Spring 2015

SPECIAL EDITION CLINICAL GUIDE FOR THE INFECTIOUS DISEASE PRACTITIONER @IDSE_O _Online

Infectiou ous Disease Special Edition Ed

Curr urrent Considerations derations in the Initiation of HIV Pre-exposur In Pre-exposure e Prophylaxis

IDSE E.net

Volume 18 • 2015

pital Acquired icile Infections: ies

Ep Epidemiology of Infect ections After Soli olid Organ and Hem ematopoietic Stem m Cell Transplantation

Commentary: A Brief Guide To E o-It-Yourself HIV Pro ophylax gram

Hepatitis is C: Recent Clinical Data

Commentar C ary: Why Do VaccinePreventable e Dise ease Outbreaks Occur in the United U ted States?

Pre-Travel Risk Ri Assessme ment ent, Travel el Health Precaut utions, s, an and Post-Tra Po Travel Illnesses: An Ov Ove verview ve

Commentary: C With Ebola Viru Biocontainment Unit U

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table of contents

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Editor’s Letter

Hepatitis C: Recent Clinical Data IDSE Staff Reports

Commentary: PrEPare: A Brief Guide To Establishing a Do-It-Yourself HIV Prophylaxis Program Giffin W. Daughtridge S. Caitlin Coyningham Caroline E. Sloan Helen C. Koenig, MD

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Current Considerations in the Initiation of HIV Pre-exposure Prophylaxis Anna K. Person, MD

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Commentary: Why Do VaccinePreventable Disease Outbreaks Occur in the United States?

James D. Cherry, MD, MSc Kathleen H. Harriman, PhD, MPH

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Preventing Hospital-Acquired Clostridium difficile Infections: Optimal Strategies Brian Currie, MD, MPH

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Pre-Travel Risk Assessment, Travel Health Precautions, and Post-Travel Illnesses: An Overview Hariharan Regunath, MD William Salzer, MD Gordon D. Christensen, MD

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Commentary: Caring for Patients With Ebola Virus in the Nebraska Biocontainment Unit John J. Lowe, PhD Katelyn C. Jelden, BS Shawn G. Gibbs, PhD Philip W. Smith, MD Michelle Schwedhelm, MSN Peter C. Iwen, PhD Elizabeth Beam, PhD Christopher J. Kratochvil, MD Kathleen C. Boulter, RN Angela Hewlett, MD

Epidemiology of Infections After Solid Organ and Hematopoietic Stem Cell Transplantation Raymund R. Razonable, MD

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Dear Readers: Welcome to the first spring issue of Infectious Disease Special Edition.

After proudly filling its niche as an annual compendium of clinical review articles at the forefront of disease diagnosis and treatment for more than 15 years, IDSE will now be published twice within the same calendar year. With so much going on in the ID field, we believe the need for more clinical resources for practitioners has never been more acute.

Consider, for example, the ongoing public debate surrounding measles. As the authors of the commentary “Why Do Vaccine-Preventable Disease Outbreaks Occur in the United States?” highlight, vaccines for diseases such as mumps and measles have been proven both safe and effective in multiple studies. Yet, just as this issue was going to press, debate between health care professionals and parents both for and against childhood vaccinations persists. It may even emerge as an issue during the early stages of the 2016 presidential election campaign, which already appears to be in full swing.

The fact is, the incidence of measles thus far in 2015, more than 100 reported cases at press time, may not

yet warrant classification as an outbreak. However, it is worth noting that incidence of the disease is on pace to more than double from the 2014 rate, and many of these cases could have been prevented by vaccination protocols. It is clear, then, that ID specialists face a significant challenge in properly educating the public on the MMR vaccine. We hope our commentary on the subject will help prepare you to face this important challenge.

This issue of IDSE E also features articles on other topics in recent headlines, including Ebola virus and travel-related diseases, HIV prophylaxis, hospital-acquired Clostridium difficile, and transplant infections. As usual, thanks to our team of authors, who are well published in their fields of expertise, we remain “ahead of the curve” regarding information and education in the ID arena. We continue to strive to develop content designed to help you do your jobs better.

So, enjoy this issue. As always, we’ll see you in the fall, with even more well-written and thoroughly researched articles that we hope will help you meet the significant clinical challenges you face over the course of your practice.

