-Alikes Two cases of growths on the fingers— one on a woman’s pinkies, the other on a man’s middle finger.

always necessary? ■ And more

Clinical Pearl ■ Remember to HALT SLIPS in older patients

Your Comments ■ Antibiotics have no effect on oral contraceptives ■ Emergency contraception is not an abortifacient

115 CME/CE Posttest 116 Alternative Meds Update Brewer’s yeast is being studied for its potential as a treatment for breast cancer as well as for premenstrual syndrome.

Evidence-based review of breastfeeding 102

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ALTERNATIVE MEDS UPDATE

Safety, drug interactions Brewer’s yeast contains the amino acid tyramine. If taken in conjunction with a monoamine oxidase inhibitor or the pain medication meperidine (Demerol), the resulting interaction can cause a hypertensive crisis.8 Allergies are always a potential with any botanical product, so people with a known sensitivity to yeast should avoid these supplements. Persons with diabetes should be careful when taking brewer’s yeast: If taken in significant quantity, the supplement can reduce serum glucose levels.8 Drugs that are metabolized through the cytochrome P-450 enzyme chain, such as antifungals, may reduce any anticipated action of the yeast supplement.3 Although studies have indicated that persons with Crohn’s disease should avoid brewer’s yeast supplements due to a potential for exacerbation of the illness, a review of several clinical trials showed conflicting results.3

Cost, how supplied, dose Brewer’s yeast is available in many forms, including tablets, flakes, powder, and liquid. The dose used in most studies is 500 mg daily of yeast equivalent. Brewer’s yeast has not been studied in pregnant or lactating women or in young children and should not be used in those populations. Brewer’s yeast supplements are relatively inexpensive, with a month’s supply costing no more than $10.1

Summary Breast cancer cells (shown) were vulnerable to brewer’s yeast cultures.

Drugs that are metabolized through the cytochrome P-450 enzyme chain may reduce any action of the yeast supplement.

118 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

Health-care providers need to be able to direct patients to products that are safe as well as effective. Brewer’s yeast is one supplement that is affordable, effective, and readily available. ■ References 1. University of Maryland Medical Center. Brewer’s yeast. Available at umm.edu/altmed/articles/brewersyeast-000288.htm. 2. Legras JL, Merdinoglu D, Cornuet JM, Karst F. Bread, beer and wine: Saccharomyces cerevisiae diversity reflects human history. Mol Ecol. 2007;16:2091-2102. 3. Natural Medicines Comprehensive Database. Brewer’s yeast. Available at naturaldatabase.therapeuticresearch.com. 4. Moyad MA, Robinson LE, Zawada ET Jr, et al. Effects of a modified yeast supplement on cold/flu symptoms. Urol Nurs. 2008;28:50-55. 5. Ghoneum M, Gollapudi S. Induction of apoptosis in breast cancer cells by Saccharomyces cerevisiae, the baker’s yeast, in vitro. Anticancer Res. 2004;24:1455-1463. Available at ar.iiarjournals.org/content/24/3A/1455.long. 6. Facchinetti F, Nappi RE, Sances MG, et al. Effects of a yeast-based dietary supplementation on premenstrual syndrome. A double-blind placebo-controlled study. Gynecol Obstet Invest. 1997;43:120-124. 7. Kovacs DJ, Berk T. Recurrent Clostridium difficile-associated diarrhea and colitis treated with Saccharomyces cerevisiae (Baker’s yeast) in combination with antibiotic therapy: a case report. J Am Board Fam Pract. 2000;13:138-140. 8. Tufts Medical Center. Brewer’s yeast. Available at www.tuftsmedicalcenter.org/apps/Healthgate/Article. aspx?chunkiid=625843. All electronic documents accessed July 15, 2011.

expected, breast-cancer cells that were actively metastatic were more vulnerable to the brewer’s yeast cells, showing a 629% increase in apoptosis when compared with normal cells and a 178% increase for the more stable, nonmetastatic breast-cancer cells.5 Another intriguing use is in the treatment of premenstrual syndrome. Participants in one clinical trial were randomized to placebo or a brewer’s yeast–based supplement. Using the Menstrual Distress Questionnaire (MDQ), participants were monitored for a period of six months at both the follicular and luteal phases of their cycles. Although the placebo users showed significant improvement in their MDQ scores, the treatment group far exceeded those, with an 82% reduction in symptoms by the end of the trial.6 Multiple studies have been conducted using various forms of probiotics to treat and prevent antibiotic-associated diarrhea. Most of these cases are attributable to Clostridium difficile (see Drug Update, page 29). Use of brewer’s yeast supplements in conjunction with traditional antibiotic treatments has been shown to reduce the duration of symptoms as well as the rate of infection recurrence.7

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Web Exclusives

Slideshows

Fetal environment may play greater role in autism than genetics Autism prevalence has increased 10-fold since the 1960s. New data from the California Autism Twins Study suggests that shared environmental factors may outweigh shared genetics in the etiology of the disorder.

Hirsutism Hirsutism refers to excess hair growth in women that occurs in areas of the body normally associated with post-pubescent males— such as above the upper lip, the chin, the chest, and the inner thigh. The disorder affects about 1 in 20 women aged 18 to 45 years.

Risk-factor prevention could dramatically cut AD incidence As many as half of all Alzheimer disease cases are attributable to modifiable risk factors. Mitigating even a fraction may substantially reduce disease incidence, researchers say.

Skin cancer Skin cancer is the abnormal growth of skin cells that most often develops on such sun-exposed areas as the scalp, face, lips, ears, neck, chest, legs arms, and hands. If left untreated, skin cancer can spread to other organs and tissues. Early detection and treatment is key for a good prognosis.

Smoke exposure may contribute to childhood learning disorders Children exposed to secondhand cigarette smoke had a 50% increased risk for neurobehavioral disorders compared with those with no exposure, data from the National Survey of Children’s Health indicates.

Derm Dx Challenge Compete with your peers by viewing the images and offering your diagnosis.

Live Meeting Coverage AANP 26th National NP Conference | Las Vegas, Nevada Nurse practitioners outscore physicians in patient-satisfaction survey Patient satisfaction, a major indicator of quality health care, was higher among low-income primary-care patients treated by nurse practitioners than among those treated by physicians, according to researchers at the American Academy of Nurse Practitioners 26th National Conference.

The Waiting Room Official Blog of The Clinical Advisor Robyn Carlisle, MSN, CNM, WHNP

Hyperpigmentation in a white female with fatigue, dizziness, and nausea A white woman aged 40 years presents to her primary-care provider with a chief complaint of fatigue, dizziness, nausea, and vomiting. She has hyperpigmented skin on her face, oral mucosa, elbow, and axillae.

Relative value units do not adequately assess clinician worth Assigning a clinician a number value based on the quantity of patients treated and services provided ignores many important aspects of health care, including patient satisfaction. Expand your contraception prescribing horizons Long-acting reversible contraceptives are highly effective, convenient, and often overlooked birth-control methods.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 13

CME CE

PROGRAM OUTLINE AUGUST 2011

Page 31 FEATURE Therapeutic strategies for bacterial conjunctivitis Kimberly A. Spering, MSN, CRNP, FNP-BC ■ LEARNING OBJECTIVES: • Identify the most commonly isolated bacteria in children with conjunctivitis. • Know what to do with a patient who has fluorescein staining suggestive of dendritic branching ulceration. • Understand which drug to recommend for prophylaxis of neonatal conjunctivitis. • Learn which fluoroquinolone is useful in patients with a history of poor compliance. ■ CREDITS: 0.5

Page 79 DERMATOLOGY CLINIC Case 1: Multiple blisters on the hands and abdomen Esther Stern, NP-C

Case 2: Home surgery leads to persistent neck mass Joe Monroe, PA-C ■ LEARNING OBJECTIVES: • To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment. ■ CREDITS: 0.25

Page 111 DERMATOLOGIC LOOK-ALIKES Growths on the fingers Noah S. Scheinfeld, MD, JD ■ LEARNING OBJECTIVE: • To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations. ■ CREDITS: 0.25

Page 115 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of August 2011. Participants may submit the selfassessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

14 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

Newsline

Does salt intake affect a person’s risk for CVD? page 16

A U G U S T 2 0 11

ACOG endorses IUDs as safe and effective page 21

COPD rates remain stable overall page 25

HbA1c can diagnose diabetes, prediabetes

HbA1c (shown here) is used to identify blood glucose levels over long periods of time.

least twice a year, and quarterly if the treatment regimen has changed or if goals are not being met. The value of HbA1c testing in diagnosing prediabetes was the focus of a longitudinal cohort study of men and women aged 24 to 82 years without diabetes at baseline. Using a controversial diagnostic criterion of 5.7% to 6.4%, screening by HbA1c alone missed 61% of the persons who were diagnosed with prediabetes when a combination of impaired fasting glucose levels and HbA1c was used. However, “The predictive value for progression to diabetes assessed by HbA1c 5.7–6.4% was similar to that assessed by impaired fasting alone,” pointed out the researchers, who suggested that using the two tests together could efficiently target people who are most likely to develop diabetes and allow for early intervention (Lancet. 2011;378:147-155).

Inpatient hospital discharges among adults aged 55-64 years Hospitalization rates for coronary artery stent insertions, hip replacements, and knee replacements rose sharply from 1996 to 2006. Source: CDC/NCHS, National Hospital Discharge Survey

Number per 10,000 population

THE AMERICAN Diabetes Association (ADA) has approved evidence-based guidelines for the use of hemoglobin A1c (HbA1c) in the diagnosis and management of diabetes, and a recent study has shown that the test is an effective tool for identifying prediabetes when used in combination with impaired glucose fasting. The recommendations, compiled by an expert committee to supplement ADA guidelines, state that HbA1c may be used for the diagnosis of diabetes, with values ≥6.5% being diagnostic (Diabetes Care. 2011;34:1419-1423). Point-of-care HbA1c assays are not sufficiently accurate for the diagnosis of diabetes. An HbA1c testing method certified by the National Glycohemoglobin Standardization Program should be performed in an accredited laboratory. Factors that interfere or adversely affect the assay will

preclude its use in diagnosis, just as they would preclude its use in management of the disease. HbA1c values that are inconsistent with the patient’s clinical presentation should be investigated further, advised the authors. The guidelines also clarify the role of HbA1c testing once the person has been diagnosed with diabetes. Treatment goals should be based on ADA recommendations, which call for maintaining HbA1c concentrations at <7%, or aiming for more stringent goals in persons who can reach those targets without experiencing significant hypoglycemia or other adverse treatment effects. Higher HbA1c targets are recommended for children, adolescents, and sometimes for patients with limited life expectancy, extensive comorbid illness, a history of severe hypoglycemia, or advanced complications. Patients should undergo HbA1c testing at

1996 2006

50 40 30 20 10 0

Coronary artery stent insertion

Total knee replacement

Total hip replacement

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 15

Newsline MOST R EC U R R E NC E s of gynecologic cancers occur within three years after primary treatment, but patients usually are transitioned back to their primary-care providers (PCPs) following the first two to three years after being treated for their original cancer. PCPs should be aware that the most effective method for detecting most gynecologic-cancer recurrences is three-pronged, according to the expert recommendations recently released by the Society of Gynecologic Oncology: (1) take a thorough history, (2) perform a thorough examination, and (3) educate the patient about concerning symptoms. “There is very little evidence that routine cytologic procedures

or imaging improves the ability to detect gynecologic cancer recurrence at a stage that will impact cure or response rates to salvage therapy,” wrote the guideline authors (Am J Obstet Gynecol. 2011;204:466-478). The new clinical document reviews the most recent data on surveillance for gynecologic cancer recurrence in women who have had a complete response to primary cancer therapy, and offers recommendations for surveillance of endometrial, ovarian, cervical, vulvar, and vaginal cancers—specifying when various examinations, tests, and imaging should be ordered in the months and years following treatment. The document also includes a checklist for surveillance of gynecologic malignancies.

Detecting gynecologic cancer recurrence

Light micrograph of a uterus showing cervical cancer.

“The goal of follow-up evaluation for the detection of recurrent disease requires both clinical and cost-effectiveness,” noted the guideline authors. “Failure to adhere to recommended guidelines results in unnecessary tests, and efforts should be made to provide effective surveillance, which will result in cost-savings.”

A LARGE review concluded that moderate reduction in dietary sodium intake does not reduce a person’s risks for cardiovascular disease (CVD) or death, whereas another major project has linked higher sodium and lower potassium intakes with significantly higher risks of any-cause mortality and death from heart attack. In a systematic review of seven studies involving 6,489 participants, a small reduction in BP occurred when dietary sodium intake was curbed (Cochrane Database Syst Rev. 2011;7: CD009217). But despite having

A small reduction in BP was seen when salt intake was curbed.

more event data than previous systematic reviews of randomized controlled trials, the investigators still did not have enough information to rule in or rule out clinically important effects of dietary salt restriction on mortality or cardiovascular morbidity in a normotensive or hypertensive population: Salt reduction showed no strong evidence of benefit on cardiovascular morbidity in people with normal or raised BP at baseline. The second study, which drew data from 12,267 participants represented in the NHANES III Linked Mortality File, found that

16 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

a high sodium intake increased the risk of CVD and mortality—especially when combined with a low potassium intake (Arch Intern Med. 2011;171:1183-1191). National guidelines recommend restricting sodium to <1,500 mg/ day or <2,300 mg/day depending on a person’s risk factors, and advise consuming 4,700 mg/day of potassium. Each 1,000-mg/day increase in salt was associated with a 20% increase in all-cause mortality, but each 1,000-mg/day increase in potassium was associated with a 20% lower mortality.

The role of salt in CVD is not clear-cut

Newsline IUDs finally Vitamin D screening guidelines endorsed by ACOG

At least 600 IU/day is suggested for pregnant and lactating women.

70 years or older; at least 600 IU/ day for pregnant and lactating women; and at least 400 IU/day for children up to age 1 year and 600 IU/day for children aged 1 year and older. A report published online ahead of print in Journal of Bone and Mineral Research by Bruce W. Hollis, PhD, and colleagues indicates that even a high amount of vitamin D supplementation is safe and effective for healthy pregnant women, with no adverse effects for newborns. In addition, an analysis of 50 trials showed vitamin D3 supplementation to reduce mortality by approximately 6% among elderly women (mean age 74 years) (Cochrane Database Syst Rev. 2011; Jul 6;7:CD007470). The Endocrine Society guideline states that vitamin D2 or vitamin D3 supplementation should be prescribed to overcome deficiency.

CT deemed best test for adult appendicitis Multidetector CT (MDCT) of the abdomen and pelvis is a useful test for routine evaluation of suspected appendicitis in adults, according to the results of a recent study. Acute appendicitis can be difficult to diagnose because its symptoms mirror those of other illnesses. Preoperative CT has been used increasingly to diagnose suspected cases since the introduction of MDCT. In the current study, researchers reviewed the hospital records of 2,871 adults with suspected appendicitis between 2000 and 2009 to determine whether MDCT could accurately rule in or rule out the diagnosis.

Among the 675 (23..5%) patients with confirmed acute appendicitis, MDCT showed 98.5% sensitivity, 98% specificity, negative predictive value of 99.8%, and positive predictive value of 93.9% (Ann Intern Med. 2011;154:789-796). In addition, MDCT provided or suggested an alternative diagnosis in 893 (42.1%) of the 2,122 patients without appendicitis or appendectomy. The researchers did point out that because the use of MDCT for suspected appendicitis is common, the results could not be compared with those of patients who did not have the same imaging.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 21

THE AMERICAN College of Obstetricians and Gynecologists (ACOG) is now recommending intrauterine devices (IUDs) as safe and effective birth control. “What you see now is a rethinking of the idea of how to prevent unintended pregnancy,” explained Adam Jacobs, MD, director of the family planning division at The Mount Sinai Medical Center in New York City and an author of the recommendations, in a statement issued by his facility. The recommendations are published in a practice bulletin in Obstetrics & Gynecology (July 2011). The endorsement represents a new chapter in the history of IUDs, which were once unpopular in the United States but remain in use. The devices may raise the risk of pelvic inflammatory disease and subsequent infertility. However, many experts say the risk is small, and Dr. Jacobs calls the IUD “the most cost-effective form” of birth control available. In other birth-control news, the CDC is advising postpartum women to avoid combined hormonal contraceptives during the first 21 days after delivery because of the high risk for venous thromboembolism. Some women should discontinue use for up to 42 days postpartum (MMWR Morb Mortal Wkly Rep. 2011;60:878-883, available at www.cdc.gov/mmwr/ preview/mmwrhtml/mm6026a3. htm, accessed July 15, 2011).

A NEW Endocrine Society guideline for treating vitamin D deficiency calls for screening of persons at high risk for deficiency, but does not endorse such testing for others. “There is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection,” concluded the authors ( J Clin Endocrinol Metab. 2011;96:1911-1930). The guideline also advises supplementation at suggested daily intake and tolerable upper-limit levels to maximize bone health and muscle function. Although people may require up to 2,000 IU/day more to maintain a vitamin D blood level >30 ng/mL, the guideline generally recommends: at least 600 IU/day for adults aged 19 to 70 years; at least 800 IU/day for persons aged

Newsline Anticholinergics may hasten mental decline

Anticholinergic meds were associated with a decline in MMSE scores.

Examination (MMSE) score compared with no anticholinergic use (published online ahead of print in Journal of the American Geriatrics Society). Use of possible anticholinergics at baseline was not associated with further decline. The other project explored the links between diet and cognitive ability in 20 healthy adults and

29 with amnestic mild cognitive impairment (aMCI), in which the person experiences some memory problems. In a four-week trial, 24 subjects followed a diet high in saturated fats and simple carbohydrates (HIGH diet); the remaining 25 followed a diet low in saturated fats and simple carbohydrates (LOW diet). Among healthy adults eating the LOW diet, some biomarkers of AD seen in the cerebrospinal fluid (CSF) decreased, as did total cholesterol levels. However, the LOW diet raised levels of these biomarkers in the aMCI patients. In healthy adults, the HIGH diet moved CSF biomarkers “in a direction that may characterize a presymptomatic stage of AD,” reported the investigators (Arch Neurol. 2011;68:743-752).

Errors seen in 12% of computerized Rxs THE COMMON mistakes made in manual prescribing systems continue to turn up in electronic versions, suggest the results of a recent retrospective cohort study. The analysis focused on 3,850 computer-generated prescriptions received across three states over four weeks in 2008. In total, 452 prescriptions (11.7%) contained 466 errors, 163 (35%) of which were considered potential adverse drug events. None of the errors was life-threatening. Omitted information was the most common mistake, accounting for 60.7% of all errors.

Error rates varied among the 13 computerized prescribing systems evaluated, ranging from 5.1% to 37.5%. Certain errors were more frequently associated with a particular system. For example, users often failed to specify length of treatment and dose in one system. When two other systems were compared, one was linked with fewer errors overall than the other, but with more mistakes that were potentially harmful. “Implementing a computerized prescribing system without comprehensive functionality and processes in place to ensure

24 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

The most common mistake was omitted information.

meaningful system use does not decrease medication errors,” cautioned Karen C. Nanji, MD, and coauthors in their report for Journal of the American Medical Informatics Association (published online ahead of print). The researchers noted that the problem of missing information should be relatively easy to rectify through improved training for users or tweaks made to the system. One option involves “forcing functions,” which would not allow a prescription to be completed if certain data were not included.

TOP PHOTO: © BSIP / PHOTOTAKE; BOTTOM PHOTO: © ISTOCKPHOTO.COM / SEAN LOCKE

THE USE OF anticholinergic medications and the adoption of certain dietary patterns have both been implicated as a factor in cognitive impairment and Alzheimer disease (AD), respectively, in recent research. First, the results of a two-year study involving 13,004 persons aged 65 years and older indicate that agents with anticholinergic activity increase the cumulative risk of cognitive impairment and mortality. At baseline, 47% of the subjects used a medication with possible anticholinergic properties and 4% used a drug with definite anticholinergic properties. Chris Fox, MD, and colleagues found that use of agents with definite anticholinergic effects was associated with a 0.33-point greater decline in Mini-Mental State

Sleep loss affects testosterone COPD A SMALL STUDY of healthy young men showed testosterone levels to be lower after sleep loss than after more appropriate rest intervals, with the effect of restricted sleep being especially apparent between 2 pm and 10 pm ( JAMA. 2011;305:2173-2174). As the investigators noted, the majority of the daily testosterone release in men occurs during sleep, and sleep fragmentation and obstructive sleep apnea are associated with reduced levels of the hormone. In addition to being a critical component of male sexual behavior and reproduction, testosterone also benefits muscle mass and strength, adiposity, bone density, vigor, and well-being.

Levels fell by 10%-15% with only five hours of sleep per night.

Normal aging is associated with a decrease in testosterone levels of 1% to 2% per year. In this study of 10 healthy men (mean age 24.3 years), daytime testosterone levels fell by 10% to 15% when the subjects had only five hours of sleep per night for one week—a sleep pattern experienced by at least 15% of the U.S. working population. Although the testosterone decline was associated with lower vigor scores, levels of cortisol—which can inhibit gonadal function—did not increase. The investigators call for further research to determine whether sleep duration should be integrated into the evaluation of androgen deficiency.

Constipation a simple clue to heart problems Constipation, an easy-to-identify condition, may be a marker for cardiovascular risk factors and increased cardiovascular risk in older women, according to the results of a large analysis. The investigators hypothesized that because many of the factors that predispose a person to constipation are also risk factors for cardiovascular disease, constipation could be related to an increased risk of cardiovascular events. Their evaluation of 73,047 participants of the Women’s Health Initiative revealed that those with moderate or severe constipation experienced more cardiovascular events (14.2 and 19.1 events per 1,000 personyears, respectively) than did those who did not suffer from constipation (9.6/1,000 person-years). However, after adjustments were made for demographics, risk factors,

dietary factors, medications, frailty, and other psychological variables, the heightened cardiovascular risk remained only in the severely constipated group: After those recalculations, the women with severe constipation had a 23% higher risk of cardiovascular events. Constipation was associated with increased age, black and Hispanic descent, smoking, diabetes, high cholesterol, family history of MI, hypertension, obesity, lower levels of physical activity, lower fiber intake, and depression. “Because constipation is easily assessed, it may be a helpful tool to identify women with increased cardiovascular risk,” concluded Elena Salmoirago-Blotcher, MD, and associates in their report in The American Journal of Medicine (published online ahead of print).

rates vary by locale, gender A REGION known as the East South Central U.S. Census d iv ision— encompassing Mississippi, Alabama, Tennessee, and Kentucky—is home to the highest prevalence of chronic obstructive pulmonary disease (COPD) of anywhere in the country among adults. At 7.5% in 2007–2009, the disease was twice as prevalent in the East South Central division as in the Pacific division (comprising California, Oregon, and Washington), which had the lowest COPD prevalence: 3.9%. Overall, however, the prevalence of COPD—which includes chronic bronchitis and emphysema—has remained stable nationwide over a recent 12-year period, according to a new CDC report (available at www.cdc.gov/ nchs/data/databriefs/db63.htm, accessed July 12, 2011): A total of 5.1% (11.8 million) adults aged 18 and older were diagnosed with the disease in 2007–2009, a rate that had been maintained since 1998. Prevalence was shown to be greater among women in all age groups except for the two oldest—75 to 84 years, and 85 years and older—and was highest for women aged 65 to 74 years (10.4%), women aged 75 to 84 years (9.7%), and men aged 75 to 84 years (11.2%). ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 25

DrugUpdate New drug information from the publishers of MPR

COPD therapy now available in pill form Product: Daliresp Company: Forest Pharmacologic class:

Selective phosphodiesterase 4 (PDE4) inhibitor. Active ingredient: Roflumilast 500 µg; tabs. Indication: To reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations in severe COPD patients with chronic bronchitis and a history of exacerbations. Not for the relief of acute bronchospasm. Pharmacology: Both roflumilast and its active metabolite (roflumilast N-oxide) selectively inhibit the activity of PDE4, an enzyme that mediates the breakdown of intracellular cyclic adenosine monophosphate (AMP). The resultant increased levels of intracellular cyclic AMP in lung cells may be related to the clinical effects of roflumilast, but the exact mechanism of action is not well defined. Clinical trials: The safety and efficacy of roflumilast in the management of COPD was evaluated in several randomized, double-blind, controlled, parallel group clinical

trials involving a total of 9,394 adult patients with nonreversible obstructive lung disease. Four of these were placebocontrolled one-year trials in patients with severe COPD that were designed to evaluate the efficacy of roflumilast on COPD exacerbations. In two of these trials, inhaled corticosteroids and short-acting beta agonists were allowed. Lung function (FEV1) and the rate of moderate or severe COPD exacerbations was

Daliresp treats symptoms of cough and excess mucus linked to bronchitis.

a co-primary endpoint. Both trials failed to show a significant reduction in the rate of COPD exacerbations. Subsequent trials were designed based on an analysis of a subset of these patients who appeared to have a better response compared to the overall population. These two trials enrolled 3,096 patients with severe COPD associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. Long-acting beta agonists and short-acting antimuscarinics were allowed, but not inhaled corticosteroids. In both of these trials, roflumilast 500 µg once daily showed a significant reduction in the rate of moderate or severe COPD exacerbations compared to placebo. Also, in these four trials, roflumilast 500 µg daily resulted in a significant improvement in lung function. Two additional studies were six-month efficacy trials in patients with moderate-tosevere COPD conducted to assess the effect on lung function of roflumilast as addon therapy to a long-acting beta agonist or a long-acting anti-muscarinic. No trials have been conducted to assess

Macrolide antibiotic Active ingredient: Fidaxomicin 200 mg; tablets. Indication: For the treatment of Clostridium difficile-associated diarrhea (CDAD). Pharmacology: Fidaxomicin is a fermentation product from the actinomycete Dactylosporangium aurantiacum. It is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases. Clinical trials: In two randomized, double-blind trials, a noninferiority design was utilized to demonstrate the efficacy of fidaxomicin (200 mg b.i.d. for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with CDAD. Enrolled patients received no more than 24 hours of pretreatment with vancomycin or metronidazole. CDAD was defined by more than three unformed bowel movements (or >200 mL of unformed stool for subjects having rectal collection devices) in the 24

Continued pg. 30

Bactericide fights C. diff. infection Product: Dificid Company: Optimer Pharmacologic class:

For more products, visit www.eMPR.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 29

DrugUpdate Daliresp from pg. 29

Warnings/Precautions:

mothers: not recommended.

the effects of roflumilast on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid. Adults: 500 µg once daily. Children: Not recommended. Contraindications: Moderate-to-severe liver impairment.

Depression. Suicidal ideation. Mild liver impairment (ChildPugh Class A). Monitor for insomnia, anxiety, depression, suicidal ideation, other mood changes; reevaluate if occurs. Monitor weight regularly; consider discontinuing if unexplained or significant weight loss occurs. Pregnancy (Cat. C). Labor & delivery, nursing

Interactions: Concomitant

Dificid from pg. 29

Sustained response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment. The results for clinical response at the end of treatment in both trials indicate that fidaxomicin is noninferior to vancomycin (Trial 1:

hours before randomization, and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled patients had either no prior CDAD history or only one prior CDAD episode in the past three months. Subjects with life-threatening/ fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded. The primary efficacy endpoint was the clinical response rate at the end of therapy, based on improvement in diarrhea or other symptoms such that, in the investigator’s judgment, further CDAD treatment was not needed. An additional efficacy endpoint was sustained clinical response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment.

Dificid is used to treat Clostridium difficile-associated diarrhea.

strong CYP450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin): not recommended. Potentiated by CYP3A4 and CYP1A2 inhibitors (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine), and by oral contraceptives containing gestodene + ethinyl estradiol

fidaxomicin 88% vs. vancomycin 86%; Trial 2: fidaxomicin 88% vs. vancomycin 87%). The results for sustained clinical response at the end of the follow-up period indicate that fidaxomicin is superior to vancomycin on this endpoint (Trial 1: fidaxomicin 70% vs vancomycin 57%; Trial 2: fidaxomicin 72% vs. vancomycin 57%). Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in patients taking fidaxomicin. Restriction endonuclease analysis was used to identify C. difficile baseline isolates in the BI group, isolates associated with increasing rates and severity of CDAD in the years prior to the clinical trials. Similar rates of clinical response at the end

For more products, visit www.eMPR.com

30 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

(possible increased adverse effects). Adverse reactions: GI upset, weight decrease, headache, back pain, influenza, dizziness, decreased appetite; psychiatric effects. How supplied: Tabs—30 For more information, call 800.678.1605 or visit www.Daliresp.com.

of treatment and proven or suspected CDAD during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients infected with a BI isolate. However, fidaxomicin did not demonstrate superiority in sustained clinical response when compared with vancomycin. Adults: ≥18 years: 200 mg b.i.d. for 10 days. Children: <18 years: not recommended. Warnings/Precautions: Not for treating systemic infections (minimal systemic absorption). Pregnancy (Cat. B). Nursing mothers. Adverse reactions: Nausea, vomiting, abdominal pain, GI hemorrhage, anemia, neutropenia. How supplied: Tabs—20, 60, 100 For more information, call 855.343.4243 or visit www.Difi cid.com. ■

CME CE FEATURE

■ LEARNING OBJECTIVES : • Identify the most commonly isolated bacteria in children with conjunctivitis. • Know what to do with a patient who has fluorescein staining suggestive of dendritic branching ulceration. • Understand which drug to recommend for prophylaxis of neonatal conjunctivitis. • Learn which fluoroquinolone is useful in patients with a history of poor compliance. ■ COMPLETE THE POSTTEST: Page 115 ■ ADDITIONAL CME/CE: Pages 79, 111

KIMBERLY A. SPERING, MSN, CRNP, FNP-BC

Therapeutic strategies for bacterial conjunctivitis Resistance has compromised the effectiveness of all ophthalmic antibiotics, but new topical treatment options are available.

amily practice clinicians frequently encounter patients with acute infective conjunctivitis. Approximately 4 million cases of bacterial conjunctivitis are seen annually in the United States in children and adults.1 Almost 25% of infectious conjunctivitis cases occur in children up to age 11 years, with children younger than age 1 year accounting for a greater percentage of cases than any other age group.2 The total cost of bacterial conjunctivitis in the United States has been estimated to be as much as $857 million annually. This estimate includes direct costs—the value of goods and services used in treatment and management—and indirect costs, which include the economic losses from illness, injuryrelated work disability, premature death, and time lost from work and leisure activities by caregivers.1

Conjunctivitis (shown) can be caused by allergy, by bacterial or viral infection, or by physical or chemical irritants.

Making the diagnosis

Allergies and bacterial or viral infections are the most common causes of conjunctivitis. 3 A presumptive diagnosis can be made by taking a www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 31

CME CE

BACTERIAL CONJUNCTIVITIS

Staphylococcus aureus is seen most frequently in older children and adults and is the most common cause of bacterial conjunctivitis worldwide. comprehensive patient history and evaluating presenting symptoms. Suggested questions to ask during a diagnostic workup include: 1. When was the onset of symptoms? Was the onset sudden or gradual?4 What is the duration of symptoms? Are they chronic or recurrent? 5 2. Are symptoms unilateral or bilateral?3,6 What is the type and amount of ocular discharge? 5,6 3. Is there any ocular pain, photophobia, or blurry vision? 5,6 4. Has the patient been in contact with anyone with conjunctivitis? 5 5. Are there such allergy symptoms as itching? Does the patient have a history of allergic rhinitis?3,7 6. Has the patient had any recent symptoms of an upper respiratory infection?3 The clinician should also obtain a medication history, including the patient’s use of OTC therapies, eye drops, and herbal products.4,8 A physical examination can determine visual acuity, visual fields, extraocular movements, and pupillary reaction. Eyelids should be examined for crusting, inflammation, and tenderness; the conjunctivae should be examined for edema and hyperemia. Evaluate the amount, color, and type of ocular

discharge; examine the cornea for clarity; and palpate for regional lymphadenopathy.8 Bacterial conjunctivitis can usually be differentiated by its symptoms from viral and allergic conjunctivitis and other causes of the red eyes common to all of these conditions (Table 1).4-6,9,10 The pathogens most frequently associated with bacterial conjunctivitis include the gram-positive bacteria Staphylococcus aureus, S. epidermidis, and Streptococcus pneumoniae, and the gram-negative bacteria Haemophilus influenzae.9 These bacteria are part of normal lid or nasopharyngeal flora.11 The types of bacteria that cause bacterial conjunctivitis vary by patients’ ages (Table 2).5,9-11 In young children, H. influenzae is the most commonly isolated bacteria, and infections with H. influenzae may occur concurrently with upper-respiratory infections or otitis media. S. aureus is seen most frequently in older children and adults and is the most common cause of bacterial conjunctivitis worldwide.9,11 Although the majority of patients can be safely managed in a family practice, consider other potentially more serious ocular disorders when evaluating a complaint of red eye. Other differential diagnoses include blepharitis, corneal abrasion, foreign body presence, subconjunctival hemorrhage, herpes simplex conjunctivitis, episcleritis, corneal ulcer, keratitis, iritis, glaucoma, chemical burn, and scleritis. Any potentially vision-threatening ocular condition should be referred immediately to an optometrist or ophthalmologist. Such conditions

TABLE 1. 1. Differential diagnosis of conjunctivitis and other ocular disorders4-6,9,10 Conjunctivitis

Bacterial

Hyperacute bacterial

• Constant crusty, discolored discharge

• Copious, thick, purulent, yellow-green

• Possible photophobia

• Some itching

• Blurry vision, but clears with blinking

• Blurry vision • Severe edema and erythema

Other ocular disorders

Viral

Allergic

• Watery discharge

• White, stringy mucoid discharge

• Photophobia

Foreign body presence

Corneal abrasion

• Watery discharge

• Eyelid crusting

Blepharitis

• Photophobia

• No photophobia

• Some itching

• Frequent photophobia

• Irritation

• Severe pain

• Some itching

• Usually no vision changes

• Very itchy

• Usually blurry vision

• Blurry vision

• No vision change

• Mild-to-moderate erythema

• Mild erythema

• Mild-to-moderate erythema

• Usually no vision changes • Mild-to-moderate erythema

• Moderate erythema

32 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

• Mild-to-moderate erythema

Topical steroids may worsen symptoms of ocular herpes, exacerbate ulceration, and increase intraocular pressure and should not be administered. include decreased visual acuity, significant photophobia, hazy cornea, ocular herpes, severe eye pain, or abnormalities in the cornea or anterior segment of the eye.5,6,10 Other symptoms warranting referral include nausea; vomiting; severe headache, which may indicate acute angle-closure glaucoma; or significant purulent discharge, which may be a symptom of hyperacute bacterial infection from gonorrhea or chlamydia.5,6 Patients may also present with an injury from their use of contact lenses, given that many wearers do not use or replace their lenses as directed.5 Of particular note, any patient who has fluorescein staining suggestive of dendritic branching ulceration should be immediately referred for evaluation of ocular herpes. A topical steroid should not be administered, because it could worsen the symptoms of ocular herpes, exacerbate ulceration, and increase intra-ocular pressure, potentially outweighing any benefit of treatment.5,6 Never use a topical ocular steroid for conjunctivitis; most primary-care clinicians lack advanced training, and microscopy is not available in daily practice.

also affect dosing frequency and drug distribution on the eye surface. For example, antibacterials in solutions or suspensions tend to be washed more rapidly from the ocular surface through tearing or rapid blinking, thus requiring frequent dosing. About 50% of an eye drop is lost from the eye almost immediately after application because it will exceed the conjunctival cul-de-sac’s maximum capacity of only 20 to 30 µl. Petrolatum or oil-based ointments are more viscous, offering more prolonged residence time and less frequent dosing, but with the trade-off of blurry vision as a common side effect.17 The addition of such viscosityenhancing agents as polyvinylpyrrolidone, polyvinyl alcohol, or carboxymethylcellulose to solutions or suspensions can dramatically increase a drug’s residence time. DuraSite (InSite Vision, Alameda, Calif.) is a recently developed TABLE 2. Common causes of bacterial conjunctivitis by age group5,9-11 Neonates Chlamydia trachomatis (neonatal)

Therapeutic options 12,13

Although bacterial conjunctivitis is usually self-limited, studies have shown the benefits of treatment with topical ophthalmic antibiotics.13 Such benefits include reducing the time to recovery, limiting spread of the infection to others, preventing the recurrence of infection, providing a quicker return to normal activities, and decreasing the risk for sight-threatening complications.9,10,13 Patients with an inadequate response to therapy may have a more serious condition.10 Topical ophthalmic antibiotics are effective because their direct on-site delivery results in high concentrations of drug on the ocular surface. Bacterial cultures are not routinely done in primary care, and antibiotic treatment is generally empirical with a broad-spectrum antibiotic.10,14 The classes of antibiotics used in the treatment of bacterial conjunctivitis include aminoglycosides, polymyxin B combinations, macrolides, and fluoroquinolones.9,10 Differences in molecular structures among drug classes and compounds affect tear concentration and conjunctival tissue penetration, which in turn impact clinical efficacy. The newer fluoroquinolones attain greater conjunctival penetration than older antibiotics, and the more recently introduced fluoroquinolones penetrate the conjunctiva better than do older ones.15,16 Antibiotic formulation can

Staphylococcus aureus Haemophilus influenzae Streptococcus pneumoniae Neisseria gonorrhoeae Children H influenzae S. pneumoniae S. aureus Moraxella catarrhalis Staphylococcus epidermis Streptococcus viridans Gram-negative intestinal bacteria Adults S. aureus Coagulase-negative Staphylococcus organisms H. influenzae S. pneumoniae N. gonorrhoeae (hyperacute form)

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 33

CME CE

BACTERIAL CONJUNCTIVITIS

The aminoglycosides gentamicin and tobramycin provoke such mild-to-moderate ocular adverse events as edema, pruritus, burning, and chemosis. polycarbophil-based mucoadhesive vehicle that is used in several topical antibiotic formulations.18,19 Some patients may be sensitive to the preservatives found in most antibiotic ophthalmic solutions, such as benzalkonium chloride (BAK), which is used in all topical antibiotic formulations except that of the fluoroquinolone moxifloxacin (Vigamox). Preservatives stabilize compounds and prevent contamination but may cause ocular irritation.20,21 Without using a biomicroscope, it is difficult to determine whether a patient’s worsening symptoms are attributable to treatment failure or sensitivity to eye drops. However, preservatives may enhance the activity of an antibiotic. In vitro comparisons of antibiotics with and without BAK showed that agents with BAK eradicated a greater percentage of bacteria more rapidly than those without.21-23 The risks and benefits of BAK as a preservative need to be studied further.22 Table 3 provides a review of the classes of antibiotics used in the treatment of bacterial conjunctivitis.24-33 Aminoglycosides. The aminoglycosides gentamicin and tobramycin (Tobrex) affect gram-negative and gram-positive

bacteria,30,34 although these agents may have limited activity against streptococci.17,34 Both drugs require frequent administration,35 which may limit compliance.36 Studies comparing gentamicin with tobramycin did not find a significant difference between the two drugs in the percentages of patients achieving clinical cures and microbial eradication.27,37 Both provoke such mild-to-moderate ocular adverse events as edema, pruritus, burning, and chemosis.35,37,38 Polymyxin B formulations. The polymyxin B-based formulations include polymyxin B/trimethoprim, polymyxin B/ bacitracin (Polysporin), and polymyxin B/bacitracin/neomycin.17 These combinations are not reliably bactericidal,17 and polymyxin B/trimethoprim provides what has been described as only fair coverage of S. pneumoniae.11 Monotherapy with polymyxin B is bactericidal for gram-negative bacteria, and trimethoprim, neomycin, and bacitracin are bactericidal for gram-positive and gram-negative pathogens. Combinations need to be administered as often as aminoglycosides, so patient compliance may be an issue.39,40 Continues on page 36

TABLE 3. 3. Antibiotics for bacterial conjunctivitis 24-33 Rates (% of patients) of clinical efficacy

Antibiotic

Classification

Bacterial susceptibility

Dosing regimen

Gentamicin 0.3%

Aminoglycoside

• Staphylococcus aureus • Staphylococcus epidermidis • Streptococcus pyogenes • Streptococcus pneumoniae • Enterobacter aerogenes • Escherichia coli • Haemophilus influenzae • Klebsiella pneumoniae • Neisseria gonorrhoeae • Pseudomonas aeruginosa • Serratia marcescens

• Severe infections: two drops every hour on Day 1, then one to two drops every four hours for five to seven days • Mild-to-moderate infections: one to two drops every four hours for five to seven days

• Clinical cure/improvement: 95% • Microbial eradication/ control: 65% (Day 11)27

Tobramycin 0.3% (Tobrex)

Aminoglycoside

Same pathogens as above, plus • Proteus mirabilis • P. vulgaris • Morganella morganii • Moraxella lacunata • Acinetobacter calcoaceticus

• Severe infections: two drops every hour on Day 1, then one to two drops q.i.d. for five to seven days • Mild-to-moderate infections: one to two drops q.i.d. for five to seven days

• Clinical cure/ improvement: 98% • Microbial eradication/ control: 85% (Day 11)27

Polymyxin B/bacitracin (Polysporin)

Cyclic lipopeptide Sulfonamide

Same pathogens as above, plus • Haemophilus aegyptius • Streptococcus faecalis

One drop every three hours for seven to 10 days

• Clinical cure: 62% • Bacteriologic cure: 71% (Days 3-5)28

34 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

TABLE 3. 3. Antibiotics for bacterial conjunctivitis 24-33 Antibiotic

Classification

Bacterial susceptibility

Dosing regimen

Rates (% of patients) of clinical efficacy

Azithromycin 1% (AzaSite)

Macrolide

CDC coryneform group G • H. influenzae • S. aureus • Streptococcus mitis • S. pneumoniae

One drop b.i.d. (eight to 12 hours apart) for two days, then one drop daily for five days

• Clinical resolution: 79.9% • Bacterial eradication: 88.1% (Day 6 +1)18

Ciprofloxacin 0.3% (Ciloxan)

Fluoroquinolone

Same pathogens as aminoglycosides, plus • Methicillin-sensitive S. aureus • S. epidermidis • S. pneumoniae • Streptococcus viridans

One to two drops every two hours for two days, then every four hours for five more days

Bacterial eradication: 76.4% (Day 3)29

Ofloxacin 0.3% (Ocuflox)

Fluoroquinolone

• S. aureus • S. epidermidis • S. pneumoniae • Enterobacter aerogenes • H. influenzae • P. mirabilis • P. aeruginosa

One to two drops every two to four hours on Days 1 and 2, then one to two drops q.i.d. on Days 3-7

• Clinical improvement: 98% • Microbial eradication: 67% (Day 11)30

Levofloxacin 0.5% (Quixin)

Fluoroquinolone

• Corynebacterium species • S. aureus • S. epidermidis • S. pneumoniae • S. viridans • S. marcescens

One to two drops every two hours on Days 1 and 2, then one to two drops q.i.d. on Days 3-7

• Clinical cure: 77% • Microbial eradication: 90% (Days 6-10 )31

Levofloxacin 1.5% (Iquix)

Fluoroquinolone

• Corynebacterium species • S. aureus • S. epidermidis • S. pneumoniae • S. viridans • S. marcescens

One to two drops every 30-120 minutes while awake, then four to six hours after retiring on Days 1-3, then one to two drops every four hours while awake on Days 4-7

Not available

Moxifloxacin 0.5% (Vigamox)

Fluoroquinolone

Same as ofloxacin, plus • Micrococcus luteus • Haemophilus parainfluenzae • Chlamydia trachomatis

One drop t.i.d. for seven days

Clinical cure: 66%-69% (Day 5 or 6)32

Gatifloxacin 0.3% (Zymar)