Brian P. Dunleavy Managing Editor

EDITORIAL ADVISORY BOARD Brian Currie, MD, MPH Professor of Clinical Medicine Division of Infectious Diseases Albert Einstein College of Medicine Assistant Dean for Clinical Research Montefiore Medical Center New York, New York Julia Garcia-Diaz, MD Program Director Infectious Diseases Fellowship Program Ochsner Health System New Orleans, Louisiana

Jerome O. Klein, MD Professor of Pediatrics Boston University School of Medicine Boston Medical Center Boston, Massachusetts Harry W. Lampiris, MD Associate Professor of Clinical Medicine University of California at San Francisco Deputy Associate Chief of Staff San Francisco VA Medical Center San Francisco, California

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Hepatitis C: Recent Clinical Data IDSE STAFF REPORTS

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he patient with a hard-totreat hepatitis C infection is becoming harder to find. The

fixed-dose combination of ledipasvir and sofosbuvir (Harvoni, Gilead) is effective in patients with the hepatitis C virus (HCV) who until now have been considered difficult to treat, according to new data presented at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases.

One study demonstrated that 12 weeks of the fixeddose combination plus ribavirin cured patients with decompensated cirrhosis of their HCV infection. Two other studies showed that the drug was effective in patients—including those with cirrhosis—who previously failed protease inhibitor triple therapy.

The FDA approved Harvoni in October 2014 for use in difficult-to-treat patients: a 12-week course in treatment-naive patients with or without cirrhosis, 12 weeks for treatment-experienced patients without cirrhosis, and 24 weeks for treatment-experienced patients with cirrhosis. However, the new trials are the first to test the drug in large numbers of these subpopulations.

Michael Fried, MD, the director of the University of North Carolina Liver Center, in Chapel Hill, called the results notable. “The SVR [sustained virologic response] rates demonstrate that these drugs are very effective, even in this very sick population,” Dr. Fried said.

Dr. Fried pointed out that in patients with decompensated cirrhosis, antiviral treatment was capable of

INFECTIOUS DISEASE SPECIAL EDITION 2015

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improving clinical status. “Patients, including those with cirrhosis who previously failed protease inhibitor–based or sofosbuvir-based therapy, can be rescued with some of the drugs that we currently have available,” he said.

SOLAR-1 Steven Flamm, MD, professor of medicine and surgery, and chief of the Liver Transplantation Program at Northwestern University, in Chicago, presented preliminary results of the prospective, multicenter SOLAR-1 trial (abstract 239). Investigators randomized patients with genotype 1 or 4 hepatitis C and decompensated cirrhosis to ledipasvir-sofosbuvir plus ribavirin for 12 (n=52) or 24 weeks (n=47). Patients had decompensated cirrhosis with Child-Pugh class B or C, determined by liver function biomarkers and symptoms.

Most patients had a Model for End-Stage Liver Disease (MELD) score greater than 10. Roughly 15% of ChildPugh class B patients and 40% of class C patients had MELD scores between 16 and 20.

In the Child-Pugh class B cohort, 60% had a history of ascites and 60% had hepatic encephalopathy. In the class C cohort, nearly all patients had a history of ascites, and 90% had hepatic encephalopathy. The investigators excluded liver transplant recipients, as well as individuals with very high MELD scores or bilirubin, extremely low platelet counts (below 30,000), serious kidney dysfunction or hepatocellular carcinoma.

Three patients discontinued treatment early because of adverse events (AEs), and 4 serious AEs were considered to be related to treatment. The SVR rate at week 12 (SVR12) was 87% in patients who received 12 weeks of treatment and 89% in patients who received 24 weeks of treatment. Response rates were similar in Child-Pugh class B and C patients.

Most individuals had an improvement in their ChildPugh scores, with 10 having no change and only 4 having higher (worse) scores. Most patients also had improvements in their MELD scores. Dr. Flamm said the regimen “resulted in a high SVR12 rate in HCV patients with genotype 1 and 4 and advanced liver disease.”

In a second study presented at the meeting, researchers provided 12 weeks of ledipasvir-sofosbuvir plus ribavirin to 51 patients with HCV genotype 1 who had failed previous sofosbuvir-based regimens (abstract 235).

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Roughly 29% had cirrhosis, 59% had genotype 1a, and 12% had NS5A resistance-associated amino acid variants (RAVs) at baseline. High rates of SVR12 were seen in all patients, those who had received prior treatment with peginterferon-ribavirin-sofosbuvir (100%), sofosbuvirribavirin (95%), and peginterferon-ribavirin (100%). (The lone failure turned out to be a patient who was incorrectly genotyped and in fact had genotype 3 infection, according to the researchers.)

A third trial enrolled cirrhotic patients with HCV genotype 1 who had failed protease inhibitor–based triple therapy (abstract LBA6). The double-blind randomized trial involved a placebo design in which patients received either 12 weeks of placebo plus 12 weeks of fixed-dose ledipasvir-sofosbuvir plus ribavirin (n=77) or 24 weeks of ledipasvir-sofosbuvir plus placebo (n=78). Patients were included if they had not achieved an SVR after sequential peginterferon-ribavirin treatment and triple therapy (protease inhibitor plus peginterferon and ribavirin).

Approximately 18% of patients had platelet counts less than 100,000/mcL and 13% had serum albumin less than 3.5 g/dL. The average MELD score was 7.

Roughly 73% had baseline NS3/4A RAVs. SVR12 rates were 96% in patients who received ledipasvir-sofosbuvir plus ribavirin for 12 weeks and 97% in patients who received the 24-week treatment.

“There was no difference in SVR12 rates among patients with or without NS3/4A RAVs at baseline,” said Marc Bourlière, MD, head of the Hepato-Gastroenterology Department at Hospital Saint-Joseph in Marseilles, France, who presented the study. Pretreatment frequencies of these RAVS have been determinants of treatment outcomes with other drugs. Ledipasvirsofosbuvir with or without ribavirin was safe and well tolerated, with most AEs being mild or moderate in severity, Dr. Bourlière said.

Dr. Fried added that future research should examine how the new medications affect transplantation rates in the long term.

Dr. Fried has received grant/research support from and consulted for Gilead.

Dr. Bourlière is on the medical advisory board of Gilead. Dr. Flamm has received research support from Gilead and is also on the company’s speakers’ bureau.

Prognostic Index May Identify HCV Patients At Risk for Deterioration

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new prognostic index shows that patients with cirrhosis related to hepatitis C virus (HCV) infection are 7 times more likely to experience hepatic decompensation, and 6 times more likely to die of liver-related illness, if they have a constellation of genetic and clinical indicators that put them at high risk for poor outcomes.

The prognostic index is composed of a 186-gene signature and several clinical measures. It was developed specifically to identify HCV patients with cirrhosis who are at high risk for disease progression. The index has several potential applications, such as stratifying patients in clinical trials and identifying those most in need of treatment with the newest—and most expensive—therapies for the infection, researchers said. It also is relevant for treated patients with liver damage even after achieving a sustained virologic response (SVR).

In addition to the highly significant prognostic accuracy for decompensation and death from liver-related causes (P<0.001 for both), patients who met the index criteria had a more than 3-fold increased risk for death from any cause (P=0.002) compared with those who did not, according to a collaboration that included investigators from the Liver Center at Massachusetts General Hospital (MGH), in Boston, and the Icahn School of Medicine at Mount Sinai Hospital, in New York City. The results of the multicenter validation study were published in a recent issue of Gutt (King et al. 2014 August 20. [Epub ahead of print]).

The 186-gene signature in the tool was derived from a previously validated, genome-wide profiling study. It was coupled with other clinical factors, including an elevated bilirubin (>1 mg/dL) and a suppressed platelet count (<100,000/mm3). The index was first tested using tissue samples and clinical data in a training cohort of 216 HCV patients in Italy, for whom there was a median 10-year follow-up period. The index was then assessed in a validation cohort, which consisted of 145 patients with HCV infection in the United States, who had been followed for a median of 8 years.

The prognostic index demonstrated similar performance in the 2 tested populations. In the validation cohort, for example, hazard ratios (HRs) for patients who met criteria for high risk, compared with those having intermediate or low risk, were 7.36 for hepatic decompensation, 6.49 for liver-related death, 4.98 for liver-related adverse events, and 3.57 for all-cause mortality. All HRs were statistically significant, according to the researchers.

As assessed with the index, 16% of the validation cohort was identified as being at high risk, with the remainder evenly divided between intermediate and low risk.