Fluoroquinolone

Same as ofloxacin, plus • Corynebacterium propinquum • S. mitis

One drop every two hours while awake on Days 1-2, then one drop q.i.d. on Days 3-7

Not available for vehiclecontrolled study

Gatifloxacin 0.5% (Zymaxid)

Fluoroquinolone

• S. aureus • S. epidermidis • S. mitis group • Streptococcus oralis • S. pneumoniae • H. influenzae

One drop every two hours while awake on Day 1, then one drop two to four times daily on Days 2-7

Not available

Besifloxacin 0.6% (Besivance)

Fluoroquinolone

Same as ofloxacin, plus • Staphylococcus lugdunensis • Staphylococcus saprophyticus • Staphylococcus warneri • Streptococcus agalactiae • Streptococci groups C, F, G • Citrobacter koseri • Legionella pneumophila

One drop t.i.d. (four to 12 hours apart) for seven days

• Clinical resolution: 84.4% • Microbial eradication: 88.4% (Day 8 or 9)33

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 35

CME CE

BACTERIAL CONJUNCTIVITIS

Fluoroquinolones have fewer adverse events than aminoglycosides and polymyxin B combinations, and ocular adverse events are typically mild. A double-masked clinical study comparing the polymyxin B/bacitracin combination (administered four times daily for seven days) with placebo found that patients receiving the combination treatment had significantly higher rates of clinical cure and bacterial eradication than those receiving placebo.28 Two clinical studies comparing different combinations of polymyxin B did not find significant differences in rates of clinical resolution or microbial eradication among the formulations.41 Polymyxin B trimethoprim has been shown to be slower in resolving the clinical signs and symptoms of bacterial conjunctivitis than the newer fluoroquinolone moxifloxacin. 39 Polymyxin B combinations have primarily moderate adverse events.39,40 Macrolides. The two macrolides used in the treatment of bacterial conjunctivitis—erythromycin and azithromycin (AzaSite)—are bacteriostatic agents.42 Erythromycin is usually recommended only for prophylaxis of neonatal conjunctivitis because the drug has limited activity against S. aureus.11,42 In vitro studies have shown that azithromycin is less active against gram-positive bacteria than erythromycin but has a broader spectrum of anti-infective activity against gramnegative pathogens, including H. influenzae.42 Azithromycin is administered less frequently than the aminoglycosides or polymyxin B combinations due to inclusion of DuraSite in the formulation (Table 3). Clinical studies with azithromycin, applied twice daily on Days 1 and 2 and once daily on Days 3 to 5, have shown that the rates of clinical efficacy and bacterial eradication are similar to those of the aminoglycosides and polymyxin B combinations.18,43 Such adverse events as burning or stinging, eye irritation, headache, conjunctival hyperemia, and worsening bacterial conjunctivitis were seen in similar numbers of patients who received azithromycin, vehicle, or tobramycin in clinical studies.43,44 Fluoroquinolones. Fluoroquinolones are broad-spectrum, bactericidal anti-infective agents with potent balanced activity against gram-positive and gram-negative pathogens.14,45

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Fluoroquinolones are administered less frequently than many of the older agents. The fluoroquinolones used in the treatment of bacterial conjunctivitis can be divided into two groups: older agents (i.e., ofloxacin [Ocuflox], ciprofloxacin [Ciloxan], and levofloxacin [Iquix]) and newer agents (i.e., gatifloxacin [Zymar, Zymaxid], moxifloxacin, and besifloxacin [Besivance]). Clinical resolution and bacterial eradication rates were significantly higher with each of the fluoroquinolones than with vehicle in double-masked, randomized, vehicle-controlled studies.12,15,19,29,31,33 The newest fluoroquinolone, besifloxacin, was noninferior to moxifloxacin when administered t.i.d. for five days46 and was shown to be safe and effective when administered b.i.d. for only three days.47 Thus, besifloxacin, which is formulated with DuraSite, may be useful in patients with a history of poor compliance or in children who are in nursery or school settings in which administering a midday dose would be difficult. Fluoroquinolones have fewer adverse events than the aminoglycosides and polymyxin B combinations. Ocular adverse events are typically mild and self-limited and have included conjunctivitis, pruritus, ocular discharge, discomfort, transient burning, stinging, pain, edema, and photophobia.19,34,31,32,48-51 In the moxifloxacin-besifloxacin comparative study, eye irritation, although infrequent, was observed in significantly more eyes treated with moxifloxacin.46 Bacterial resistance among ocular pathogens

Bacterial resistance to all classes of ophthalmic antibiotics has been increasing steadily in recent decades, with each class exhibiting varying degrees of resistance to different organisms. The increase in resistance can be attributed to excessive use of oral antibiotics, prophylactic use of antibiotics, extended dosing, prolonged duration of treatment, use of subtherapeutic dosages by noncompliant patients, treatment of viral and other nonbacterial infections with antibiotics, and agricultural use.52 Aminoglycosides have shown decreased activity against S. aureus and Streptococcus and Pseudomonas species. Thus, S. pneumoniae and methicillin-resistant S. aureus (MRSA) have exhibited high rates of resistance to tobramycin and gentamicin.53-56 A Brazilian study found that there was no resistance among S. pneumoniae cultures obtained from the cornea or conjunctiva from 1989 through 1992 for either tobramycin or gentamicin. However, by 1997 through 2000, resistance to these antibiotics had increased in corneal and

36 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

The newer fluoroquinolones are more active than older ones against gram-positive bacteria associated with bacterial conjunctivitis. conjunctival infections to 43.6% and 46% for tobramycin and 42.3% and 56% for gentamicin, respectively.55 The majority of penicillin-susceptible and nonsusceptible S. pneumoniae isolates demonstrated resistance to polymyxin B and polymyxin B/neomycin in a study with isolates from 250 pediatric patients with bacterial conjunctivitis.56 Similarly, the Ocular TRUST longitudinal surveillance study conducted from 1999 to 2006 in 19 states found that 100% of S. pneumoniae isolates were resistant to polymyxin B.53 An increase in resistance by S. aureus and H. influenzae to the macrolide antibiotics has been attributed partially to their bacteriostatic effect and, especially for azithromycin, to frequent prescribing for other infections and prolonged elimination half-life.57-59 A 10-year surveillance study identified a doubling of resistance to erythromycin by gram-positive isolates from 22.1% (1994-1995) to 45.1% (2002-2003) and by S. aureus isolates from 23.8% to 48.9%.60 In studies in the United States and Israel, resistance to azithromycin and erythromycin was observed in 76% and 78%, respectively, of H. influenzae isolates.57,61 Resistance to fluoroquinolones

Development of resistance to fluoroquinolones is related to their mechanism of action. The primary targets of these medications in susceptible species are the bacterial DNA replication enzymes DNA gyrase and topoisomerase IV. Ciprofloxacin and ofloxacin preferentially target one replication enzyme over the other, and resistance, especially among gram-positive organisms, is increasing to both of those fluoroquinolones.62 Structural modifications of the newer fluoroquinolones help provide more balanced binding to both enzymes. As a result, newer fluoroquinolones are more active than older ones against gram-positive bacteria associated with bacterial conjunctivitis, including staphylococci and streptococci strains that are not susceptible to other antibiotics.14,63,64 Of the newer fluoroquinolones, besifloxacin has been found to have balanced inhibitory activity at concentrations that are much lower than the concentrations needed for ciprofloxacin and moxifloxacin.65 A 10-year study of cultures obtained between 1994 and 2003 from patients with bacterial conjunctivitis found a threefold increase in resistance to ciprofloxacin for gram-positive pathogens (11.7% to 35.6%).60 Two studies of resistance among S. aureus isolates identified increases from 8% of isolates in 1990-1995 to 20.7% in 1996-2001 for ciprofloxacin, and

from 11% in 1990 to 28% in 1998 for both ciprofloxacin and ofloxacin.66,67 The balanced binding of the newer fluoroquinolones to DNA gyrase and topoisomerase IV has delayed the development of resistance to these agents. However, resistance is being reported: 18.9% and 15.9% of methicillin-sensitive S. aureus isolates were resistant to gatifloxacin and moxifloxacin, respectively, in the Ocular TRUST surveillance study.53 An in vitro study of coagulase-negative staphylococci isolates from patients with clinical endophthalmitis found that resistance to gatifloxacin increased from 0% in 1990-1994 to 22% in 1995-1999 and to 31% in 2000-2004. At least 65% of ciprofloxacin-resistant coagulase-negative Staphylococcus isolates were resistant to gatifloxacin and moxifloxacin.68 The continuing increase in the presence of MRSA and methicillin-resistant S. epidermidis (MRSE) has become especially worrisome because fluoroquinolone resistance often occurs concurrently with methicillin resistance. The percentage of isolates with MRSA bacteria recovered from patients with bacterial conjunctivitis in one study increased from 4.4% in 1994-1995 to 42.9% in 2002-2003.60 Another U.S. study of MRSA isolates obtained from ocular infections, which were primarily conjunctivitis, reported resistance rates of 68% for moxifloxacin, 71% for gatifloxacin, and 94% for ciprofloxacin and ofloxacin.69 Resistance by MRSE endophthalmitis isolates to fluoroquinolones has been less than that of MRSA, but a rate of 33% for moxifloxacin and gatifloxacin is still relatively high.70 Besifloxacin was not included in the surveillance studies because it was not available until after those studies were concluded. However, MRSA bacteria accounted for 14% of S. aureus isolates obtained in three clinical studies that evaluated AT A GLANCE ●

The most common causes of conjunctivitis are allergies and bacterial or viral infections.

●

Bacterial conjunctivitis is usually self-limited, but studies have shown the benefits of topical ophthalmic antibiotics.

●

Bacterial resistance to all classes of ophthalmic antibiotics has been increasing steadily in recent decades.

●

Fluoroquinolones remain the best choice for the treatment of bacterial conjunctivitis.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 37

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the efficacy and safety of besifloxacin for the treatment of bacterial conjunctivitis. Sixty-five percent of the MRSA isolates were resistant to ciprofloxacin, and all ciprofloxacinresistant isolates were resistant to levofloxacin, ofloxacin, gatifloxacin, and moxifloxacin.71 In the same analysis, MRSE constituted 46% of S. epidermidis isolates, including 47% that were resistant to ciprofloxacin and other comparator fluoroquinolones. In contrast, besifloxacin demonstrated potent in vitro activity against ciprofloxacin-resistant MRSA and MRSE.71,72 Besifloxacin is the first fluoroquinolone developed solely for topical ophthalmic use. The absence of a systemic counterpart reduces the contribution to resistance development from previous systemic use.

2. Rietveld RP, ter Riet G, Bindels PJ, et al. Do general practitioners adhere to the guideline on infectious conjunctivitis? Results of the Second Dutch National Survey of General Practice. BMC Fam Pract. 2007;8:54. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2034564. 3. Teoh DL, Reynolds S. Diagnosis and management of pediatric conjunctivitis. Pediatr Emerg Care. 2003;19:48-55. 4. Granet D. Allergic rhinoconjunctivitis and differential diagnosis of the red eye. Allergy Asthma Proc. 2008;29:565-574. 5. Tarabishy AB, Jeng BH. Bacterial conjunctivitis: a review for internists. Cleve Clin J Med. 2008;75:507-512. Available at www.ccjm.org /content/75/7/507.long. 6. Galor A, Jeng BH. Red eye for the internist: when to treat, when to refer. Cleve Clin J Med. 2008;75:137-144. Available at www.ccjm.org /content/75/2/137.long.

Choosing effective therapy

7. Medscape Education. The diagnosis and treatment of bacterial

Bacterial conjunctivitis is a self-limited disease, but treatment with an ophthalmic antibiotic can reduce the time to resolution of symptoms and prevent potentially vision-threatening complications. To treat bacterial conjunctivitis effectively, select a medication with broad-spectrum activity against ocular pathogens, rapid bactericidal activity, high concentrations in the eye, a long residence time, and safety and tolerability for patients. It is also important to consider how an antibiotic’s formulation will affect its efficacy and tolerability. Choosing an appropriate treatment has become more difficult because increased bacterial resistance has compromised the effectiveness of many options. Such older ophthalmic medications as the aminoglycosides, polymyxin B combinations, and macrolides have become especially susceptible to bacterial resistance. Fluoroquinolones remain the best choice for the treatment of bacterial conjunctivitis, but the older fluoroquinolones have experienced increasing resistance by the bacteria that most often cause bacterial conjunctivitis. Further, fluoroquinolone-resistant MRSA bacteria have exhibited high rates of resistance to most of the newer fluoroquinolones. In vitro studies have shown that besifloxacin is active against fluoroquinolone-resistant MRSA, although further studies are needed to confirm these results. ■

conjunctivitis in pediatric patients. Available at www.medscape.org/ viewarticle/575864_6. 8. Uphold CR, Graham MV. Clinical Guidelines in Family Practice. 4th ed. Gainesville, Fla.: Barmarrae Books; 2003:326. 9. Høvding G. Acute bacterial conjunctivitis. Acta Ophthalmol. 2008;86:5-17. 10. Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician. 1998;57: 735-746. 11. Diamant JI, Hwang DG. Therapy for bacterial conjunctivitis. Ophthalmol Clin North Am. 1999;12:15-20. 12. Rose P. Management strategies for acute infective conjunctivitis in primary care: a systematic review. Expert Opin Pharmacother. 2007;8:1903-1921. 13. Sheikh A, Hurwitz B. Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database Syst Rev. 2006;2:CD001211. Available at onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD001211/frame.html. 14. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49 Suppl 2:S79-S83. 15. O’Brien TP. Evidence-based review of moxifloxacin. Int Ophthalmol Clin. 2006;46:61-72. 16. Wagner RS, Abelson MB, Shapiro A, Torkildsen G. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue. Arch Ophthalmol. 2005;123:1282-1283. 17. Leeming JP. Treatment of ocular infections with topical antibacterials. Clin Pharmacokinet. 1999;37:351-360.

Ms. Spering is a nurse practitioner with Brndjar Medical Associates in Emmaus, Pa. Editorial assistance in the development of this manuscript was provided by Churchill Communications and funded by Bausch + Lomb. The author has no relationship to disclose relating to the content of this article.

18. Abelson M, Protzko E, Shapiro A, et al. A randomized trial assessing the clinical efficacy and microbial eradication of 1% azithromycin ophthalmic solution vs tobramycin in adult and pediatric subjects with bacterial conjunctivitis. Clin Ophthalmol. 2007;1:177-182. Available at www.ncbi.nlm .nih.gov/pmc/articles/PMC2704516. 19. Karpecki P, Depaolis M, Hunter JA, et al. Besifloxacin ophthalmic sus-

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50. Comstock TL, Paterno MR, Usner DW, Pichichero ME. Efficacy and

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in staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006;124:479-

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properties of azithromycin in a kinetics-of-kill model and implications for bacterial conjunctivitis treatment. Adv Ther. 2008;25:208-217. 59. Bergman M, Huikko S, Huovinen P, et al. Macrolide and azithromycin use are linked to increased macrolide resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2006;5:3646-3650. Available at aac. © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

asm.org/cgi/content/full/50/11/3646. 60. Cavuoto K, Zutshi D, Karp CL, et al. Update on bacterial conjunctivitis in South Florida. Ophthalmology. 2008;115:51-56. 61. Buznach N, Dagan R, Greenburg D. Clinical and bacterial characteristics of acute bacterial conjunctivitis in children in the antibiotic resistance era. Pediatr Infect Dis J. 2005;24:823-828. 62. Chen F-J, Lo H-J. Molecular mechanisms of fluoroquinolone resistance. J Microbiol Immunol Infect. 2003;36:1-9. 63. Kaliamurthy J, Nelson Jesudasan CA, Geraldine P, et al. Comparison of in vitro susceptibilities of ocular bacterial isolates to gatifloxacin and other topical antibiotics. Ophthalmic Res. 2005;37:117-122. 64. Schlech BA, Blondeau J. Future of ophthalmic anti-infective therapy and the role of moxifloxacin ophthalmic solution 0.5% (VIGAMOX). Surv Ophthalmol. 2005;50:S64-S67. 65. Cambau E, Matrat S, Pan XS, et al. Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother. 2009;63:443-450. Available at jac.oxfordjournals.org/content/63/3/443.long.

40 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

“What’s the next best medicine?”

FEATURE: CARL SHERMAN

New data on managing atrial fibrillation Updated guidelines address recommendations for strict vs. lenient rate control and combined use of antiplatelet and anticoagulant therapy.

Lenient control is fine for patients with no symptoms and stable ventricular function.

he most common cardiac rhythm disorder, atrial fibrillation (AF) affects an estimated 2.3 million Americans and is becoming more widespread as the population ages. The American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the European Society of Cardiology published practice guidelines for the condition in 2006. The years since have seen approval of several new drugs for use in the disorder and the discovery of additional evidence to support or modify existing treatments, leading to this year’s publication of two “focused updates” on the management of patients with AF, with the help of the Heart Rhythm Society (HRS). The extent to which AF can be managed in primary care depends on such factors as patient age and comorbidity, symptoms, and the complexity of the condition. “Stroke is the primary thing I worry about in AF. If you can keep the patient from having a stroke, you are two-thirds of the way home,” said L. Samuel Wann, MD, director of cardiology at Wisconsin Heart Hospital, Milwaukee, and chair of the group that wrote the updates. Several of the changes described in the ACCF/ AHA/HRS guideline updates simplify treatment or apply to areas of management that are particularly germane to general practice. Rate control

Accelerated ventricular heart rate—at rest and during exercise—is a frequent concern in AF, and 44 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

ATRIAL FIBRILLATION MANAGEMENT

Always

92%

Sometimes

Never n=313

1% 0

20%

40%

60%

80%

100%

For more polls, visit www.ClinicalAdvisor/polls

one commonly endorsed goal has been “strict rate control,” which entails keeping heart rate <80 beats per minute at rest and <110 bpm during moderate exercise. The ACCF/AHA/HRS update draws on several large recent trials to conclude that this approach is no more beneficial than “lenient control”—maintaining a resting heart rate <110 bpm— for patients who have no or minimal symptoms and stable ventricular function. In this population, strict control appeared to have no advantage in symptoms, quality of life, or such clinical endpoints as cardiac events, hospitalization, or death. In practical terms, this means a simpler, less aggressive approach to rate control. For most patients, “There is no reason for repeated Holter monitoring or exercise tests or for adding drugs or increasing doses in pursuit of an arbitrary cutoff,” explained Dr. Wann. But “lenient control” does not mean “no rate control,” he added. Pronounced tachycardia can have detrimental cardiac effects over the long term, including cardiomyopathy, and patients who remain symptomatic despite lenient control might well be referred to a cardiologist or electrophysiologist for further evaluation and treatment.

going back and forth to have their INR [international normalized ratio] checked. There are also dietary restrictions.” Bruising and bleeding can be problematic as well. It should be kept in mind that while the aspirin-clopidogrel combination is more effective than aspirin alone in preventing vascular events in AF patients, it is considerably inferior to warfarin in this regard. The second focused update endorses dabigatran (Pradaxa), a new drug that, like warfarin, represents a first-line choice to prevent thromboembolism in AF.2 Dabigatran was approved by the FDA in October 2010. It is, the authors point out, “the first new oral anticoagulant to become available for clinical use in more than 50 years.” In a large randomized trial, rates of stroke and systemic embolism were comparable in AF patients treated with dabigatran and warfarin, and the new drug carried a 20% lower risk of major bleeding episodes. Dabigatran’s principal advantage is ease of use. The drug requires neither dietary restrictions nor regular INR testing and

ECG of an individual without AF shows a normal sinus rhythm (a P wave followed by a QRS at a constant interval).

Expanded anticoagulation options

Oral anticoagulation therapy to prevent thromboembolism is indicated for AF patients with a history of stroke or transient ischemic attack and should be considered for those otherwise at risk for stroke. In the 2006 guidelines, this essentially meant using warfarin (Coumadin). The first of the 2011 focused updates recommends another regimen —aspirin combined with clopidogrel (Plavix)—as a reasonable alternative for patients in whom anticoagulation with warfarin is considered unsuitable.1 “Warfarin is a tough drug to give, and a sizeable number of patients won’t take it,” Dr. Wann warned. “They don’t like

This ECG shows the heartbeat during AF of a man aged 80 years. Rhythm is irregularly irregular, and atrial activity is seen as small, irregular baseline undulations of variable amplitude and morphology.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 47

POLL POSITION

Results of our online poll show that 92% of your peers always discuss thromboembolism with patients who present with atrial fibrillation.

ATRIAL FIBRILLATION MANAGEMENT

CLINICAL SLIDESHOW For more tips on how to identify atrial fibrillation in your practice, view the slideshow at ClinicalAdvisor.com/A-fibSlideshow

is given in a fixed dose. Because it is metabolized independently of liver enzymes, drug-drug interactions are unlikely. On the other hand, GI side effects are more common with dabigatran than with warfarin, and the additional expense of the newer drug may be a deterrent for some patients. Dr. Wann observed that dabigatran was approved as an anticoagulant for AF only and is not indicated for patients who have prosthetic heart valves or valvular disease or other conditions that require anticoagulation therapy. Although the update committee did not address the use of the aspirin-clopidogrel combination in the context of dabigatran, it would seem logical to consider the combination only for patients who, for whatever reasons, cannot or will not take either of the two anticoagulants, Dr. Wann said. A new anti-arrhythmic drug

Patients in whom paroxysmal or persistent AF is highly symptomatic or leads to hospitalization may require antiarrhythmic pharmacotherapy to maintain sinus rhythm. (This will generally mean referral to, or at least consultation with, a cardiologist.) The ACCF/AHA/HRS update adds dronedarone (Multaq) as a reasonable option for rhythm control. Dronedarone, which chemically resembles the anti-arrhythmic amiodarone (Cordarone), is safer but less effective than the older drug. Safety, in fact, is its chief advantage: dronedarone does not pose the risk of serious side effects—thyroid and pulmonary toxicity in particular—that represent the chief drawbacks of amiodarone. On the other hand, a head-to-head trial of the two drugs found dronedarone significantly less effective than amiodarone in reducing recurrences among patients with persistent AF. Because of its superior safety, dronedarone may be considered early in treating most patients with persistent or recurrent

MAKING CONTACT

paroxysmal AF, whereas amiodarone is generally recommended for use after other agents have failed. For patients with heart failure, however, the more powerful amiodarone remains a drug of choice, while dronedarone is not recommended. Catheter ablation

Additional evidence in support of catheter-based ablation therapy—radiofrequency destruction of small areas of heart tissue responsible for rhythm disturbance—has strengthened recommendations for its use in patients with persistent AF who have failed to improve with antiarrhythmic drugs. The ACCF/AHA/HRS update also recommends that catheter ablation be considered for a wider group of patients, including those with symptomatic paroxysmal AF. “Catheter ablation is a great procedure in the right hands for the right patients. It is not for everyone,” said Dr. Wann. The authors of the ACCF/AHA/HRS update noted that in the studies cited, “all ablation procedures were performed by highly experienced operators in high-volume centers.” They also pointed out that while most patients appear to remain free of recurrent AF for at least one year after catheter ablation, data on long-term efficacy are lacking. Similarly, there is no clear evidence on when—or indeed whether—it is safe to discontinue anticoagulation after successful catheter ablation, according to Dr. Wann. ■ Mr. Sherman is a freelance medical writer in New York City. References 1. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:104-123. Available at circ.ahajournals.org/cgi/content/full/123/1/104. 2. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123:1144-1150. Available at circ.ahajournals.org/cgi /content/full/123/10/1144. All electronic documents accessed July 15, 2011.