The researchers, led by Lindsay Y. King, MD, of MGH, and Yujin Hoshida, MD, PhD, of Mount Sinai Hospital, characterized the prognostic index as “readily available for clinical use.” Dr. Hoshida said. that efforts to develop a commercially viable version of the index are now underway.

The data are encouraging because there is a major unmet need for better methods of predicting outcomes, said Thomas Baumert, MD, a hepatologist and professor of medicine at the University of Strasbourg, in France. Dr. Baumert noted that although the development of highly effective antiviral regimens has increased opportunities for eradication of HCV, he said patients with advanced liver disease remain at risk for liver failure even after HCV has been eradicated.

“Treatment-induced viral cure reduces, but does not eliminate, the risk for disease progression and development of liver cancer in patients with cirrhosis,” Dr. Baumert said in an interview. “Furthermore, in settings with limited resources, better tools for prognosis may identify those HCV patients most in need of the effective, but very expensive, antiviral regimens that have become available.”

Drs. King, Hoshida and Baumert reported no relevant financial conflicts of interest.

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Commentary:

A Brief Guide To Establishing a Do-It-Yourself HIV Prophylaxis Program GIFFIN W. DAUGHTRID DGE Perelman School of Medicin ne University of Pennsylvania Philadelphia, Pennsylvania

S. CAITLIN COYNINGHAM Practice Coordinator YHEP Health Center/Philad delphia FIGHT Philadelphia, Pennsylvania

CAROLINE E. SLOAN Perelman School of Medicin ne University of Pennsylvania Philadelphia, Pennsylvania

HELEN C. KOENIG MD D, MPH Clinical Assistant Professorr of Medicine Division of Infectious Diseases Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

F

or 6 young males, it was too late; they tested HIV positive at baseline screening for

the I Am Men’s Health program at the University of Pennsylvania.

Their results underscore a sobering reality in the United States: The incidence of HIV continues to rise among young men who have sex with men of color (yMSMc). Fortunately, we finally have the tools to reverse this trend, thanks to the FDA’s approval of daily emtricitabine/tenofovir (Truvada, Gilead) for pre-exposure prophylaxis (PrEP) in July 2012.

PrEP has been shown to be 92% effective at reducing HIV infection when taken daily. But how can we help a population of young, high-risk men with significant barriers to health care take a daily medication? For the past 2 years, the I Am Men’s Health program has run a PrEP distribution program that focuses on ensuring high adherence rates, thereby reducing the HIV burden in the community. Here, we present guidelines for building a similar program in a step-by-step format, which we hope

INFECTIOUS DISEASE SPECIAL EDITION 2015

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will inspire you to help increase PrEP’s availability to the population that needs it most.

Step 1: Identify the population—Our program focuses on yMSMc between the ages of 18 and 30 from low socioeconomic backgrounds, because they comprise the group at highest risk for acquiring HIV in our area.

Step 2: Identify a setting for medication distribution—Our program is located at the Youth Health Empowerment Project (YHEP) in downtown Philadelphia. YHEP focuses on reducing the spread of HIV and sexually transmitted infections (STIs) among adolescents through programs that teach leadership, decision making, and self-empowerment. YHEP currently serves more than 3,000 high-risk and hard-to-reach youth.

Step 3: Assemble a team—The following personnel have been essential to our program: Medical provider: A physician, physician assistant, or nurse practitioner must be present to address participants’ medical concerns.

Social worker: Our social worker is a full-time employee at YHEP and coordinates recruiting, enrollment, and insurance issues.

Phlebotomist: In line with US Centers for Disease Control and Prevention recommendations, baseline laboratory work includes HIV viral load, hepatitis B serology, chemistry panel, and STI screening. We repeat these labs every 3 months (with the exception of hepatitis B) and perform a rapid HIV test monthly. Of note, our labs are provided at no cost through the Jonathan Lax Treatment Center; otherwise, they would represent the only expense to operate the PrEP program described here.

Volunteers: Made up of undergraduates, medical students, and research assistants, our volunteers call participants, distribute medications, and assist with concurrent research studies.

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Step 4: Recruit—Focus on your target population.

We recruit participants from YHEP’s various educational programs, advertise at local universities, and receive referrals from local providers. Many of our participants learn about our program through word of mouth.