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FEATURE: DONALD GRAHAM, CRNP

Raising awareness of HIV drug interactions Antiretroviral agents can cause alterations the liver enzymes that are responsible for metabolizing many common medications.

ccording to the CDC, there are 1.1 million people currently living with HIV in the United States, and 56,300 new infections occurring each year.1 Most individuals who are diagnosed with HIV will receive care for this disease from an infectious disease specialist or HIV clinic. While these patients receive excellent care from their HIV specialists, they will likely rely on their primary-care practitioners for other related medical conditions. The past 15 years have seen great strides in the development of highly active antiretroviral therapy (HAART) medications. These medications have made HIV a very manageable disease and offer new hope to those infected with the virus. While HAART therapy is effective in controlling HIV, the medications do have many interactions with commonly prescribed drugs. The purpose of this article is to ensure that the busy clinician is aware that there may be serious drug-drug interactions between medications they prescribe and the HIV-related medications these patients are taking. HIV antiretroviral medications

A combination of at least three antiretroviral drugs is recommended.

The five main classifications of HIV antiretroviral agents available for use today are:2 1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 3. Protease inhibitors (PIs) Continues on page 52

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ANTIRETROVIRAL DRUG INTERACTIONS

In addition to HIV medications, patients are often receiving treatment for comorbid conditions and prophylaxis of opportunistic infections. 4. Entry inhibitors (including fusion inhibitors) 5. Integrase inhibitors Drug interactions have become a complex challenge for primary-care clinicians treating patients infected with HIV. Current treatment guidelines recommend the use of a combination of at least three antiretroviral drugs. In addition to HIV-related medications, patients are often receiving treatment for comorbid conditions and prophylaxis of opportunistic infections.3 HIV medications—particularly NNRTIs and PIs—can cause and are affected by alterations of the cytochrome P450 enzymes in the liver.4 These enzymes are responsible for metabolizing many medications. General recommendations

Although there are no specific guidelines regarding how to prevent drug interactions, the best way to avoid complications is to conduct a thorough medication history at each visit. This history should comprise prescription medications (including those prescribed by other providers), OTC medications, herbal/alternative therapies, and recreational/street drugs. Table 1 lists some of the most commonly prescribed antiretroviral therapies and their contraindications. HIV drug-drug interactions

It is beyond the scope of this article to describe all possible drug-drug interactions in persons taking HIV antiretroviral medications, but this section will identify the most frequent interactions between HAART drugs and medications frequently prescribed for patients. Antifungals and antibiotics. Medications to treat opportunistic infections are prone to interactions with some NNRTIs and PIs. The “azole” antifungals can increase concentration of other medications. The use of voriconazole (Vfend) with ritonavir (Norvir) 400 mg or efavirenz (Sustiva) is contraindicated because it results in a decreased blood concentration of voriconazole. Fluconazole (Diflucan) is a better choice.4

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The use of such macrolide antibiotics as erythromycin and clarithromycin (Biaxin) appear to increase the risk for fatal cardiac arrhythmia when co-administered with antiretroviral drugs using the CYP450 pathway. The use of macrolide antibiotics can inhibit this system, resulting in prolonged QT interval, which can lead to cardiac arrhythmias.5 Azithromycin (Zithromax, Zmax) is a better choice because it does not have a detrimental effect on this pathway. Interactions between antiretrovirals and rifamycins (used to treat TB) are a growing concern, especially in resourcelimited countries where TB remains a major cause of AIDSrelated death. Although rifampin (Rifadin, Rimactane) is part of the standard first-line regimens for TB prophylaxis and treatment, it is a known inducer of CYP3A4 and can reduce the levels of PIs and NNRTIs to subtherapeutic levels.6 Rifampin should not be used with any PI. Rifabutin (Mycabutin) is a more moderate enzyme inducer than is rifampin. Concurrent use of NRTIs and rifamycins is not contraindicated and does not require dose adjustments Dose adjustments needed when HIV antiretrovirals and TB medication are co-administered are listed in Table 2. Acid-lowering drugs. This classification of drugs must be looked at carefully before being prescribed to patients on HAART. These medications, which reduce the acidity of gastric secretions, can interfere with the absorption of certain PIs. Atazanavir (Reyataz) requires an acid environment for absorption; co-administering such drugs as proton pump inhibitors can alter the pH of stomach acidity for 24 hours or longer and will prevent atazanavir from being absorbed.4 OTC antacid medications exert their acid-neutralizing effects for short intervals and can be taken within one to two hours of HAART. Cholesterol-lowering drugs. Research has shown that just being HIV-positive increases a person’s risk for elevated cholesterol and lipid levels.7 In addition, PIs are linked to increased cardiovascular risk factors, thus requiring the addition of a lipid-lowering medication. The statins are one class of commonly prescribed drugs used for this purpose; their concentrations can be increased to dangerous levels when used with PIs.8 Table 3 serves as an excellent guide for practitioners who find it necessary to prescribe cholesterol-lowering medications to their patients who are taking antiretrovirals. Continues on page 54

52 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

ANTIRETROVIRAL DRUG INTERACTIONS

TABLE 1. Antiretroviral contraindications Medication and classification

Contraindication

NNRTIs CYP3A substrates that may cause serious events if blood levels are elevated (e.g., cisapride [Propulsid], pimozide [Orap], alprazolam [Xanax], midazolam [Versed], triazolam [Halcion], ergots)

Efavirenz (Sustiva)

Concomitant bepridil (Vascor), cisapride, ergots, midazolam, triazolam, pimozide, St. John’s wort

Indinavir (Crixivan)

Concomitant alfuzosin, amiodarone (Cordarone, Pacerone), cisapride, oral midazolam, triazolam, alprazolam, pimozide, ergots, sildenafil (Revatio; only when used to treat PAH)

Lopinavir/ritonavir (Kaletra)

• Loss of virologic response or resistance with rifampin, St. John’s wort • Drugs metabolized by CYP3A that may cause serious events if blood levels are elevated (e.g., cisapride, ergots, pimozide, midazolam, triazolam)

Moderate-to-severe hepatic impairment

NRTIs/N NRTIs/ NtRTI RTIss Abacavir (Ziagen)

• See literature regarding fatal hypersensitivity reactions (which may include fever, rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, or respiratory symptoms); discontinue as soon as suspected; do not restart, regardless of HLA-B*5701 status.

Nelfinavir (Viracept)

CYP3A substrates that may cause serious events if blood levels are elevated (e.g., cisapride, pimozide, midazolam, triazolam, lovastatin, simvastatin, ergots, amiodarone, quinidine)

Ritonavir (Norvir)

Concomitant alfuzosin, amiodarone, bepridil, flecainide (Tambocor), quinidine, propafenone (Rythmol), voriconazole (Vfend), ergots, oral midazolam, triazolam, pimozide, cisapride, St. John’s wort, lovastatin, simvastatin, sildenafil (Revatio; only when used to treat PAH)

Saquinavir (Invirase)

• Congenital long QT syndrome

• Moderate or severe hepatic impairment Abacavir/lamivudine (Epzicom)

• See literature regarding fatal hypersensitivity reactions (signs/symptoms include fever, rash, nausea, vomiting, diarrhea, abdominal pain, malaise/fatigue, or respiratory symptoms); discontinue as soon as suspected; do not restart, regardless of HLA-B*5701 status.

• Refractory hypokalemia or hypomagnesemia • Complete atrioventricular block without implanted pacemakers, or those who are at high risk

• Hepatic impairment Abacavir/lamivudine/ zidovudine (Trizivir)

• Severe hepatic impairment • Concomitant alfuzosin, amiodarone, bepridil, cisapride, dofetilide (Tikosyn), ergots, flecainide, lidocaine (Xylocaine), oral midazolam, pimozide, propafenone, quinidine, rifampin, sildenafil (Revatio; only when used to treat PAH), lovastatin, simvastatin, trazodone (Desyrel, Oleptro), triazolam

• Hepatic impairment Didanosine (Videx)

Concomitant allopurinol (Lopurin, Zyloprim) or ribavirin (Copegus, Rebetol, RibaTab, Ribasphere)

Tipranavir (Aptivus)

Concomitant rifampin (Rifadin, Rimactane), alfuzosin (UroXatral), ergots, cisapride, St. John’s wort, lovastatin (Altocor, Altoprev, Mevacor), simvastatin (Zocor), pimozide, oral midazolam, triazolam, sildenafil (Viagra), Revatio (only when used to treat pulmonary arterial hypertension [PAH])

• Moderate-to-severe hepatic insufficiency (Child-Pugh score B-C) • Concomitant potent CYP3A inducers or substrates (e.g., alfuzosin, amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, ergots, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, sildenafil, oral midazolam, triazolam)

PIs Darunavir (Prezista)

Contraindication

PIs (cont’d)

Delavirdine mesylate (Rescriptor)

Nevirapine (Viramune)

Medication and classification

Adapted from eMPR.com. Antiretroviral contraindications and drug interactions chart. Available at www.empr.com/antiretroviral-contraindications-and-drug-interactions /article/158625/, accessed July 15, 2011.

54 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

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TABLE 2. Dose adjustments needed between antiretroviral therapies and rifamycins Rifampin (normal daily dose 600 mg)

Rifabutin (daily, unless mentioned; normal daily dose 300 mg)

NRTIs

Caution when using with triple nucleoside therapy

Normal rifabutin dose

Efavirenz (Sustiva)

Dose efavirenz at 600-800 mg

Increase rifabutin dose to 450-600 mg Normal efavirenz dose

Nevirapine (Viramune)

Can probably be used at normal nevirapine dose

Normal dose of each

Delavirdine (Rescriptor)

Contraindicated

Amprenavir (Agenerase)

Contraindicated

Decrease rifabutin to 150 mg

Atazanavir (Reyataz)

No data

Decrease rifabutin to 150 mg thrice weekly

Indinavir (Crixivan)

Contraindicated

Decrease rifabutin to 150 mg, increase indinavir to 1,000 mg every eight hours

Nelfinavir (Viracept)

Contraindicated

Decrease rifabutin to 150 mg

Saquinavir (Fortovase, Invirase)

Can use with low-dose ritonavir “boost”

Normal rifabutin dose

Ritonavir (Norvir)

Use only at full dose

Decrease rifabutin to 150 mg two times weekly

Lopinavir/ritonavir (Kaletra)

Probably can be used with dose increased to 400/400 mg or 800/200 mg

Decrease rifabutin to 150 mg three times weekly

Adapted from de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med. Med. 2004;55:283-301.

TABLE 3. 3. Recommendations on concomitant use of antiretrovirals and statins Antiretroviral

Statin Atorvastatin (Lipitor)

Pravastatin (Pravachol)

Simvastatin (Zocor)

Rosuvastatin (Crestor)

Lovastatin (Altocor, Altoprev, Mevacor)

Lopinavir/ritonavir (Kaletra)

Start with 10 mg

Standard dose

Not recommended

Standard dosing

Not recommended

Nelfinavir (Viracept)

Start with 10 mg

Standard dose

Not recommended

Standard dosing

Not recommended

Ritonavir (Norvir) + saquinavir (Fortovase, Invirase)

Start with 10 mg

Standard dose

Not recommended

Standard dosing

Not recommended

Ritonavir-boosted PIs

Start with 10 mg

Standard dose

Not recommended

Standard dosing

Not recommended

Efavirenz (Sustiva)

Start with 10 mg

Standard dose

Standard dosing

No data available

Delavirdine (Rescriptor)

Use lowest possible dose

No data available

Not recommended

Standard dosing

Not recommended

Adapted from HIVwebstudy.org. Drug-drug interactions. Available at depts.washington.edu/hivaids/drug/case5/discussion.html. Accessed July 15, 2011.

Medications for psychiatric conditions. Many HIVinfected individuals complain of anxiety and depression. Agents used to treat these conditions have many interactions with HAART that the clinician must be understand before prescribing. • Benzodiazepines. Such benzodiazepines as midazolam (Versed), triazolam (Halcion), alprazolam (Xanax),

and diazepam (Valium) can reach high levels of toxicity when used concomitantly with HIV antiretrovirals. Lorazepam (Ativan) and temazepam (Restoril) are safer alternatives.9 • Anticonvulsants. The antiseizure medications phenytoin (Dilantin), carbamazepine (Tegretol) and phenobarbital (Solfoton) are CYP450 inducers that can render some

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 57

ANTIRETROVIRAL DRUG INTERACTIONS

Establish a respectful relationship with a patient taking HIV medications so recreational drug use can be discussed in a constructive manner. PIs and NNRTIs ineffective. PIs may decrease levels of phenytoin. To avoid possible drug interactions, consider valproic acid (Depakote), lamotrigine (Lamictal), or levetiracetam (Keppra).10 • Antidepressants. When taken with PIs—especially ritonavir—doses of medications in the SSRI classification might result in increased serum levels of antidepressants. This is a result of ritonavir being an inhibitor of 2D6 and CYP 3A4 pathways—the same pathway used for metabolism of most SSRIs.4 The Columbia University Medical Center publication Psychiatric Medications and HIV Antiretrovirals: A Guide to Interactions for Clinicians is an excellent source of information when prescribing an antidepressant for a patient on HAART therapy.11 Oral contraceptives. HIV-positive women taking efavirenz, nevirapine (Viramune), nelfinavir (Viracept), ritonavir, and lopinavir while using oral birth control that contains ethinyl estradiol or other forms of estrogen should be cautioned that these drugs may reduce hormone levels low enough to cause pregnancy.12 HIV-positive women taking the aforementioned antiretrovirals should be advised to use an additional method of birth control. Suggested contraceptives include combination estrogen/progesterone pills, progesterone-containing pills, or a barrier method (i.e., condoms). Erectile dysfunction drugs. Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are commonly prescribed drugs for complaints of erectile dysfunction (ED). It is important to be aware that concentrations of these agents—especially sildenafil—are elevated when co-administered with PIs.10 ED drugs should be used less frequently and in lower doses by patients taking this classification of HIV medicine. Migraine headache medications. Drug levels of such ergot alkaloid derivatives as ergotamine (Cafergot) and

●

HIV medication can cause—and is affected by—alterations of the cytochrome P450 enzymes in the liver.

●

Statin concentrations can be increased to dangerous levels when used with protease inhibitors (PIs).

dihydroergotamine (Migranal) can be increased if coadministered with PIs. This combination of medications should be avoided. The anticonvulsant topiramate (Topamax, Topiragen) can be given instead, because it does not interfere with HIV medications that depend on liver metabolism.10 Heart medicine. Many patients are prescribed calciumchannel blockers (CCBs) for hypertension, angina, and cardiac rhythm disorders. PIs can increase the serum levels of these drugs. Close monitoring of individuals using both of these medications is recommended. Most of the agents taken for heart disease do not interact with NNRTIs or PIs. CCBs, however, need to be used with caution. Amlodipine (Norvasc) has minimal CYP3A4 metabolism and is safe to prescribe. Blood levels of cardizem (Diltiazem) and verapamil (Calan, Covera, Isoptin, Verelan) may be increased by concomitant use with antiretrovirals and should be avoided.10 Recreational and street drugs. Few studies show the interaction between HAART therapy and recreational drug use. There is some evidence that ritonavir can increase the concentration of the drug ecstasy (MDMA), which can lead to high levels of agitation, seizures, and increased heart rate.13 It is important to establish a respectful relationship with a patient taking HIV medications so recreational drug use can be discussed in a constructive manner. Methadone. Levels of methadone are reduced by the NNRTIs efavirenz and nevirapine. The plasma concentration of methadone may be reduced to a level at which withdrawal symptoms start to become evident. This occurs because methadone undergoes hepatic biotransformation by the CYP450 system.14 Since this is the same system used by many HIV antiretroviral medications, interactions between the two medications can cause the patient to feel as if their methadone is either too strong or weakened. Collaboration between the patient’s methadone clinic and the prescribing practitioner is vital. Herbal therapies. St. John’s wort, an herbal supplement used to treat depression, is associated with a significant decrease in levels of indinavir (Crixivan). St John’s wort should not be used with HIV medications in the NNRTI or PI classification.15

●

Benzodiazepines can reach high levels of toxicity when used concomitantly with HIV antiretroviral drugs.

Conclusion

●

PIs can increase the serum levels of calcium channel blockers, so close monitoring is recommended.

AT A GLANCE

Obviously, no clinician can memorize every possible drug interaction. Having worked with HIV patients and medications every day for years, I still find it difficult to keep up

58 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

St John’s wort should not be used with HIV medications in the non-nucleoside reverse transcriptase inhibitor or protease inhibitor class. with the ever-expanding list of interactions. A Web site created by the University of California, San Francisco, offers a useful database of antiretroviral drug interactions that have been reported in published articles, abstracts from major conferences, or presented to the FDA (generally reflected in product labeling). The database is searchable by antiretroviral drug, interacting drug, or interacting drug class.16 ■

10. Rainey PM. HIV drug interactions: the good, the bad, and the other. Ther Drug Monit. 2002;24:26-31. 11. Columbia University HIV Mental Health Training Project. Psychiatric medications and HIV antiretrovirals: a guide to interactions for clinicians. Available at www.columbia.edu/cu/hivmentalhealthtraining/pdf /Drug_Interactions.pdf 12. AIDS Education and Training Centers. Antiretroviral medications and hormonal contraceptive agents. Available at www.aidsetc.org/

Mr. Graham is a family nurse practitioner with Associates in Family Health Care, a rural health clinic that provides care to a medically underserved population in Westmoreland County Pennsylvania.

aidsetc?page=cg-703_contraceptive_agents. 13. Antoniou T, Tseng AL. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacother. 2002;36:1598-1613. 14. Pinzani V, Faucherre V, Peyriere H, Blayac JP. Methadone withdrawal symp-

References

toms with nevirapine and efavirenz. Ann Pharmacother. 2000;34:405-407.

1. Centers for Disease Control and Prevention. Diagnoses of HIV infection

15. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and

and AIDS in the United States and dependent areas, 2009. Available at

St John’s wort. Lancet. 2000;355:547-548.

www.cdc.gov/hiv/surveillance/resources/reports/2009report/index.htm.

16. HIV InSite. Database of antiretroviral drug interactions. Available at

2. National Institute of Allergy and Infectious Diseases. Classes of HIV/

hivinsite.ucsf.edu/insite?page=ar-00-02.

AIDS antiretroviral drugs. Available at www.niaid.nih.gov/topics/HIVAIDS/ Understanding/Treatment/pages/arvdrugclasses.aspx.

All electronic documents accessed July 15, 2011.

3. AIDS Education and Training Centers. Drug-drug interactions with HIV-related medications. Available at www.aidsetc.org/ aidsetc?page=cg-702_drug-drug_interactions. © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

4. HIVGuidelines.org. HIV drug-drug interactions. Available at www. hivguidelines.org/clinical-guidelines/adults/hiv-drug-drug-interactions/. 5. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 10, 2011; 1-166. Available at aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. 6. Centers for Disease Control and Prevention. Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morb Mortal Wkly Rep. 2000;49:185-189. Available at www.cdc.gov/mmwr/preview/mmwrhtml/ mm4909a4.htm. 7. National AIDS Treatment Advocacy Project. HIV has as much impact on heart health as traditional risk factors. Available at www.natap.org/2009/ CROI/croi_26.htm. 8. Dubé MP, Sprecher D, Henry WK, et al. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis. 2000;31:1216-1224. Available at cid. oxfordjournals.org/content/31/5/1216.long. 9. Farber EW, McDaniel JS. Clinical management of psychiatric disorders in patients with HIV disease. Psychiatr Q. 2002;73:5-16.

“O.K., Mom, I’m off the plane. I’ll call you when I check into the hotel, and when I check out of the hotel, when I get on the plane home, and when I get off the plane home, and I’ll call you when I’m in the driveway —glad you’re not worrying.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 59

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum AUGUST 2011

Consultations One pill to treat hypertension and migraine . . . . . . . . . . . . . . . . . .62 New-onset alopecia in women . . . . . .62 Fish oil for gallstones? . . . . . . . . . . . .62 When to repeat Pap smear . . . . . . . . .70 What to do after a positive FOBT . . .70 Dialysis access when both arms have shunts . . . . . . . . . . . . . . . . . . .70 Intertriginous warts . . . . . . . . . . . . . .70 Vitamin B12 deficiency caused by metformin . . . . . . . . . . . . . . . . .71 And more . . . . . . . . . . . . . . . . . . . . .71

Clinical Pearls Remember to HALT SLIPS in older patients . . . . . . . . . . . . . . . . . .74

Your Comments Antibiotics have no effect on oral contraceptives . . . . . . . . . . . . . .74 Emergency contraception is not an abortifacient . . . . . . . . . . . . . . . .74

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

CONSULTATIONS CAUSES OF DELIRIUM Is it possible to have a geriatric patient in serious delirium while all labs and urinalysis are within normal limits?— LINDA MANJARREZ, EdD, RN-PC, Sudbury, Mass. Many predisposing factors unrelated to an acute infection can cause delirium. Such medications as anticholinergics, anticonvulsants, antidepressants, antihistamines, antipsychotics, barbiturates, opioid analgesics, H2 receptor antagonists (e.g., cimetidine [Tagamet]), corticosteroids, and anti-Parkinson’s drugs can put older adults at higher risk for developing delirium. Be alert for illicit drug use as well. Abrupt withdrawal of alcohol or benzodiazepines can also cause acute confusion. Disorders that contribute to the development of delirium include an acute pulmonary or cardiac event, fecal impaction, and urinary retention. A fall that may have resulted in a closed head injury should also be considered. Always reconcile medications the patient is taking with the family to ensure accuracy. The presence of dementia increases the risk of delirium two to three times.—Deborah L. Cross, MPH, CRNP, ANP-BC (154-01)

WHAT TO DO WITH AN ELEVATED HOMOCYSTEINE LEVEL What are the consequences of elevated homocysteine in young asymptomatic patients with and without comorbidities?

OUR CONSULTANTS

Bruce D. Askey, MSN, CRNP, is

Rebecca H. Bryan, APRN, CNP, is a

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD, is clinical

Peter F. Cohn, MD, is chief of

a clinician in the Department of Hepatology/ Gastroenterology at the Guthrie Clinic in Sayre, Pa.

lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia

associate professor of dermatology, University of Texas Medical Center, Houston.

cardiology and professor of medicine at State University of New York at Stony Brook.

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Deborah L. Cross, MPH, CRNP, ANPBC, is associate

program director, gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia

JoAnn Deasy, PA-C, MPH,

Virginia H. Joslin, PA-C, MPH, is

a primary-care clinician, teaches in the PA program at Pace UniversityLenox Hill Hospital, New York City.

assistant professor and PA Program division director at Emory University School of Medicine in Atlanta.

When do you treat? What further workup is necessary with an elevated homocysteine?—ATUL SHARMA, PA-C, MMS, MPH, CHES, Sacramento, Calif.

one-month waiting period if it is not given with the other immunizations—live or attenuated.—LAURIE L. PIEPER, ARNP-c, Tempe, Ariz.

Persons with coronary heart disease or stroke commonly have elevated homocysteine levels. Homocysteine may contribute to atherosclerosis by damaging the inner layer of arterioles. Elevated homocysteine was shown to be a strong, independent risk factor for cardiovascular disease (CVD) in large cohort and retrospective studies. This led to the hypothesis that lowering homocysteine levels would reduce risk for cardiovascular events. Homocysteine is readily reduced by administration of folic acid supplements with or without B vitamins. Several studies looking at such interventions have shown significant reductions in homocyteine levels; however, no reduction in cardiovascular events was seen up to five years out. Homocysteine may be a marker for CVD rather than a cause. Further study is needed. For more information, see Arch Intern Med. 2010;170:1622-1631. Meanwhile, it is prudent to discuss overall risk of CVD with patients who have elevated homocysteine; emphasize the need to exercise, avoid smoking, and take extra B vitamins, especially if the patient has a family history of CVD.—Claire Babcock O’Connell, MPH, PA-C (154-02)

It is recommended that MCV4 be administered with other vaccines that are indicated during the same visit when feasible. There are two MCV4 vaccines available: Menactra and Menveo. Both use a diphtheria protein as the conjugate protein. In prelicensure studies, administering Td and MCV4 simultaneously, or Td first followed by MCV4 one month later, were acceptable safe practices. If simultaneous vaccination is not feasible, inactivated vaccines can be administered any time before or after a different inactivated or live vaccine. Because Tdap (or Td) and MCV4 all contain diphtheria toxoid, a person who recently received one diphtheria toxoidcontaining vaccine could theoretically have increased rates of adverse reactions after a subsequent diphtheria-toxoid-containing vaccination when diphtheria antibody titers remain elevated from the previous vaccination.—JoAnn Deasy, PA-C, MPH (154-03)

IS SIMULTANEOUS VACCINATION ALWAYS NECESSARY? In adolescents aged 11 to 14 years, must the human papillomavirus; meningococcal (MCV4); tetanus, diphtheria, and pertussis (Tdap); and, if needed, varicella vaccines be given simultaneously? A speaker at a recent conference mentioned that because of the components of the MCV4 and Tdap, it was recommended that both be given at the same time or one month apart to allow a full antibody response. It is understood that a live vaccine (i.e., varicella) should have a

Susan Kashaf, MD, MPH, is assistant

Debra August King, PhD, PA, is senior

professor of medicine, Yale University School of Medicine, New Haven, Conn.

physician assistant, New YorkPresbyterian Hospital, New York City.

Claire Babcock O’Connell, MPH, PA-C, is an

associate professor, University of Medicine and Dentistry of New Jersey, PA program, Piscataway.

Sherril Sego, FNP-C, DNP, is a

primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

EXTENDED USE OF PPIS What are the consequences of taking proton pump inhibitors (PPIs) over an extended period of time? It seems we start patients on these medications and never discontinue them.— CHERIE HOWK, PhD, FNP-BC, Terre Haute, Ind. The use of PPIs is indeed extensive and increasing. PPIs are often initiated by primary-care providers for the management of dyspeptic symptoms or gastroesophageal reflux disease, or as prophylactic treatment for patients who are taking long-term nonsteroidal antiinflammatory drugs. Up to 33% of patients who start PPI therapy refill prescriptions without an obvious indication for maintenance therapy. Rebound acid hypersecretion (RAHS) is defined as an increase in gastric-acid secretion above pretreatment levels after anti-

Lisa Stern, APRN,

is a nurse practitioner with Planned Parenthood Los Angeles.

Daniel G.Tobin, MD, is assistant

Julee B.Waldrop, DNP, is associate

professor of medicine, Yale University School of Medicine, New Haven, Conn.

professor at the University of Central Florida (UCF), Orlando, and practices pediatrics at the UCF Health Center.

Reuben W. Zimmerman, PA-C, is a full-time

practitioner with Esopus Medical, PC, an independent family practice in Rifton, N.Y.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 61

Advisor Forum secretory therapy. RAHS is observed in patients within two weeks of stopping PPIs and could theoretically lead to such acid-related symptoms as dyspepsia, acid regurgitation, or heartburn and result in restarting treatment with a PPI. In one study, acid inhibition with a PPI for eight weeks was shown to induce acid-related symptoms in a significant number of asymptomatic subjects after withdrawal of therapy (Gastroenterology. 2009;137:80-87). The theory that PPI dependency could contribute to the extensive use of long-term PPI needs to be investigated further.—Eileen F. Campbell, MSN, CRNP (154-04)

ONE PILL TO TREAT HYPERTENSION AND MIGRAINE A hypertensive patient with migraines experienced undesirable side effects (irritability and weight gain) while taking the nonselective beta-blockers nadolol (Corgard) and propranolol (Inderal). The calcium-channel blocker verapamil (Calan, Verelan, Isoptin, Covera) was unsuccessful in controlling the patient’s hypertension. Is there a single medication that will treat both conditions?—TODD E. BERENDS, NP, Holland, Mich. Angiotensin II receptor blockers (ARBs) (JAMA. 2003;289:6569; available at jama.ama-assn.org/content/289/1/65.long, accessed July 15, 2011) and angiotensin-converting enzyme (ACE) inhibitors (BMJ. 2001;322:19-22; available at www .bmj.com/content/322/7277/19.long, accessed July 15, 2011) have been shown to provide effective migraine prophylaxis. These two classes of drugs are recommended by The Seventh Report of the Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure (available at www.nhlbi.nih.gov/guidelines/hypertension, accessed July 15, 2011) for the treatment of hypertension and thus may be reasonable options for the hypertensive patient with migraine headache.—Eileen F. Campbell, MSN, CRNP (154-05)

NEW-ONSET ALOPECIA IN WOMEN What is the appropriate workup in an otherwise healthy woman aged 75 years with new-onset hair loss? What medications might be contributory?—MARY ELLEN WILKOSZ, RN, FNP-BC, PhD, Novato, Calif. The approach to evaluating hair loss in women has recently been reviewed (Dermatol Nurs. 2007;19:531-535 and J Fam Pract. 2009;58:378-380). Alopecia areata, androgenic alopecia, and telogen effluvium are the most common forms of nonscarring alopecia; other causes include hair-shaft abnormalities, traction alopecia, tinea capitis, and trichotillomania. Discoid lupus erythematosus, infections (bacterial and inflammatory fungal), lichen planus, local surgery, morphea, neoplastic disease (cutaneous metastases and skin cancer), and trauma (burn or injury) are disorders associated with scarring alopecia. Similar to the new onset of alopecia in men, the workup begins with a comprehensive history that includes family history, hair-care practices, endocrine dysfunction (thyroid disease), chronic systemic illnesses, dermatologic conditions (lichen planus and lupus erythematosus), and medications (anticoagulants, nonsteroidal anti-inflammatory drugs, beta-blockers, H2 receptor antagonists, neoplastic drugs, hormones, retinoids, and antihyperlipidemic agents) (Int J Dermatol. 1995;34:149-158). A scalp biopsy may be useful—especially if a scarring alopecia is suspected (Can Fam Physician. 2000;46:1469-1477; available at www.cfp.ca/content/46/7/1469.long, accessed July 15, 2011). —Philip R. Cohen, MD (154-06)

FISH OIL FOR GALLSTONES? Is there any reason an adult with gallstones should not take fi sh-oil supplements?—TERRI FROCK, EdD, MSN, ARNP-BC, Lighthouse Point, Fla. Even though diets rich in fats are often seen as a trigger for gallbladder disease and acute cholecystitis, omega-3 fatty acids and other monounsaturated fats are thought to lower the risk of developing gallstones. Specifically, fish oils are being studied for their potential to improve the kinetic action of the gallbladder, especially in patients with elevated triglycerides.—Sherril Sego, FNP-C, DNP (154-07) Frontal abdominal x-ray shows lithiasis in the gallbladder.

62 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

Continues on page 70

Advisor Forum

Enlarged cervical cell nuclei (black) is a sign of abnormal cell division.

WHEN TO REPEAT PAP SMEAR When reviewing Pap smear results with absent endocervical cells, what is the recommended next step? If repeat testing is advised, how soon should it be done?—JACKIE SHUEY, PA-C, Tacoma, Wash. The Bethesda System represents the accepted standards for evaluating Pap smears of cervical tissue. Specimens are reported as either adequate or inadequate. To be deemed adequate, a specimen must contain endocervical or transition-zone cells. Specimens are otherwise deemed inadequate, and patients must be rescreened. There are no time parameters to rescreening in this instance, as the issue is one of specimen collection, not pathology. More information can be found through the National Cancer Institute (nih.techriver.net, accessed July 15, 2011).—Claire Babcock O’Connell, MPH, PA-C (154-08)

WHAT TO DO AFTER A POSITIVE FOBT A man aged 52 years has a positive fecal occult blood test (FOBT) just two years out from a normal colonoscopy screening. He has no GI symptoms, does not take aspirin or nonsteroidal anti-inflammatory drugs, and has a normal blood count. Should this patient be referred back to gastroenterology?—KIM HORTON, PA-C, Boston There are a few issues to address here. First, why did this patient have a FOBT so soon after a normal colonoscopy? The use of FOBT within five years of a negative colonoscopy is discouraged (CA Cancer J Clin. 2006;56:143–159; available at caonline. amcancersoc.org/cgi/content/full/56/3/143, accessed July 15, 2011; Gastrointest Endosc. 2007;6:757–66).

Second, the use of standard FOBT is no longer recommended, as the use of newer guaiac and fecal immunochemical testing are preferred because of their higher sensitivity. The recent guideline developed jointly by the American Cancer Society, the MultiSociety Task Force on Colorectal Cancer, and the American College of Radiology explicitly recommends that screening be limited to tests that have single-application sensitivity for cancer >50%, thus excluding standard guaiac tests as an acceptable option (Gastroenterology. 2008;134:1570–1595; Am J Gastroenterol. 2009;104:739-750). Finally, any positive FOBT needs to be followed up with a colonoscopy. Refer the patient back to gastroenterology.—Sharon Dudley-Brown, PhD, FNP-BC, co-director, gastroenterology & hepatology, nurse practitioner fellowship program, Johns Hopkins University Schools of Medicine & Nursing, Baltimore (154-09)

DIALYSIS ACCESS WHEN BOTH ARMS HAVE SHUNTS If a patient has a nonfunctional arteriovenous (AV) shunt in one arm and a functional shunt used for dialysis in the other, does the avoidance of an IV access in the arm with the nonfunctional shunt still apply? If the extremity with the nonfunctional shunt were used for IV therapy, would this impact any future plans for using that extremity for a shunt if the patent one fails? I have always been taught that the affected arm should not be accessed. However, if both extremities are excluded due to shunts, available IV access is a huge challenge.—PEGGY GUIN, PhD, ARNP, Gainesville, Fla. It is acceptable to use the arm with the nonfunctioning AV fistula for IV access. However, care must be taken not to use the specific vein that is occluded (typically, the cephalic or basilic vein). Carefully examine the vein, and complete a vascular duplex ultrasonography study for patency and flow. If the vein is suitable in size/caliber but has questionable patency, consider placing an AV graft. Aside from the cephalic and basilic veins, other veins in the arm and hand are usable for IV access. If the IV is temporary, veins in the feet or ankles are alternative points of access. A portable ultrasonography or a vascular Doppler at bedside may assist in vein location and identification for difficult cases.—Debra August King, PhD, PA (154-10)

INTERTRIGINOUS WARTS Which type of human papillomavirus (HPV) is associated with nonmucosal, condyloma acuminatum-appearing warts found under the pannus in intertriginous areas? Is there an

70 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

HPV can be associated with genital and mucosal lesions or with nongenital lesions. The former are most commonly observed clinically as bowenoid papulosis, cervical intraepithelial neoplasia (CIN), cervical cancer, condyloma acuminatum, giant condyloma of Buschke and Lowenstein, laryngeal papilloma, and oral papilloma; these lesions are most frequently associated with HPV types 6, 11, 16, and 18. Nongenital (nonmucosal) lesions can present in such various settings as Bowen’s disease, common warts, epidermodysplasia verruciformis, flat warts, myrmecia warts, plantar warts, and squamous cell carcinoma. Although certain HPV types are more commonly associated with each of the specific clinical lesions, many reviews do not describe the HPV type(s) associated with condyloma acuminatum-appearing warts found under the pannus in intertriginous areas (J Cutan Med Surg. 2001;5:43-60, and Int J Dermatol. 2001;40:373-379). The risk for genital cancer is usually related to the HPV type. HPV types 6 and 11 have been associated with CIN, and HPV types 16 and 18 are more commonly observed in cervical cancer. However, some of the other HPV types that have been less frequently associated with either CIN or cervical cancer include 30, 31, 33, 35, 39, 41, 43, 45, 51, 52, 54, 56, 58, 59, 62, 66, and 67.—Philip R. Cohen, MD (154-11)

VITAMIN B12 DEFICIENCY CAUSED BY METFORMIN Evidence shows that chronic use of metformin (longer than one year) causes vitamin B12 deficiency. I routinely screen all my diabetic patients for a B12 level, especially those with complaints of neuropathy. What is the treatment goal for B12 in a patient with diabetic neuropathy, given the wide range of normal (200-950 pg/mL)? If a patient’s B12 is on the lower end of normal and the methylmalonic acid (MMA) level is normal, would you treat him or her? Would you routinely draw a methylmalonic acid level with every B12 level?— KRISTIN ANDRS, NP, CCRN, CDE, Richmond, Va. In approximately 30% of diabetics, metformin blocks absorption of vitamin B12 by inhibiting calcium-channel pathways in the intestines. It is most appropriate to treat these patients with both calcium and vitamin B12 supplementation. Unfortunately, there is no research or guideline to tell us what B12 levels are optimal. It is known that MMA levels begin to rise when B12 is <400 pg/mL and that neurologic impairment begins at the same level. It seems reasonable to get patients above that. With regard to simultaneously testing MMA and B12, it depends on the insurance companies—will they

cover MMA before it is known if the patient is B12 deficient? I have had a number of symptomatic patients with B12 levels <400 pg/ mL who have normal MMA measurements. I treat B12 deficiency regardless of MMA level, especially since there is a limited window of opportunity to reverse neurologic impairment.—Rebecca H. Bryan, APRN, CNP (154-12)

SEROTONIN SYNDROME IN DEPRESSED PATIENTS WITH MIGRAINE How concerned should clinicians be about serotonin syndrome when prescribing a triptan with a selective serotonin reuptake inhibitor (SSRI)? Some patients with migraines are also depressed. Triptans work well, but I am reluctant to prescribe them with an SSRI. Trials of amitriptyline (Elavil, Endep, Vanatrip) and other tricyclic antidepressants (TCAs) for migraine prophylaxis have failed.—MELISSA HEUBERGER, FNP-C, McMinnville, Ore. SSRIs, selective norepinephrine reuptake inhibitors (SNRIs), and triptans increase levels of serotonin independently. The combination of these medications can cause serotonin syndrome in some patients. The risk of this occurring is increased when starting or increasing doses of the SSRI, SNRI, or triptan. While use of triptans with SSRIs and SNRIs is not contraindicated, the FDA recommends that patients are informed of the possibility of serotonin syndrome. Serotonin syndrome occurs when high levels of serotonin stimulate peripheral and central postsynaptic serotonin receptors. Symptoms include mental status changes, hyperactivity of the autonomic system, and neuromuscular dysfunction. Symptoms may range from mild © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

associated risk for cervical or oropharyngeal cancers?— TIFFANY C. COUGHENOUR, PA-C, Idaho Falls

“See? It never hurts to ask.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 71

Advisor Forum to life-threatening. TCAs have also been associated with serotonin syndrome.—Eileen F. Campbell, MSN, CRNP (154-13)

CLINICAL PEARL REMEMBER TO HALT SLIPS IN OLDER PATIENTS Here is a useful mnemonic device to help prevent falls in older patients: Home safety Ask about falls at least yearly. Look for and treat vitamin D deficiency. Treat osteoarthritis. Stop or reduce problem medications. Look for orthostatic hypotension. Immobility must be avoided; promote exercise. Prevent and treat osteoporosis. Stop pain wherever possible.—KATHY KEMLE, PA-C, Augusta, Ga. (154-14)

YOUR COMMENTS

ANTIBIOTICS HAVE NO EFFECT ON ORAL CONTRACEPTIVES Studies have shown (Am J Obstet Gynecol. 1991;164:28-33, and J Am Acad Dermatol. 1997;36:705-710) that the use of such broad-spectrum antibiotics as amoxicillin and tetracycline do not reduce the efficacy of oral contraceptives (OCs) (Item 152-12). While it is true that lower serum ethinyl

“How about moving in a little closer?”

estradiol and progestin levels have been found in women using combination OCs and antibiotics, these women remain well within the therapeutic window. The World Health Organization’s Medical Eligibility Criteria for Contraceptive Use (available at whqlibdoc.who.int/publications/2010/9789241563888_eng.pdf, accessed July 15, 2011) and the CDC’s U.S. Medical Eligibility Criteria for Contraceptive Use (available at www.cdc.gov/mmwr/pdf/rr/rr59e0528. pdf , accessed July 15, 2011) classify antibiotics (with the exception of rifampicin and griseofulvin) as Category 1 (no restrictions on use). Too often, women using antibiotics frequently or chronically simply stop their combination OC, thereby putting themselves at risk for pregnancy.—BETH KUTLER, FNP-C, Ithaca, N.Y. It is true that, thankfully, most current sources agree that antibiotic use does not inactivate OCs. However, it is also true that the typical OC doses are now much lower than they used to be, and many times clinicians cannot assure the dosing adherence of our patients with those low-dose pills. Consequently, we may be unwittingly putting patients at risk of unintended pregnancy in cases where hormone levels may already be precarious and, when nudged a little lower by concomitant medications, fail to do their job. Two other classes of drugs that are rapidly rising in use are antiepileptics and atypical antipsychotics. As strong competitors in the cytochrome P450 chain, these drugs have significant impact on the metabolism of OCs, and careful consideration should be given to using a higher-dose OC or alternative method in patients using these medications.—Sherril Sego, FNP-C, DNP (154-15)

EMERGENCY CONTRACEPTION IS NOT AN ABORTIFACIENT The opening sentence of the June 2011 Commentary (“Emergency contraception: just a hoax?”), “Emergency contraception is no more contraception than abortion,” illustrates the misunderstanding surrounding the pharmacology of this medication. The erroneous belief that emergency contraception is an abortifacient may be one reason why it is underutilized. While I completely agree with the author’s desire for women to be responsible for their actions, after-thefact contraception is still preferable to an unwanted pregnancy and/or abortion. The author later states that emergency contraception is sometimes confused with the abortion pill, so it appears that she understands the difference, but the lead sentence only serves to confuse the issue.—BARBARA FARLEY, NP, Norman, Okla. (154-16) ■

74 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

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Derm Dx Challenge Test your clinical acumen with our monthly quizzes

Hyperpigmentation with dizziness, fatigue, and nausea A white woman aged 40 years presents to her primary-care provider with chief complaints of fatigue, dizziness, nausea, and vomiting. She has hyperpigmented skin on her face, oral mucosa, elbow, and axillae. What is your diagnosis?

• • • •

Acanthosis nigricans Lentigo Melasma Addison’s disease

A boy aged 7 years presents with knee pain and a rash on his lower extremities. The rash started two days earlier as small red spots and progressed to raised maculopapular areas mixed with urticarial wheals. What is your diagnosis?