Step 5: Enroll—To enroll in our program, each participant must complete an informed consent document as well as the Gilead patient assistance medication form, which requires proof of household income. Gilead’s patient assistance program provides free emtricitabine/tenofovir to participants who do not have insurance and are under 500% of the federal poverty line. We ensure that participants with insurance have coverage for PrEP through our local pharmacy. Once these 2 documents are verified, the medications are delivered to YHEP usually within 2 weeks. Participants may start taking PrEP once we receive their medications and baseline laboratory results.

Step 6: Maintain adherence—This is arguably the most important and difficult step. Key factors that have allowed us to maintain adherence rates of >50% include: Setting: The PrEP program is located within a youth center that stays open late.

Frequency of Contact: Most patients pick up their pills weekly, promoting close follow-up.

Holistic focus provider: The services available to PrEP participants include STI screening, medical care as needed, YHEP’s support groups, free condoms, organized sports, and tutoring services.

Co-ownership: Weekly workshops and frequent solicitation of feedback help participants feel involved in the program and provide a sense of community.

By following these steps, you can construct a successful HIV prevention program that both raises awareness for and protects the community from HIV.

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ecent data suggest that some progress is being made in slowing

the HIV epidemic worldwide.

The annual HIV diagnosis rate in the United States declined by 33% from 2002 to 2011, and HIV incidence decreased in many at-risk groups. However, there was a 132% increase in HIV diagnoses during this time period among men having sex with men (MSM) between the ages of 13 and 24 years,1 representing a possible “epidemic within an epidemic” and a group in dire need of urgent action to stem the tide of new infections.

Globally, there was a 33% decline in new HIV infections from 2001 to 2012,2 but some subgroups remain at exceptionally high risk for HIV infection. For example, one study suggested that more than 1 in 3 female sex workers in sub-Saharan Africa are infected with HIV.3 These data suggest that there is a critical need for additional tools to combat the HIV epidemic, especially within key subgroups. Some might argue that with studies such as HPTN (HIV Prevention Trials Network) 052 showing the use of antiretroviral therapy (ART) leading to a 96% reduction in risk for HIV transmission to a partner,4 that “treatment as prevention” is the best strategy.

However, most believe that a multifaceted method of HIV prevention including use of condoms, circumcision, and behavioral interventions remains the most effective approach. Additionally, a method of HIV prevention that gives the power of prevention to the uninfected

ANNA K. PERSON, MD Assistant Professor, Adult Infectious Disease Vanderbilt University School of Medicine Nashville, Tennessee

individual remains a goal—a method that does not involve relying on a partner’s adherence to HIV medication or negotiating condom use. Thus, when the use of tenofovir/emtricitabine (Truvada, Gilead Sciences; TDF/ FTC) was approved in July 2012 for pre-exposure prophylaxis (PrEP), many felt that the armamentarium of HIV prevention tools had been expanded. This article will review some of the latest data on PrEP, and highlight some questions that remain.

Who Benefits Most From PrEP? PrEP is currently recommended for those at “substantial risk for HIV acquisition,” including those who have an HIV-infected sexual partner,5 but how much additional protective benefit might PrEP provide for monogamous couples in which the HIV-infected partner is consistently virally suppressed?

The original studies done leading to FDA approval of TDF/FTC for HIV prevention involved study populations at high risk for HIV acquisition. In the iPrEX (Chemoprophylaxis for HIV Prevention in Men) study, for example, participants were MSM or transgender women who had on average 18 sexual partners within a 12-week period, and 41% reported a history of transactional sex activity.6 In the Partners PrEP study, participants were

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Table. Clinical Considerations for the Initiation of PrEP 1. Is the patient truly at high risk for HIV acquisition?

Is the individual in a monogamous relationship?

If yes: Is the HIV-infected partner virally suppressed?

Discuss risks–benefits of PrEP if patient not at high-risk for HIV acquisition.

2. Document negative HIV test result.

Consider acute HIV at each visit.

Order an HIV-RNA if any question of viral-like syndrome before prescribing PrEP. 3. Document hepatitis B status and immunization status.

4. Consider safety.

Does patient have normal renal function or risk factors for chronic or acute kidney disease (ie, NSAID overuse, proteinuria)?

Does patient have osteoporosis or history of fractures?

Note: Some change in creatinine clearance and bone density has been seen in some clinical trials, and this may alter the risk–benefit analysis when considering PrEP.