• • • •

Rheumatic fever Rocky Mountain spotted fever Henoch-Schönlein purpura Lyme disease

To post your answer, obtain more clues, or view similar cases, visit www.ClinicalAdvisor.com/derm-dx. Learn more about diagnosing and treating these conditions, and see how you compare with your peers.

Jamie Tripp, an ARNP in Seminole, Fla., entered the July Derm Dx contest and won an Apple iPad. “Since this is my first year of practice as a family ARNP, I learn something every day. These challenges expose me to new conditions that I may see in my patients.”

78 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

Test your clinical acumen with our monthly quiz

CME Dermatology Clinic CE

■ LEARNING OBJECTIVES: To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment. ■ COMPLETE THE POSTTEST: Page 115

■ ADDITIONAL CME/CE: Pages 31, 111

CASE #1

Multiple blisters on the hands and abdomen ESTHER STERN, NP-C

A disoriented man aged 82 years was brought in by his wife after she noticed several nickel-sized blisters on his abdomen and smaller blisters on his hands. She reported that the blisters appeared suddenly one week earlier. Some had since ruptured and become itchy. The man had not started any new medications or suffered trauma to the affected area. On exam, several tense clear bullae were noted on his upper abdomen, flanks, and dorsal hands. The underlying skin appeared normal with no erythema, induration, or inflammation appreciated. Scattered erosions were also noted on the patient’s lower back. What is your diagnosis? Turn to page 80.

CASE #2

Home surgery leads to persistent neck mass JOE MONROE, PA-C

A man aged 70 years presented with a slightly tender neck mass that had developed in the same location as a pea-sized nodule. The nodule had been present for at least 20 years and caused no problems until the patient tried to squeeze out the contents at home. The man reported no illness, was afebrile, and otherwise felt healthy. Other than the original nodule, he had no history of other similar lesions. The “boil” persisted despite two courses of oral antibiotics (cephalexin [Keflex] and trimethoprim/sulfamethoxazole [Bactrim, Septra]). A culture of the pus produced by the lesion showed mixed flora. What is your diagnosis? Turn to page 81. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 79

CME CE

CASE #1

Dermatology Clinic

Bullous pemphigoid

Bullous pemphigoid (BP) is an uncommon chronic autoimmune inflammatory skin disease. BP is characterized by the subacute or acute appearance of large, tense vesicles with a predilection for the groin, axillae, trunk, thighs, and flexor surfaces of the forearms. After the bullae rupture, large denuded areas remain. These areas heal spontaneously without scarring or milia formation. In some patients, there are scattered erythematous patches and urticarial plaques. Significant pruritus is frequently present. Several distinct clinical forms of BP exist. In the most frequent generalized bullous form, tense bullae arise on normal-appearing or erythematous skin anywhere on the body. Oral and mucosal involvement, if present, is minimal. In the vesicular form, small tense vesicles are present on urticarial or inflamed skin. The vegetative verrucous subtype is uncommon, and the disease is manifested in the intertriginous areas. Persistent urticarial lesions with or without conversion to bullous eruptions characterize the urticarial form. Rarely, BP may be manifested as a generalized erythroderma, a nodular eruption, or a disease limited to the acral skin only. BP has no racial or sexual predilection. It generally affects older adults in the fi fth through seventh decades of life, with an average age at onset of 65 years. There are case reports of childhood-onset BP. Untreated, BP persists over a five- to six-year period, often with spontaneous remissions and exacerbations. If treated, the disease usually remits within 18 months to five years, although relapses may occur. Immunoglobulin (Ig)G autoantibodies attach to the basement membrane zone of the skin. This activates complement via the classic and alternate pathways, attracting inflammatory mediators. Released proteases and reactive oxygen species from infi ltrating neutrophils degrade local proteins and lead to blister formation. The layer of the basement membrane zone where IgG binding occurs has been localized to the lamina lucida, with accentuation near hemidesmosomes.1 It is thought that the antibodies directed at BP230 (BPAg1) and BP180 (BPAg2)—two hemidesmosomal bullous pemphigoid antigens—are the primary pathogenic factors in BP. In addition, it is postulated

that infi ltrating T-helper lymphocytes may play a role in blister formation. BP has been reported to be precipitated by and localized to areas of radiation, burns, or psoriasis. Medications associated with BP include furosemide (Lasix), nonsteroidal anti-inflammatory drugs, captopril (Capoten), penicillamine, neuroleptics, and antibiotics. BP has been reported to develop shortly after vaccination, particularly in children. Diagnosis of BP is established with histopathologic analysis of skin from the edge of a blister as well as direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. Histologic analysis reveals a subepidermal blister. Superficial dermal infi ltrate contains many eosinophils, although mast cells and basophils may predominate early in the disease course. There is absence of acantholysis.

If treated, bullous pemphigoid usually remits within 18 months to five years, although relapses may occur. DIF is positive for IgG and/or complement C3 deposition in a linear band at the dermal-epidermal junction. Because this pattern may be seen in pemphigus and epidermolysis bullosa acquisita, a repeat DIF study utilizing a salt-split skin preparation should be performed. DIF on salt-split skin localizes IgG to the blister roof (epidermal side) in patients with BP, while in the other bullous disorders, the IgG localizes to the blister floor. Experimental diagnostic procedures, including direct and indirect immunoelectron microscopy, immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay, are available in research laboratories. The goal of treatment is to decrease blister formation with the most minimal dose of therapy necessary. In addition, avoiding trauma to the skin is beneficial. Although there are many treatment options available, relatively few controlled studies have been performed.2 The two most common approaches include the use of anti-inflammatory agents and immunosuppressants. Such anti-inflammatory agents as corticosteroids, tetracyclines, and dapsone obstruct the inflammatory process by inhibiting specific cytokine production and vascular permeability. Such immunosuppressants as azathioprine (Azasan, Imuran),

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Clinical Challenge The effects of two boat trips linger even after coming ashore LAURA E. DAVIS, PA-C, JOSEPH R. DURIO, PA-C, AND DAVID M. BARRS, MD

After vacationing on a houseboat, a woman could not stop feeling like she was rocking, especially when walking.

The rocking sensation was most intense while upright and walking.

Ms. W, aged 35 years, experienced an intense sensation of rocking after spending five days on a houseboat. The sensation was present in all body positions but was most noticeable when she was upright and walking. She had no history of similar motion exposure and had previously taken ocean cruises without difficulty. There was no fluctuation of hearing, tinnitus, ear pressure, or spinning vertigo (either spontaneously or positional). Ms. W was otherwise healthy and had no history of such neurologic conditions as migraine. She had taken no motion sickness medication before or during the cruise. The patient did not seek medical attention, and her symptoms improved slowly over two months without treatment. One year later, Ms. W went on another cruise and had a recurrence of symptoms. Physical examination showed normal tympanic membranes, no cranial nerve abnormalities, and no spontaneous nystagmus; the rest of the neurologic examination was normal, as was a hearing test. Although the patient felt as if she were rocking back and forth, Rhomberg and gait testing were normal. Dix-Hallpike testing for benign paroxysmal positional vertigo (BPPV) was unremarkable. Ms. W underwent vestibular testing that included videonystagmography, rotational chair testing, and computed dynamic posturography. A discussion of these tests is beyond the scope of this case presentation, but all results were normal. Specifically, there was no evidence of a reduced vestibular response on caloric testing, and Ms. W’s balance on the swaying posturography test was also within normal limits. An MRI of the head and a neurologic consultation showed no evidence of a specific central abnormality. The differential diagnosis included BPPV, Ménière disease, recurrent vestibular neuritis, and migraine, but the patient’s symptoms and test results pointed toward none of these. A tentative diagnosis was made of mal de debarquement (MDD). Neither treatment

CASE #1

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Clinical Challenge with such vestibular suppressant medications as meclizine (Dramamine) and diazepam (Valium) nor vestibular rehabilitation physical therapy was helpful. As had happened previously, Ms. W’s symptoms gradually resolved over a two- to three-month period. A recommendation was made to avoid situations involving similar types of motion.

1. ANALYSIS Balance function is a complex system involving input from vision, somatosensory, cervical, and vestibular sensors to the central nervous system, which instantaneously orients the body in space. Common causes of unsteadiness or dizziness include viral labyrinthitis or neuritis, BPPV, Ménière disease, migraine, and disequilibrium of aging (sometimes referred to as “multisensory deficit syndrome”). Patients with such abnormalities in the vestibular system as BPPV or Ménière disease usually present with a sense of spinning or whirling vertigo, whereas a somatosensory abnormality like peripheral neuropathy causes unsteadiness. Disequilibrium of aging is the most common abnormality causing unsteadiness and is marked by a sense of imbalance caused by gradual deterioration of central and peripheral sensory function. Individuals with disequilibrium of aging notice their symptoms almost exclusively when they are ambulating. However, the less well-known syndrome of MDD, consisting of a feeling of rocking, swaying, unsteadiness, and disequilibrium after exposure to motion, should also be considered.1-6 MDD (or “sickness of disembarkment”) has been defi ned as the inappropriate sensation of movement after exposure to motion and it is most commonly felt after a long sea voyage. MDD can also occur after traveling by any means of transportation, including an automobile or an airplane.7 The condition may also be associated with space fl ight, waterbeds, fl ight-simulator training, helmetmounted virtual movement, and rotating rooms.1 For most people, the sense of movement duplicates the inciting motion. For example, patients with MDD after an ocean cruise may feel as if they are still rocking back and forth like the boat on the waves. This feeling may last hours, weeks, or, in rare cases, years.3,6 Symptoms may be improved or alleviated by a return to the precipitating mode of transportation. Patients who experience a rocking sensation after a cruise may feel quite normal once they are back onboard a ship, or even with such other motion as riding in an automobile.6 This temporary symptom relief leads some patients to jokingly request a prescription for a cruise.1

Short-term MDD can be a common occurrence. For example, most cruise passengers initially feel unsteady when the ship is rocked by ocean waves. Within a short period (typically one or two days), they adapt to the ship’s motion. After the cruise ends and they return to shore, passengers may temporarily feel a rocking sensation that usually lasts just minutes to hours. However, a small percentage of travelers can have a prolonged sense of rocking or swaying that lasts weeks to months. The symptom can also relate to the size of the ship. Patients who have recurrent bouts on large ships may be able to tolerate the motion of smaller boats, such as a houseboat, or vice versa, which suggests that the frequency of sway may be a key contributing factor.6,7

2. PATIENT POPULATION AND SYMPTOMS There is no known occupational risk for or protection from MDD symptoms. Even such professional seafarers as sailors and fishermen may experience the sensation after coming ashore.2,3 A study of 116 healthy, seagoing Navy crew members found that 75% experienced transient MDD after disembarkment.8 Of these subjects, 88% had symptom resolution within six hours, and all had symptom resolution within two days. These fi ndings have led some authors to define MDD as abnormal when symptoms last longer than three days, whereas others diagnose abnormality only if MDD symptoms last longer than one month.3,4,6,8 A recent study proposed using the term “prolonged MDD” to describe symptoms lasting three days to one month and “persistent MDD” for symptoms present longer than one month.6 By inference, MDD symptoms lasting up to two days would be considered a normal reaction to such passive motion as that experienced on a cruise. Unlike BPPV, which is marked by the onset of vertigo with head movements, there is no postural inciting factor in MDD. Symptoms can occur in any body position but may be more noticeable when the individual is lying in bed, standing in the shower with eyes closed, or leaning against a stable fi xture.4 MDD differs from seasickness or motion sickness in that symptoms occur only after disembarking rather than during the actual travel. Nausea, vomiting, diaphoresis, and vertigo are absent from the typical presentation. Thus, symptoms are not relieved with such preventive motion sickness medication as meclizine or diphenhydramine (Benadryl).1

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Continues on page 90

Clinical Challenge Patients with MDD may have symptoms of rocking (93%), swaying (81%), imbalance (74%), and tilting (50%).3 They may also experience anxiety, unsteadiness, and difficulty concentrating.6 The disorder does not generally include vertigo, vomiting, excessive sweating, or visual disturbance.3,9 Although most patients can continue their day-to-day functioning and are not totally incapacitated, the disorder is a distinct definable category, clearly separate from spinning vertigo or unsteadiness when ambulating.10 Hain et al3 found the mean duration of MDD symptoms in their patients to be 3.5 years (range, 1-10 years). The average age of patients at symptom onset was 49.3 years (range, 35-72 years), and 26 of 27 patients were women. Otologic symptoms of fullness (73%), tinnitus (69%), hyperacusis (61%), otalgia (42%), and decreased hearing (39%) were experienced by 24 patients at some point after MDD onset.3 In contrast, Ms. W was followed for a relatively brief period and had no changes in otologic or audiologic symptoms. As in Ms. W’s case, Cha et al6 identified no neurologic or vestibular abnormalities in their patients. This study had a predominance of female participants (75%) but a lower incidence than Hain et al3 or Mair2 and a nearly equal incidence of male patients (44%) among persons with symptoms lasting longer than two years. Just over half (51%) of the patients had symptoms lasting longer than one month; 18% had symptoms lasting longer than one year; 15% longer than two years, and 11% longer than five years.6 Repeated exposure to motion—either similar to or different from the precipitating type—may lead to recurrent episodes of MDD. There is some evidence that subsequent episodes may last longer.6 One published case report described MDD in a 71-year-old woman whose symptoms developed after two different cruises two years apart. On both occasions, her symptoms resolved within one month.11 This tendency toward recurrent MDD was the experience of Ms. W as well.

3. PATHOGENESIS Although the cause of MDD has not been identified, several factors have been proposed. MDD may occur because of an abnormal adaptation to motion, otolith dysfunction, migraine, or a psychogenic mechanism.6,10 Other possible causes include hormonal imbalance, central nervous system (CNS) dysfunction, and inner-ear (perilymph) fistula. Of these possible causes, an abnormality of multisensory adaptation is currently the most popular theory. This may

be the result of a memory of the passive motion, essentially a “pseudo-hallucination” from vestibular memory.6,12 CNS adaptation that is defective or delayed after motion ceases may be a causative factor.2,4 In other words, the brain is capable of compensating for the new input of motion but loses the ability to readapt when that motion stops.4 Although MDD differs from seasickness in that symptoms fi rst appear after disembarking, the strong correlation between the susceptibility to seasickness and the occurrence of MDD implies a similar pathogenesis.1 Abnormal perception of linear acceleration, resulting in faulty vestibular input, may also result from a dysfunction of the otolith systems, specifically the utricle.10 Hormonal imbalance has been suspected because of the predominance of women with MDD and the age range of those affected.3 Psychogenic factors have been suspected but do not appear to be a factor.4 The late age at onset and the lack of other medical complaints do not indicate a somatization disorder. The predominance in women is also inconsistent with psychogenic causes, which tend to be more evenly distributed by sex.3 Migraine headaches are strongly associated with motion sensitivity and have a prevalence of 11% in the general public and 20% in women during their reproductive years.10 The 38% prevalence of migraine in one study of MDD patients was twice that in the general female population.6 MDD clearly occurs in healthy persons, particularly women predisposed to migraine.3,10

4. DIAGNOSIS AND TREATMENT Most patients with suspected MDD will have a negative physical examination, including a normal otoscopic ear examination, normal eye movements, no spontaneous or provoked nystagmus, negative Dix-Hallpike testing, and normal vestibulo-ocular reflexes.4,6,7 Further vestibular testing—including computerized dynamic posturography, electronystagmography, and rotational chair testing and MRI—are usually unremarkable.6,10 There is no specific pharmacologic treatment aimed at preventing MDD.3 A survey of patients with clinical features of MDD found that meclizine and scopolamine—medications used to prevent motion sickness—were not effective in 17 and 12 patients, respectively.3 However, it was discovered that such benzodiazepines as clonazepam (Klonopin) were helpful in three of six patients and that such tricyclic antidepressants as amitriptyline (Elavil, Endep, Vanatrip) were successful for two of seven patients in alleviating subjective

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Clinical Challenge 4. Brown JJ, Baloh RW. Persistent mal de debarquement syndrome:

What’s your story? Do you have your own clinical challenge? Your colleagues would love to read about it. Go to www.clinicaladvisor.com and check out our writers’ guidelines.

Click Here

a motion-induced subjective disorder of balance. Am J Otolaryngol. 1987;8:219-222. 5. Murphy TP. Mal de debarquement syndrome: a forgotten entity? Otolaryngol Head Neck Surg. 1993;109:10-13. 6. Cha YH, Brodsky J, Ishiyama G, et al. Clinical features and associated syndromes of mal de debarquement. J Neurol. 2008;255:1038-1044. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2820362. 7. Lewis RF. Frequency-specific mal de debarquement. Neurology. 2004;63:1983-1984. 8. Gordon CR, Spitzer O, Doweck I, et al. Clinical features of mal de debarquement: adaptation and habituation to sea conditions. J Vestib Res. 1995;5:363-369. 9. Haybach PJ. Mal de debarquement. On the Level. Q Newsl Vestib Disord Assoc. 2003;20:1-8. 10. The American Institute of Balance. Classification of audiovestibular symptoms related to migraine, part 2: mal de debarquement syndrome. Available at www.dizzy.com/CMS/file/migraine1.pdf. 11. Teitelbaum P. Mal de debarquement syndrome: a case report. J Travel Med. 2002;9:51-52. 12. Moeller L, Lempert T. Mal de debarquement: pseudo-hallucinations from vestibular memory? J Neurol. 2007;254:813-815. 13. Hillier SL, Hollohan V. Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. Cochrane Database Syst Rev. 2007;4:CD005397. Available at onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/rel0002/ CD005397/frame.html. 14. Cohen HS. Disability and rehabilitation in the dizzy patient. Curr Opin Neurol. 2006;19:49-54. 15. Black FO, Pesznecker SC. Vestibular adaptation and rehabilitation. Curr Opin Otolaryngol Head Neck Surg. 2003;11:355-360. All electronic documents accessed July 15, 2011. © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

symptoms. In the Cha et al6 series, patients rated benzodiazepines as having a small to moderate benefit, whereas antiemetics, tricyclic antidepressants, diuretics, and dietary modifications were considered unhelpful. Other studies recommended vestibular rehabilitation therapy (VRT) or exercise for possible subjective relief.2,5 VRT is occupational or physical therapy designed to promote central adaptation to various balance problems by using repetitive, provocative motions and exercise regimens. This therapy can include eye movements, head movements, or a combination of both to promote central compensation for unilateral loss of vestibular function from such conditions as vestibular neuritis, inner ear trauma, or removal of an acoustic neuroma.13 In disequilibrium of aging, therapy might include an attempt to lessen dependence on vision by having patients practice walking on uneven surfaces or with their eyes closed. Compensation with VRT for these conditions is far superior to vestibular suppressant medications or simple expectant observation.13-15 An increased awareness of the symptoms of MDD can facilitate its diagnosis, giving patients comfort and leading to an exploration of treatment options. Although the pathogenesis of MDD is not clear and its treatment not definitive, a trial of benzodiazepines, amitriptylines, and vestibular rehabilitation may prove useful. At the very least, clinicians can reassure patients that MDD is usually a short-lived and self-correcting phenomenon and can make suggestions regarding future motion exposure. Ms. Davis, Mr. Durio, and Dr. Barrs are clinicians in the Division of Otolaryngology/Head and Neck Surgery at Mayo Clinic in Phoenix. References 1. Nachum Z, Shupak A, Letichevsky V, et al. Mal de debarquement and posture: reduced reliance on vestibular and visual cues. Laryngoscope. 2004;114:581-586. 2. Mair WS. The mal de debarquement syndrome. J Audiol Med. 1996;5:21-26. 3. Hain TC, Hanna PA, Rheinberger MA. Mal de debarquement. Arch Otolaryngol Head Neck Surg. 1999;125:615-620. Available at archotol.amaassn.org/cgi/content/full/125/6/615.

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“Hi–I got your note.”

Clinical Challenge

Burning rash spreads from the trunk to the rest of the body ANN WELTIN, MSN, FNP, CNM

A Fite stain leads to the correct diagnosis of these lesions in a man originally from Micronesia.

The rash consisted of large (15 cm) erythematous plaques with central clearing (Figure 1). Multiple plaques were present on the trunk, neck, and thighs. Smaller lesions were present across the back and forehead. Initial treatment with antihistamines and topical steroids was unsuccessful: The lesions continued to grow larger and were still painful over the two-month treatment period. Punch biopsies were then obtained from two lesions. Initial pathology indicated granuloma annulare; however on the recommendation of an astute dermatology consultant, a Fite stain was performed. The Fite stain on the biopsied skin was positive, revealing a diagnosis of granulomatous dermatitis with acid-fast bacterial organisms consistent with cutaneous leprosy.

1. DISCUSSION

FIGURE 1. Pathology first indicated a diagnosis of granuloma annulare.

Mr. B, aged 40 years, presented with complaints of a rash that had been present for the past six months. After beginning on his trunk, the rash spread to his arms and legs three months later and his forehead two months after that. Mr. B stated the lesions were growing larger and burning in nature. The patient lived with his wife and three children, and no one else had been ill or had a similar rash. Mr. B had no chronic health problems or known allergies and was not taking any medications. Having emigrated from the Marshall Islands in the North Pacific Ocean, Mr. B had lived in northeast Iowa for the past five years and had not traveled recently.

CASE #2

Leprosy (also known as Hansen disease) is a chronic disease caused by the bacillus Mycobacterium leprae.1 The bacteria multiply very slowly with an incubation period of five to 20 years. Leprosy is not highly infectious. It is transmitted via droplets from the nose and mouth during close and frequent contact with an untreated case. Most individuals (95%) are naturally immune. Leprosy mainly affects the skin, peripheral nerves, mucosa of the upper respiratory tract, and eyes. If left untreated, the disease can lead to permanent damage of the skin, nerves, eyes, and limbs. Early diagnosis and treatment can prevent complications and help eliminate leprosy as a public health concern.1,2 While leprosy remains endemic in some regions of the world, (Angola, Brazil, the Central African Republic, the Democratic Republic of the Congo, India, Madagascar, Mozambique, Nepal, and the United Republic of Tanzania), only about 150 new cases are diagnosed yearly in the United States.1-3 Most of these cases occur in immigrants, but there is an endemic focus in the Gulf Coast region of Texas.4 California, Florida, Hawaii, Louisiana, Massachusetts, New York, and Texas accounted for 65% of cases registered in 2008. Only 16 cases have been reported in Iowa in the past 10 years. Up to 40% of those affl icted identify themselves as Asian or Pacific Islander in national origin.2 Classic features of leprosy include erythematous or hypopigmented plaques and alopecia. Clinically, leprosy can resemble tinea, contact dermatitis, vitiligo, pityriasis alba, and myxedema. Diagnosis in the United States is often delayed because clinicians are unaware of the disease and symptoms.2,4 Leprosy can be classified according to the Ridley-Jopling system, which places the symptoms on a spectrum of disease that includes lepromatous, borderline-

96 THE CLINICAL ADVISOR â&#x20AC;˘ AUGUST 2011 â&#x20AC;˘ www.ClinicalAdvisor.com

lepromatous, borderline-tuberculoid, tuberculoid, and indeterminate classif ication. Lepromatous lesions are symmetrical and include nodules or macules. Borderline tuberculoid involves three to 10 lesions with satellites. Tuberculoid leprosy involves one to three sharply outlined, dry, flaky, hairless, and erythematous or hypopigmented plaques. The World Health Organization simply defines leprosy cases as multibacillary (including lesions similar to lepromatous classes) and paucibacillary (encompassing the remaining categories). A leprosy case with only one hypopigmented macule that may be poorly defined is deemed indeterminate.2,4

2. TREATMENT

Ms. Weltin an assistant professor of nursing at Clarke University in Dubuque, Iowa.

“Still itchy?”

Treatment with a multidrug regimen of rifampin (Rifadin, Rimactane), dapsone, and clofazimine (Lamprene) taken daily for two years has been shown to be highly successful. Patients are noninfectious after a week and do not need to be isolated from work or family. The National Hansen’s Disease Program in Baton Rouge, La., offers therapy for patients and aids clinicians in the appropriate follow-up. Clients are typically monitored every three months.2,4,5 Mr. B has begun his two-year therapy regimen and will be monitored closely. It is critical for clinicians to be aware that leprosy continues to occur in the United States; consideration of this condition in the differential diagnosis the the key to successful diagnosis and treatment. ■

References 1. World Health Organization. Leprosy fact sheet. Available at www.who. int/mediacentre/factsheets/fs101/en/. 2. Health Resources and Services Administration. A Summary of Hansen’s Disease (Leprosy) in the United States 2008. Available at www.hrsa.gov/ hansensdisease/pdfs/hansens2008report.pdf. 3. Global leprosy situation, 2010. Wkly Epidemiol Rec. 2010;85:337-348. Available at www.who.int/wer/2010/wer8535.pdf. 4. Anderson H, Stryjewska B, Boyanton BL, Schwartz MR. Hansen disease in the United States in the 21st century: a review of the literature. Arch Pathol Lab Med. 2007;131:982-986. 5. Centers for Disease Control and Prevention. Hansen’s disease (leprosy). Available at www.cdc.gov/nczved/divisions/dfbmd/diseases/hansens_disease/technical.html. All electronic documents accessed July 15, 2011.

“This is a teaching hospital.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2011 97

Stat Consult

A quick review of common conditions, using the best global evidence

General principles

Breastfeeding ALAN EHRLICH, MD, AND JESSIE M. PETTIT, MD

Dr. Ehrlich is a family physician and deputy editor for DynaMed (www. ebscohost.com/dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics. Dr. Pettit is an assistant professor at the University of Arizona, medical director of the Tucson Family Advocacy Program, and a peer reviewer for DynaMed.

• Human milk is the preferred feeding for all infants. • Exclusive breastfeeding is recommended for the first six months of life. • All breastfeeding newborn infants should be seen by an experienced health-care professional at age 3-5 days. — Check for adequacy of feeding. • Normal pattern is eight to 12 feeds/day. • Weight loss >7% from birth weight suggests possible breastfeeding problems. • Gains of 30 g/day are expected after nadir. — Physical exam, especially for jaundice and hydration — Maternal history of breast problems (painful feedings, engorgement) — Infant elimination patterns (expect passage of meconium by day 5 of life, three to five urines and three to four stools per day by age 3-5 days and four to six urines and three to six stools per day by age 5-7 days) • Breastfeeding infants should have a second visit at age 2-3 weeks for — Monitoring of weight gain — Providing additional support and encouragement to mother • Child should continue breastfeeding for at least the first year of life and as long as mutually desired by mother and child. • Infants weaned before age 12 months should receive iron-fortified infant formula (not cow’s milk).

Supplementation

Children should be breastfed for at least the first year of life.

• Fluid supplements (water, glucose water, formula, and other fluids) should not be given to breastfeeding newborn infants unless medically indicated. • Medical indications for supplemental feeding in term healthy infants — Breastfeeding contraindicated — Infant unable to feed at breast (e.g., congenital malformation or illness) Continues on page 105

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Stat Consult • Possible indications for supplemental feeding in term, healthy infants — Asymptomatic hypoglycemia unresponsive to frequent breastfeeding (symptomatic hypoglycemia treated with IV glucose) — Significant dehydration — Delayed bowel movements or continued meconium stools on day 5 — Hyperbilirubinemia — Poor milk production — Other supplements • Start vitamin D drops 400 IU/day orally during first few days of life, and continue until daily intake of vitamin D-fortified formula or milk is one liter. • Supplementary fluoride should not be provided during first six months of life. • Iron supplementation — Introduce complementary foods rich in iron at about age 6 months. — Start iron supplementation earlier in preterm infants, low-birth-weight infants, and infants with hematologic disorders. Cautions

• Breastfeeding may be associated with pain and discomfort, especially with latching on, but this should resolve within one to two weeks. • Assume maternal medications will appear in breast milk. — Most medications can safely be given while breastfeeding. — Medication compatibility with breastfeeding can be checked at Toxnet (toxnet.nlm.nih.gov/cgi-bin/sis /htmlgen?LACT, accessed July 15, 2011). Contraindications

• Breastfeeding contraindicated in — U.S. mothers who are HIV-positive (but not necessarily mothers in developing part of world) — Mothers receiving selected medications ■ Antimetabolites ■ Chemotherapeutic agents ■ Diagnostic or therapeutic radioactive isotopes ■ Check risks of all medications mother is taking — Mothers with exposure to radioactive materials (for as long as there is radioactivity in milk) — Mothers using drugs of abuse — Mothers who have herpes simplex lesions on a breast (infant may feed from other breast if clear of lesions)

— Infants with classic galactosemia — Mothers with active untreated TB — If severe hyperbilirubinemia, breastfeeding may need to be interrupted temporarily • Breastfeeding not contraindicated in — Most newborns with nonsevere jaundice and hyperbilirubinemia — Infants born to mothers who are hepatitis B surface antigen-positive — Mothers infected with hepatitis C virus — Mothers who are febrile — Mothers exposed to low-level environmental chemicals — Mothers who smoke tobacco — Mothers with history of breast augmentation or breast reduction • Alcohol consumption can inhibit milk production, but an occasional single, small alcoholic drink is acceptable; avoid breastfeeding for two hours after drinking. Medical aspects

• Mastitis — Exclude noninflammatory conditions (i.e., engorgement, plugged ducts) that do not benef it from antibiotics. — Continued breastfeeding using both breasts is considered safe during mastitis except in an HIV-positive mother. — Treatment ■ Express milk to prevent milk stasis. ■ Emptying breast every six hours may shorten duration of mastitis. ■ Antibiotics » Antibiotics may shorten duration of infectious mastitis. » Typical antibiotic regimens include dicloxacillin (Dycill, Dynapen) 125-500 mg every six hours or cephalexin (Keflex) 250-500 mg every six hours for 10-14 days. ■ Supportive treatments may include analgesia, increased fluid intake, and rest. • Breast candidiasis — Findings with breast candidiasis ■ Intense pain after period of pain-free breastfeeding ■ Pain in both nipples or breasts ■ Burning pain during or after feeds ■ No fever ■ No infl ammation of breast ■ May have itchy, fl aky, or shiny nipples, but rule out contact dermatitis

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Stat Consult Signs of fungal infection may be present in baby’s mouth or diaper area. — Treatment of nipple candidiasis ■ Topical antifungal (miconazole [Monistat] or clotrimazole [Lotrimin] cream) is the most common treatment. » If nipple fissures are present, also treat with such topical antibiotics as mupirocin (Bactroban) or triple antibiotic ointment (Neosporin), because Staphylococcus aureus is significantly associated with nipple fissures. » Mid- or low-potency topical steroid cream if red, inflamed nipples » Simultaneous treatment of mother and baby is required. ■ Oral fluconazole (Diflucan) (not approved by FDA for mammary candidosis) is often used for persistent cases of nipple yeast or presumptive ductal yeast. » 200-400 mg loading dose and then 100-200 mg once daily for 14-21 days » Continue breastfeeding while taking fluconazole. » Inform nursing mother of lack of data prior to prescribing. » Be alert to drug-drug interactions.

Postpartum contraception

• Women with exclusive breastfeeding and amenorrhea within the first six months postpartum have low (1% 2%) likelihood of pregnancy. • Indications to begin contraception — Menstruation resumes — Breastfeeding reduces in frequency or duration — Bottle feeds are started — Infant reaches age 6 months • Contraceptive options — First-choice methods ■ Natural family planning ■ Barriers ■ Intrauterine devices — Second choice—progestin-only methods ■ Not recommended <6 weeks postpartum ■ Recommended ≥6 weeks postpartum — Third choice—estrogen-containing contraceptives ■ Combination hormonal contraceptives ■ Not recommended <6 weeks postpartum ■ Not recommended 6 weeks to 6 months postpartum ■ May be used ≥6 months postpartum ■ Diaphragms or cervical caps previously used should be refitted at 6 weeks postpartum. ■

■

“We’re in a dying industry, and you’re just sitting there! Well, I’m going to do something about it–I’m starting a Web site.” 106 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

Early signs of appendicitis are missed

ANN W. LATNER, JD

How many patients does a busy clinician see every day? Every week? Chances are the number is high. The days of being able to spend large blocks of time with each patient are long gone. The current economic climate has squeezed everyone, particularly health-care providers who now need to see more patients in less time. This means that clinicians no longer enjoy the same type of personal relationships with patients that were commonplace in the past. In fact, there may be times when a clinician does not even remember treating a patient. Mr. D, aged 32 years, worked as a physician assistant for a practice with four doctors and three PAs. It was not unusual for Mr. D to see 25 to 30 patients a day, sometimes even more. And while some stood out in his memory because they came in more often or they had an unusual story, there were many whose names and details slipped his mind over time. In fact, when a former patient, Mrs. Z, sued him for malpractice, he had no idea who she was. After looking over the lawsuit, Mr. D rushed to speak to Dr. A, the physician with whom

The clinician did not recall treating the patient, and the medical record lacked a number of vital details.

It was not unusual for Mr. D to see 25 to 30 patients a day. There were many whose details slipped his mind over time.

108 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

he worked most closely. Dr. A was also named in the lawsuit. Both clinicians were alleged to have failed to diagnose Mrs. Z’s perforated appendix nearly one year ago. Mr. D had no recollection of the patient or the incident, but Dr. A remembered treating Mrs. Z. According to the records, Mrs. Z, aged 68 years, had originally come in for a checkup almost two months prior to developing the ruptured appendix. She was treated by Dr. A, who noted in the chart that the patient had a history of gastroesophageal reflux disease, allergies, and arthritis, which were being treated with meloxicam (Mobic), cetirizine (Zyrtec), and esomeprazole (Nexium). The notes indicated that Dr. A examined the patient’s heart, lungs, and abdomen, which were all normal. Mrs. Z was diagnosed with hypertension. Dr. A ordered a urinalysis and blood tests, which showed nothing abnormal Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR except slightly elevated cholesterol. Mrs. Z was instructed to return in two weeks to recheck her BP. At the second visit, her BP was still elevated and a decision was made to monitor it. She was told to return in another two weeks. At the third visit, Dr. A added amlodipine (Norvasc) to Mrs. Z’s medications to address the still elevated BP. There was no notation on the chart that Mrs. Z had ever complained about pain on any of her three visits. Mrs. Z returned to the clinic the following week. On that date, she complained about intolerance to amlodipine, and Dr. A switched her to enalapril (Renitec, Vasotec) and instructed the patient to return in another two weeks. Mrs. Z showed up unexpectedly three days later and was seen by Mr. D. According to the patient record, Mr. D ordered additional blood tests, which were normal aside from a slightly elevated cholesterol and RBC, and Mr. D recommended a change in diet and exercise to address Mrs. Z’s hypertension.

Mr. D explained that, based on his usual practice, he likely conducted a focused exam and palpated the patient’s abdomen. “Do you remember any of this?” asked Dr. A. “No,” confessed Mr. D. “I don’t remember the patient at all.” The clinicians’ defense attorney explained that more information would surface at the examination before trial (EBT), where they would have an opportunity to question the plaintiff. At the EBT, Mrs. Z testified that on her final visit to the clinic, she was suffering from serious pain radiating down her right leg. She stated that even after she complained about this, Mr. D never examined her and only recommended ibuprofen for the pain. Four days later, she said, she went to the emergency department (ED) and was diagnosed with a perforated appendix and underwent an open appendectomy. The ED records indicated a pelvic abscess, extensive adhesions, and inflammation in the pericecal area.

What do you think? Was settling before trial the right decision in this case? Add your comments to this article — or any article — by going to www.ClinicalAdvisor.com.

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When questioned at his EBT, Mr. D explained that he didn’t specifically remember the incident, but based on his usual practice, he likely conducted a focused examination of Mrs. Z and palpated her abdomen. If something had been abnormal, or if the patient had complained of pain, he would have noted it in the fi le. Before trial, the defense attorney fi led a motion for summary judgment, asking the court to dismiss the cases against Dr. A and Mr. D. After examining the facts in the record, the case against Dr. A was dismissed. The court did not dismiss the case against Mr. D. Before going to trial, Mr. D settled with the plaintiff for $250,000. Legal issue

Summary judgment is a determination made by a judge without a full trial. One party in a case will apply for summary judgment to save the time and expense of a trial when the outcome is obvious. A judge only grants summary judgment if there are no material issues of fact in question—in other words, if there is nothing for a jury to decide, both sides agree about the facts, and it’s simply a matter of law. In such cases, and if one party is clearly the winner after applying the law to the undisputed, a judge may grant summary judgment. Otherwise, the decision is left to a jury. The judge granted summary judgment to Dr. A because there were no material issues of fact. Dr. A’s version of what happened was the same as Mrs. Z’s version, and the judge could clearly determine that there was no legal basis for a malpractice claim. However, the same could not be said for Mr. D, since he and Mrs. Z had differing versions of what had transpired during treatment. Protecting yourself

Many of the cases covered in this column have the same lesson, but it is one worth repeating: Document everything. If you are seeing 10, 20, or 30 patients a day, you will not be able to remember them all. And if a patient sues, months or even years down the road, it is doubtful you will remember every detail of treatment. Mr. D should have noted in the chart what actions he performed at the appointment (e.g., complete physical, palpated abdomen) and recorded the outcomes (e.g., elevated BP, normal abdomen). Taking a few minutes to write complete notes could have spared him a lot of anxiety and money in the long run. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

110 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations. ■ COMPLETE THE POSTTEST: Page 115

■ ADDITIONAL CME/CE: Pages 31, 79

Growths on the fingers NOAH S. SCHEINFELD, MD, JD

CASE #1

CASE #2

A skin exam of a black woman aged 45 years revealed papules on the outside of her pinkies. According to the patient, the papules had been present since birth and did not bother her. She also stated that they had not changed in size since childhood. An x-ray of the lesion revealed that these nubbins of flesh, containing no bone. The woman stated that to the best of her knowledge, neither her parents nor her brother and two sisters had similar lesions. Her three children had no lesions that resembled hers, either.

A man aged 40 years presented with a six-month history of a growth on the side of one middle finger. The lesion did not itch, burn, or hurt. OTC wart treatments had no affect. The patient was not taking any medication and had no history of any systemic disease. The lesion was removed by a shave excision. Histologic examination showed a dermal core composed of thick, closely intertwined collagen bundles with numerous capillaries, varying numbers of fibroblasts, and thin elastic fibers oriented along the vertical axis of the lesion.

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CME CE

CASE #1

Dermatologic Look-Alikes

Accessory digits

Polydactyly is the most common congenital digital anomaly of the hand. The three types of this condition are: (1) type I, in which the extra fi nger is a soft small tissue segment (post-axial nubbin); (2) type II, in which the extra finger includes bone, tendon, and cartilage without any joints; and (3) type III, in which the extra finger is fully developed with own metatarsal and is a complete, functioning digit.1 Some patients have accessory toes as well as fingers, but most have either one or the other. An accessory digit most commonly appears as a solitary finding. This patient was most likely a case of autosomal dominant disease with incomplete penetrance (only about 30% of patients will have a positive family history for polydactyly or sporadic inheritance). Duplications occur bilaterally in about 40%-50% of patients, but these are often not symmetric. Extra digits occur most commonly on the ulnar side of the hand (postaxial polydactyly), less commonly on the radial side (preaxial polydactyly), and very rarely on one of the middle three digits (central polydactyly).2,3 Central polydactyly is often inherited with an associated syndactyly, a condition in which two or more digits are fused together. The extra digit is most commonly an abnormal fork of one of the five digits. Rarely, the extra digit may originate at the wrist as a normal digit does. Polydactyly is a finding of 267 syndromes listed in Online Mendelian Inheritance in Man (available at www.ncbi.nlm. nih.gov/omim, accessed July 15, 2011), a database of human genes and genetic disorders, and syndromic polydactyly is commonly an autosomal recessively inherited trait.4 Because hand and foot polydactyly are associated with congenital defects in 23.4% of patients, a genetic workup and thorough medical examination should be performed in these patients. A number of syndromes include polydactyly as a finding: acrocallosal syndrome, basal cell nevus syndrome,

What to remember Extra digits occur most commonly on the ulnar side of the hand (postaxial polydactyly).

Bardet-Biedl syndrome, Biemond syndrome, ectrodactylyectodermal dysplasia-cleft lip/palate syndrome, Ellis van Creveld syndrome, Hirschsprung disease, unilateral renal agenesis, hypertelorism, congenital deafness, Meckel Gruber syndrome, Joubert-Boltshauser syndrome, Laurin-Sandrow syndrome, McKusick-Kaufman syndrome, mirror hand deformity (ulnar dimelia), Mohr syndrome, oral-facialdigital syndrome, Pallister-Hall syndrome, Rubinstein-Taybi syndrome, Smith-Lemli-Opitz syndrome, short rib polydactyly, trisomy 13 and 21, tibial hemimelia, VATER association (Vertebral [defects], [imperforate] Anus, Tracheoesophageal [fistula], Radial and renal [dysplasia]).5 Polydactyly has an incidence of one in every 500-1,000 live births. Postaxial hand polydactyly is a common isolated disorder in African black and African-American children, and autosomal dominant transmission is the likely mode of inheritance. Postaxial polydactyly is approximately 10 times more frequent in blacks than in whites and is more frequent in male children. Among blacks, polydactyly occurs in about four of 1,000 births, compared with 0.3 to 1.3 out of 1,000 births among whites. Polydactyly appears to be slightly more common in males. In contrast, postaxial polydactyly seen in white children is usually syndromic and associated with an autosomal recessive transmission. Diagnosis of polydactyly can be made in utero with ultrasound. A radiologist can identify fetal fi nger buds utilizing transvaginal ultrasound as early as 9 weeks’ and reliably by 13 weeks’ gestation.6,7 If polydactyly is noted, conduct a through examination of the heart, nervous system, limbs, and kidneys to identify associated syndromes. Skeletal dysplasias can be linked to polydactyly (i.e., short rib polydactyly). Follow-up ultrasound between 17-34 weeks with biometric profi le can establish the diagnosis of isolated polydactyly. Histologic examination postaxial or preaxial nubbin tissue resembles the histology of a congenital traumatic neuroma and demonstrates hyperkeratosis and acanthosis overlying many nerve bundles in the dermis. Abundant Merkel cells8 may appear at first and then disappear after the development of these nerve bundles, which form Meissner corpuscles in the dermal papillae and stain positively with S-100 protein.9 If a type I polydactyly is present at birth and x-ray shows no bone in the post-axial duplicated digit, the postaxial nubbin can be removed through suture ligation in the newborn nursery. It should be noted that suture ligation is not usually performed in older infants.10-12 Suture ligation of supernumerary digits with residual cartilage and/or an

112 THE CLINICAL ADVISOR • AUGUST 2011 • www.ClinicalAdvisor.com

underlying duplicated metatarsal will lead to future deformity.13 If type II or type III polydactyly is present, a surgeon can perform formal amputation after x-rays are taken to ensure that there are no underlying deformed metatarsals, in which case the supranumerary digit should be surgically excised. Postponing excision until age 9 to 12 months is advisable to decrease anesthesia risk. Adequate web space should be preserved and the digit removed. As the digits did not affect the health of the patient, it was decided to leave them in place. A complete physical showed no systemic findings related to the accessory digits.