5. Discuss the concept of resistance that may develop with poor adherence.

Although not seen at high levels in clinical trials, “real-world” data is lacking and development of resistance remains a consideration.

6. Schedule follow-up visits every 3 mo.

Provide STI screening (if needed), HIV testing, and screen for side effects.

Test renal function at 3 mo, and at each subsequent 6-mo interval.

Assess pregnancy intent and perform pregnancy testing every 3 mo.

7. Consider the PrEP cascade.

Recognize that “dropout” occurs at each step from the initial PrEP prescription to follow-up visits.

Emphasize adherence at each visit and use support staff (pharmacy staff, nursing, adherence counselors) to guide patient through each step of the cascade.

Provide support for ongoing adherence beyond the initial prescription.

8. Consider risk compensation.

Although not seen in clinical trials, “real-world” data is not yet available. Consider discussing condom use and number of partners/risk behaviors at each follow-up visit.

NSAID, nonsteroidal anti-inflammatory drug; PrEP, pre-exposure prophylaxis; STI, sexually transmitted infection Adapted in part from: Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV infection in the United States—2014. A Clinical Practice Guideline. http://www.cdc.gov/hiv/pdf/guidelines/ PrEPguidelines2014.pdf.

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heterosexual and were in serodiscordant relationships in the high-prevalence countries of Kenya and Uganda; the HIV-infected partners were not on ART.7 However, some of those seeking out PrEP may be seronegative partners of virally suppressed individuals in monogamous relationships. As the PARTNER study showed in an interim analysis, there were no cases of HIV transmission during 44,440 condomless sex acts when the HIV-infected partner was virally suppressed.8 In a modeling study using data from 7 studies, including PARTNER data, the HIV transmission rate among heterosexuals was estimated to range from 5.2 to 7.9 per 100,000 sex acts.9 This suggests a very low transmission rate in these cases, but not a rate of 0. Based on these data, in the case of a monogamous couple in which the HIV-infected partner is consistently virally suppressed, the appropriate acceptable risk should be considered for each individual, and health care providers should include discussion of risk–benefit analysis for those who are likely at low risk for HIV infection.

Should PrEP Be Targeted to Highest-Risk Groups?

Analysis of the iPrEx data looked at the number needed to treat (NNT) to prevent a single HIV infection per year for different risk groups within the iPrEx population. The NNT per year was 62 overall (95% confidence interval, 44-147). For MSM and transgender women reporting receptive anal intercourse without a condom, NNT was 36; for those who reported cocaine use, NNT was only 12. Having one partner resulted in an NNT of 100.10 This data suggests that PrEP is most effective for those at greatest risk for HIV acquisition. The US PrEP Demonstration Project of MSM and transgender women in Miami and Washington, DC showed that those who sought out PrEP were likely to be at highrisk for HIV acquisition, with just over 60% reporting condomless receptive anal intercourse in the preceding 3 months and more than 50% reporting recent substance use or abuse.11

Does PrEP Efficacy Depend on Adherence?

It has long been known that the efficacy of PrEP is related directly to adherence.6 PrEP was ineffective in heterosexual African women in the FEM-PrEP (Preexposure Prophylaxis Trial for HIV Prevention among African Women) and VOICE (Vaginal and Oral Interventions to Control the Epidemic) trials, which was thought to be due to TDF levels being detected in less than 30% of individuals.12,13 And, in a cohort study of 3 randomized controlled trials of PrEP, there were no infections (100% efficacy) in those whose dried blood–spot drug levels suggested they were taking at least 4 doses of TDF/FTC per week.14 The overall effectiveness for all trial participants (regardless of adherence level) was around 50%. Notably, there was significant early dropout rate from the trial and age was the strongest determinant of adherence. Those over 40 years of age were

3 times more likely to have detectable drug levels compared with those younger than 25 years old.14 In clinical trials of PrEP, serum drug levels were more reliable than self-report of medication adherence, and a recent study demonstrated the feasibility of using hair samples to measure drug adherence to PrEP.15

What About Intermittent Dosing?

Currently, recommendations are for once-daily dosing of PrEP.5 Recently however, the IPERGAY (Intermittent PrEP) trial, which enrolled a population of in MSM in France and Canada, demonstrated that 2 tablets of TDF/FTC taken 12 hours before intercourse, 1 tablet taken 24 hours after intercourse, and another tablet taken 48 hours after intercourse showed substantial effectiveness for HIV prevention. The study was stopped early as a result,16 suggesting the possibility that eventual intermittent dosing of PrEP may be an option.