CASE #2

Acquired digital fibrokeratomas

Acquired digital fibrokeratomas (ADFKs) are uncommon skin neoplasms that manifest as asymptomatic, solitary, smooth, dome-shaped, fleshcolored papules or nodules, usually with a collarette at the base creating a moatlike configuration at their bottom. These growths are usually solitary, but multiple lesions have rarely been reported. Most ADFKs measure 0.5 to 1.5 cm in height or diameter, but larger growths with a diameter or height greater than 3 cm have been noted. ADFKs develop most commonly on the fingers and toes. A number of cases have been noted on the heel. A few patients with ADFKs occurring on the elbow, wrist, calf, and the prepatellar area have been seen. The epidemiology of ADFKs is not well defined. ADFKs are most common in men, but the paucity of reports makes a true sexual predilection difficult to establish. ADFKs most commonly arise in middle age, with reported ages of onset ranging from 12 to 70 years (average age 40 years). No racial predilection has been noted. Investigators first described ADFKs in 1968 in a series of 10 patients with hand lesions.14 Later that year, investigators noted 28 cases of similar lesions, with some occurring on the arms and legs and suggested that “acquired acral fibrokeratoma” would be a more accurate description.15 The differential diagnosis of ADFKs includes: corn, superficial acral fibromyxoma, aggressive digital papillary adenocarcinoma, squamous cell carcinoma (in particular,

subungual keratoacanthoma), osteoma, cutaneous horn, verruca vulgaris, supernumerary digit, Koenen’s tumor (periungual fibromas), pyogenic granuloma (lobular capillary hemangioma), acrochordon, infantile digital fibromatosis, and neurofibroma. Papules or nodules that arise before puberty and fit the description of ADFKs are most likely supernumerary digits. Supernumerary digits occur on the proximal portion of the fifth digit and are made up of abundant nerve bundles. Unlike an ADFK, an acquired periungual fibrokeratoma arises from the proximal nail fold. Although similar in appearance to ADFKs, Koenen’s tumors occur in association with tuberous sclerosis and possess atypical stellate myofibroblasts. Aggressive digital papillary adenocarcinoma, which can be fatal, is the most important condition to exclude from ADFK. The cause of ADFKs is unknown. While researchers point toward trauma or repetitive irritation, there may be an unknown genetic factor at work. The conditions that most closely resemble ADFKs—supernumerary digits and the periungual fibromas of tuberous sclerosis—have a genetic basis. Reports of ADFKs occurring with a pyogenic granuloma buttresses the idea that trauma relates to their etiology.16 The histology of ADFK is well described. The lesion manifests as a small, well-circumscribed, dome-shaped or narrow elongated papule. The stratum corneum is usually hyperkeratotic, with the hyperkeratosis greatest at the top of the ADFK. An acanthotic epidermis with slightly attenuated or elongated rete ridges is typically found. The dermal core of an ADFK demonstrates three possible histological patterns.14,17 The most common, type I, consists of a dermal core composed of thick, closely intertwined collagen bundles with numerous capillaries, varying numbers of fibroblasts, and thin elastic fibers oriented along the vertical axis of the lesion. Type II ADFKs resemble type I but also possess many more fibroblasts arranged in fascicles and greatly reduced numbers of elastic fibers. Type III ADFKs are the least common and possess a dermal core that is poorly cellular and edematous with a reduced number of elastic fibers. Continues on page 114

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CME CE

Dermatologic Look-Alikes

Interestingly, cyclosporine (Gengraf, Neoral, Sandimmune) has been linked to the development of ADFKs.18 Acquired periungual fibrokeratoma developing after acute staphylococcal paronychia has been noted as well.19 ADFK treatment is not complex. Unlike warts, ADFKs cannot be treated with cryotherapy.20 These lesions are usually just a cosmetic problem, and no cases of malignant transformation have been reported. Occurrence in locations at which pressure is constant (e.g., the dorsum or plantar surface of the foot) can cause pain. In such cases, removal has a medical rather than a cosmetic basis. Removal with a shave or simple surgical excision is curative, with recurrence after surgery unlikely. Six months after removal of this patient’s lesion, it had not recurred. ■

15. Pinkus H. Discussion—acquired digital fibrokeratoma. Arch Dermatol. 1968;97:128-129. 16. Lee DR, Lee JY, Ahn JY, Park MY. A case of acquired digital fibrokeratoma accompanied by pyogenic granuloma. Dermatol Online J. 2009;15:8. Available at dermatology.cdlib.org/1501/case_presentations /fibrokeratoma/park.html. 17. Kint A, Baran R. Histopathologic study of Koenen tumors. Are they different from acquired digital fibrokeratoma? J Am Acad Dermatol. 1988;18:369-372. 18. Qiao J, Liu YH, Fang K. Acquired digital fibrokeratoma associated with ciclosporin treatment. Clin Exp Dermatol. 2009;34:257-259. 19. Sezer E, Bridges AG, Koseoglu D, Yuksek J. Acquired periungual fibrokeratoma developing after acute staphylococcal paronychia. Eur J Dermatol. 2009;19:636-637. 20. Frydman AF, Mercer SE, Kleinerman R, et al. Acquired fibro-

Dr. Scheinfeld is assistant clinical professor of dermatology at Columbia University in New York City, where he has a private practice. The author has no relationships to disclose relating to the content of this article.

keratoma presenting as multiple plantar nodules. Dermatol Online J. 2010;16:5. Available at dermatology.cdlib.org/1610/2_case_presentations/5_10-00228/mercer.html. All electronic documents accessed July 15, 2011.

References 1. Hosalkar HS, Shah H, Gujar P, Kulkarni AD. Crossed polydactyly. J Postgrad Med. 1999;45:90-92. 2. Cohen MS. Thumb duplication. Hand Clin. 1998;14:17-27. 3. Hung L, Cheng JC, Bundoc R, Leung P. Thumb duplication at the metacarpophalangeal joint. Management and a new classification. Clin Orthop Relat Res. 1996;323:31-41. 4. Temtamy SA, McKusick VA. The genetics of hand malformations. Birth Defects Orig Artic Ser. 1978;14:i-xviii, 1-619. © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

5. Castilla EE, Lugarinho R, da Graça Dutra M, Salgado LJ. Associated anomalies in individuals with polydactyly. Am J Med Genet. 1998;80: 459-465. 6. Bromley B, Shipp TD, Benacerraf B. Isolated polydactyly: prenatal diagnosis and perinatal outcome. Prenat Diagn. 2000;20:905-908. 7. Zimmer EZ, Bronshtein M. Fetal polydactyly diagnosis during early pregnancy: clinical applications. Am J Obstet Gynecol. 2000;183:755-758. 8. Ban M, Kitajima Y. The number and distribution of Merkel cells in rudimentary polydactyly. Dermatology. 2001;202:31-34. 9. Shapiro L, Juhlin EA, Brownstein MH. “Rudimentary polydactyly”: an amputation neuroma. Arch Dermatol. 1973;108:223-225. 10. Morley SE, Smith PJ. Polydactyly of the feet in children: suggestions for surgical management. Br J Plast Surg. 2001;54:34-38. 11. Graham TJ, Ress AM. Finger polydactyly. Hand Clin. 1998;14:49-64. 12. Hare PJ. Rudimentary polydactyly. Br J Dermatol. 1954;66:402-408. 13. Heras L, Barco J, Cohen A. Unusual complication of ligation of rudimentary ulnar digit. J Hand Surg Br. 1999;24:750-751. 14. Bart RS, Andrade R, Kopf AW, Leider M. Acquired digital fibrokeratomas. Arch Dermatol. 1968;97:120-129.

“You need to get your cholesterol where your sperm count is.”

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POSTTEST Expiration date: August 2012

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

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page 31

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Therapeutic strategies for bacterial conjunctivitis

Case #1: Bullous pemphigoid

Case #1: Accessory digits

1. What is the appearance of the most common form of bullous pemphigoid (BP)? a. Tense bullae on normal-appearing or erythematous skin b. Small tense vesicles on urticarial or inflamed skin c. Persistent urticarial lesions with or without conversion to bullous eruptions d. Disease limited to the acral skin only

1. Postaxial hand polydactyly is a common isolated disorder in children who are a. Hispanic b. Native American c. Caucasian d. African-American

1. What are the most commonly isolated bacteria in young children with conjunctivitis? a. Streptococcus pneumoniae b. Staphylococcus epidermidis c. Staphylococcus aureus d. Haemophilus influenzae 2. Any patient who has fluorescein staining suggestive of dendritic branching ulceration should be immediately referred for evaluation of a. Corneal abrasion b. Blepharitis c. Ocular herpes d. Foreign body presence 3. Which drug is usually recommended only for prophylaxis of neonatal conjunctivitis? a. Erythromycin b. Gentamicin c. Tobramycin (Tobrex) d. Polymyxin B/bacitracin (Polysporin) 4. Owing to its convenient twice-a-day dosing, which fluoroquinolone is useful in patients with a history of poor compliance or in children in a school setting? a. Ciprofloxacin (Ciloxan) b. Levofloxacin (Iquix) c. Moxifloxacin (Vigamox) d. Besifloxacin (Besivance) TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureAug2011

2. Which drug is associated with BP? a. Cyclophosphamide (Cytoxan) b. Methotrexate (Rheumatrex, Trexall) c. Furosemide (Lasix) d. Azathioprine (Azasan, Imuran) Case #2: Epidermal cyst 3. Gardner syndrome should be suspected in adult patients who develop cysts in association with a. Acne vulgaris b. Appearance in unusual locations c. An extensive wide blush of erythema d. An overlying punctum 4. What is the first-line treatment for inflamed epidermal cysts? a. Incision and drainage b. Intralesional corticosteroids c. Topical antibiotics d. Phototherapy TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermClinicAug2011

2. What is the treatment for a type I polydactyly present at birth? a. Cryotherapy b. Formal amputation c. Suture ligation d. Watchful waiting Case #2: Acquired digital fibrokeratomas 3. Where do acquired digital fibrokeratomas (ADFKs) most commonly appear? a. Elbow b. Toes c. Wrist d. Calves 4. The development of ADFKs has been linked with which medication? a. Cyclosporine (Gengraf, Neoral, Sandimmune) b. Interferon c. Tacrolimus (Prograf) d. Azathioprine (Azasan, Imuran)

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermLookAlikeAug2011

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This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of August 2011. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken. CREDITS: 0.5

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Feature

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Therapeutic strategies for bacterial conjunctivitis

Case #1: Bullous pemphigoid

Case #1: Accessory digits

1. Postaxial hand polydactyly is a common isolated disorder in children who are a. Hispanic b. Native American c. Caucasian d. African-American

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermLookAlikeAug2011

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ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Brewer’s yeast

As its name implies, brewer’s yeast was originally identified as a primary ingredient in the beer-making process.1 As with other plants, the yeast family has many members, all of which are one-celled fungi. Brewer’s yeast, or Saccharomyces cerevisiae, is specifically grown as a nutritional substance rich in chromium, selenium, proteins, and B-complex vitamins.1 Single-celled yeast organisms were first used in baking and fermentation 4,000 years ago in ancient Egypt.2 Centuries later, famed French microbiologist Louis Pasteur discovered that alcohol was the natural by-product of yeast fermentation.2

Background As a probiotic, brewer’s yeast lives naturally in the digestive tract, creating the balance of yeasts, bacteria, and enzymes to form a critically stable environment. As one of more than 1,500 species of yeasts in existence, brewer’s yeast is one of the better-known and most valued member of this eukaryotic kingdom.2

Science Depending on the intended use, brewer’s yeast has differing mechanisms of action. As a dietary supplement, brewer’s yeast is a nonliving, dried product.3 Overall, the mechanisms of action of brewer’s yeast are largely dictated by its nutrients. The substantial chromium content of brewer’s yeast is responsible for significant improvement in potentiating human insulin receptors, decreasing insulin resistance, and increasing beta-cell function in the pancreas.3

Brewer’s yeast supplements also are commonly used to enhance immunity. One small trial enrolled more than 100 patients during the cold-and-flu season. Participants were given either 500 mg of a standardized brewer’s yeast supplement or placebo every day for 12 weeks and were monitored periodically for cold and flu symptoms. Three months later, patients who had taken the active brewer’s yeast supplement experienced 16% fewer symptoms, and the symptoms that did develop were 11% shorter in duration.4 Perhaps the most exciting potential for brewer’s yeast is in cancer treatment. Bench researchers are exploring the in vitro use of brewer’s yeast cells incorporated into breastcancer-cell cultures. Actively metastatic breast-cancer cells are known to be aggressively phagocytic, engulfing and destroying surrounding healthy cells. When brewer’s yeast cultures were introduced into the cell cultures and subsequently phagocytized, apoptosis of the cancer cells rapidly escalated. After only 30 minutes, 13% of the cells died, with the rate increasing to 38% at four hours.5 As might be

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,200 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

INJECTIONS OF DEXTRANOMER GEL IN STABILIZED HYALURONIC ACID REDUCE FECAL INCONTINENCE Level 1: Likely reliable evidence Fecal incontinence is a common problem for which patients may be reluctant to seek treatment, and there has been little evidence to support any medical or surgical interventions. Local injections to narrow the anal canal have been investigated but have shown little efficacy to date (Cochrane Database Syst Rev. 2010;5:CD007959, available at onlinelibrary.wiley.com/o/cochrane /clsysrev/articles/CD007959/frame.html, accessed July 15, 2011). However, a new randomized trial appears to show promise for this approach (Lancet. 2011;377:997-1003). Patients (mean age 61 years) with fecal incontinence for one year or more (at least four episodes per two-week period) were randomized to transanal submucosal injections of a dextranomer gel (NASHA/Dx) in stabilized hyaluronic acid vs. sham injection and were followed for six months. All patients were offered repeat treatment at one month if their symptoms had not improved and they were not experiencing persistent adverse effects. The primary outcome was treatment response, defined as ≥50% reduction in incontinence episodes. At six months, the dextranomer gel group had a significantly higher rate of treatment response (52% vs. 31%, p=0.0089, NNT 5). The mean increase in incontinence-free days per two-week period was 3.1 days for the gel group vs. 1.7 days for the sham group (p=0.0156), and the gel was associated with a trend toward greater reduction in number of incontinence episodes per two-week period (median reduction six vs. three, p=0.09). Adverse event rates (including

proctalgia, rectal hemorrhage, and diarrhea) were higher in the gel group. There were no significant differences between groups in qualityof-life measures. After an additional six months of unblinded follow-up, 69.1% of the gel users were found to have at least a 25% reduction in incontinence episodes from baseline.

At six months, the dextranomer gel group had a significantly higher rate of treatment response.

PRUNES MAY BE MORE EFFECTIVE THAN PSYLLIUM FOR CONSTIPATION Level 2: Mid-level evidence Prunes (dried plums) have long been considered effective for constipation and are the most common food that people associate with an anti-constipation effect. However, there has been little direct evidence to evaluate the efficacy of prunes as a dietary treatment or to compare prunes with other treatments for constipation. A recent trial, supported by the California Dried Plum Board, provides some comparative efficacy evidence (Aliment Pharmacol Ther. 2011;33:822-828). Forty adults (37 women) with chronic constipation were studied in a randomized crossover trial with blinding of the outcome assessors. Participants had mild to moderate constipation; those with comorbidities, alarm symptoms, or irritable bowel syndrome were excluded. Treatment periods lasted three weeks, separated by a one-week washout period. One treatment period used prunes 50 g (about six prunes) twice daily with meals; the other treatment period The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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Evidence-Based Medicine used psyllium 11 g twice daily with eight ounces of water. Prunes were more effective than psyllium using measures of number of complete spontaneous bowel movements (3.4 vs. 2.8 per week, p=0.006) or stool consistency (p=0.02). Improvement in global constipation symptoms (the most clinically relevant outcome) was reported by 70% with prunes and by 55% with psyllium, but this difference was not statistically significant. There were no significant differences between treatments in palatability, satiety, bloating, or adverse events.

HYDROXYUREA REDUCES PAIN EVENTS IN VERY YOUNG CHILDREN WITH SICKLECELL DISEASE Level 1: Likely reliable evidence Painful symptoms of sickle-cell disease begin within the fi rst year of life. Hydroxyurea (hydroxycarbamide) has been shown to reduce pain in adults (N Engl J Med. 1995;332:1317-1322, available at www.nejm.org/doi/ full/10.1056/NEJM199505183322001, accessed July 15, 2011) and has been associated with reduced hospitalization in school-age children (Pediatrics. 2008;122:1332-1342, available at pediatrics.aappublications.org/content/122/6/1332. long, accessed July 15, 2011), but it has not previously been investigated in toddlers. The BABY-HUG trial evaluated the effects of hydroxyurea in 193 children aged 9-18 months (Lancet. 2011; 377:16631672). Children with sickle-cell disease were randomized to hydroxyurea 20 mg/kg/day vs. placebo for two years. The hydroxyurea group had significantly lower rates of pain events (177 events in 62 patients vs. 375 events in 75

Sickle-cell disease causes RBCs to form into a crescent shape (shown).

patients, p=0.002) and dactylitis (24 events in 14 patients vs. 123 events in 42 patients, p <0.0001). Hydroxyurea was also associated with reduced gastroenteritis (p=0.001) and trends toward reductions in acute chest syndrome, transfusions, and hospitalizations. The risk of mild-moderate neutropenia was increased in the hydroxyurea group, but no other treatment-related adverse events were noted. There were no significant differences in the primary surrogate outcomes of splenic and renal function.

ADDITION OF GP100 VACCINE TO INTERLEUKIN-2 IMPROVES CLINICAL RESPONSE IN ADVANCED MELANOMA Level 2: Mid-level evidence There is currently little evidence for the efficacy of vaccines to limit the progression of metastatic cancer. Vaccine treatment (sipuleucel-T) has been associated with increased survival in men with prostate cancer (N Engl J Med. 2010;363:411422, available at www.nejm.org/doi/full/10.1056/ NEJMoa1001294, accessed July 15, 2011), but a recent high-quality trial investigating the GP100 vaccine in patients with metastatic melanoma found no survival benefit for the combination of vaccine plus ipilimumab compared with ipilimumab alone and found reduced survival in patients receiving vaccine alone (N Engl J Med. 2010;363:711-723, available at www.nejm.org/doi/full/10.1056/NEJMoa1003466, accessed July 15, 2011). However, a new trial indicates that GP100 plus interleukin-2 increases clinical response, delays recurrence, and may improve survival (N Engl J Med. 2011;364:2119-2127, available at www.nejm.org/doi/ full/10.1056/NEJMoa1012863, accessed July 15, 2011). A total of 185 patients with stage III-IV melanoma without brain metastases were randomized to GP100 plus incomplete Freund’s adjuvant in combination with interleukin-2 vs. interleukin-2 only. The GP100 group received the vaccine once per three-week cycle. All patients had interleukin-2 at a dose of 720,000 units/kg IV bolus every eight hours up to 12 doses per cycle. Complete clinical response was defined as disappearance of all lesions. At mean follow-up of 41.5 months, the GP100 group had significantly higher rates of both complete clinical response (9% vs. 1%, p =0.01, NNT 13) and any clinical response (16% vs. 6%, p=0.03, NNT 10), and had longer progression-free survival (median 2.2 months vs. 1.6 months, p=0.008). Also, there was a trend toward increased overall survival in the GP100 group (median 17.8 months vs. 11.1 months, p=0.06). The risk of arrhythmias was significantly increased in the GP100 group (15% vs. 2%, p <0.002, NNH 7). ■

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COMMENTARY Judi Greif RN, MS, APNC, is a family nurse practitioner and medical writer currently residing in East Brunswick, N.J.

The 100-day cough: clinicians be(a)ware The Chinese call it “the 100-day cough,” and hearing this, I am reminded of another reference, “the Hundred Years’ War”: Both the cough and the war were persistent, could be divided into phases, and could result in tragedy. The cough—pertussis, also known as “whooping cough” because of the characteristic violent sound it produces—was first described in the 1600s, but it would be another 300 years before the causative coccobacillus, Bordetella pertussis, a highly contagious gram-negative organism, was discovered. U.S. epidemiologists have been tracking pertussis cases since the first reports were made to the Public Health Service in 1922, and in the 1920s, Dr. Louis Sauer perfected a vaccine.

The ACIP advises that pregnant women get pertussis vaccination now rather than waiting until after giving birth.

Before pertussis vaccination became routine in the 1940s, approximately 200,000 to 250,000 cases were reported annually. Once the DPT vaccine was introduced, the numbers declined steadily until they reached an all-time low in 1976, when the CDC recorded just over 1,000 cases. Since then, however, reports of pertussis among adults and adolescents have increased in disproportionate numbers. This may be due to the waning effects of childhood vaccinations coupled with the fact that the 2006 Advisory Committee on Immunization Practices (ACIP) guidelines, which called for a one-time booster with Tdap (containing the acellular pertussis vaccine) for adults and adolescents (www.cdc.gov/mmwr/pdf/rr/ rr5517.pdf), still have not been fully implemented by clinicians; only 5.9% of eligible candidates received the vaccine in 2008. Pertussis remains one of the leading causes of vaccine-preventable deaths in this country and worldwide. In 2009, nearly 17,000 pertussis cases were reported to the CDC. In 2010, 8,383 cases (including 10 infant deaths) were reported in California—the highest incidence there in more than half a century. Ohio had its highest number of cases in 25 years. In Michigan, an increase in pertussis was first observed in the second half of 2008, and has continued to date. Because the symptoms of pertussis resemble those of other respiratory illnesses, many more cases go undiagnosed and unreported. Clinicians

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must be mindful of the signs and symptoms— initially coryza and intermittent cough, followed by the disease’s paroxysmal phase: spasmodic cough, posttussive vomiting, and inspiratory whoop, frequently lasting for weeks to months. Nasal swab culture, polymerase chain reaction, and serology tests can confirm the diagnosis, and the patient can be treated with antibiotics. Tests vary in sensitivity and specificity, so practitioners need to be cognizant of case definitions (which vary slightly between the CDC and The World Health Organization) and use clinical judgment so as to avoid over- or under-diagnosis. Goals of vaccination and treatment include preventing and/or curtailing pertussis outbreaks to reduce morbidity and mortality, which is especially high among infants. Between 2000 and 2009, 178 of 194 pertussis deaths reported to the CDC occurred among infants aged <12 months. Tdap is recommended for adults aged 19 to 64 years, especially those in contact with infants, and the FDA has just approved the first vaccine to prevent pertussis in adults aged 65 years and older. In addition, the ACIP is now advising previously unvaccinated pregnant women to get the pertussis vaccine in their second or third trimester rather than waiting until after they give birth. Most deaths occur in infants younger than age 2 months, and there is some evidence that vaccinated women may pass on the immunity to their newborns. ■

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