The PrEP Cascade Initial concerns regarding adherence to PrEP as it relates to effectiveness and risk for development of resistance have remained at the forefront of questions surrounding its widespread implementation.

Having some perceived risk for HIV acquisition was associated with improved adherence in the FEM-PrEP study, although overall adherence in this trial was still quite low, and risk perception alone was not thought to fully explain adherence.17 The iPrEx OLE open-label extension study demonstrated what was referred to as a “PrEP cascade.” Investigators found that of those who engaged in high-risk behavior, 75% started PrEP, and 93% came back at 3 months for refills. However, only 70% of these individuals were taking PrEP at that time, resulting in just 39% of those at high risk for HIV taking meaningful doses of PrEP 12 weeks after the initial prescription.14 This attrition was within the context of a tightly monitored clinical trial with adherence counseling, frequent medical contact, and condom provision; the “real-world” PrEP cascade data may look even worse.

In the US PrEP Demonstration Project of MSM or transgender women who self-referred or were referred for PrEP by a clinic, uptake of PrEP was 60.5%,11 but further data about the PrEP cascade in this trial is not yet available.

PrEP Safety In the Bangkok Tenofovir study, in which more than 2,400 HIV uninfected IV drug users (IVDUs) were randomized to either tenofovir or placebo, statistically significant decreases in measures of kidney function were detected for those on tenofovir. However, these differences were of unclear clinical significance; tenofovir use was associated with only a 2.7 to 5.2 mL per minute decrease in creatinine clearance that was reversible after the drug was stopped.18 Furthermore, in an analysis of toxicities within the FEM-PrEP study there were no differences in serum

creatinine between the TDF/FTC and the placebo groups, but there was a significant increase in transaminitis for those who received TDF/FTC if they had previous exposure to hepatitis B (based on HBsAb positivity) or if they were more adherent to the drug.19 In a subset of the US MSM Safety Trial, 184 men who received tenofovir for PrEP were analyzed for effects on bone density. There was a small decrease of 1% at the femoral neck and 0.8% at the hip in bone mineral density by dual-energy x-ray absorptiometry scan, again, of unclear clinical significance. No fractures were seen.20 The effects that longer exposure to the drug may have on bone health in HIV-uninfected individuals are not known at present.

Resistance The development of antiretroviral resistance has been feared in the setting of low PrEP adherence or in the case of “missed” acute infections. No resistance was demonstrated in several of the initial largescale clinical trials of PrEP among those who became infected during the trials.6,7,21,22 However, in some trials a handful of individuals were found to have been infected with HIV at baseline (ie, “missed” acute infections) and subsequently randomized to receive PrEP; some of these study participants went on to develop resistance.6,7 Even in those individuals who demonstrated FTC resistance, mutations waned within 6 months of discontinuing the drug.23 During the US PrEP Demonstration Project, 20 individuals were diagnosed with the HIV infection during screening for the trial, and 3 others were found to have acute HIV,11 suggesting that medical care at the point of screening for PrEP use may be an ideal time to identify new infections, including acute seroconversions. In an analysis of those who seroconverted during the FEM-PrEP study (in which adherence was very low), TDF resistance was not seen. FTC resistance was rare and may have been accounted for by transmitted resistance.24 This suggests that even in the setting of “missed” acute infections or in the setting of low adherence, clinically meaningful antiretroviral resistance is rare.

Is Risk Compensation Occurring?

Risk compensation exists when individuals engage in high-risk behaviors due to perceived protection from an intervention.

No risk compensation was seen in the context of several large-scale clinical trials of PrEP, and in fact, participants had fewer sexual partners and more condom use during the trials.6,7,14,21,22 These were highly controlled environments, often with free condom distribution and frequent contact with medical providers.

What is happening “in the real world”? In the US PrEP Demonstration Project, nearly 5% of study participants reported their main reason for enrolling in the trial was “to make it safer for me to have sex without condoms,” and 59% cited “to make it safer for me to

INFECTIOUS DISEASE SPECIAL EDITION 2015

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have sex without condoms” as one of several other reasons for enrolling.11 More longitudinal follow-up data is needed to better understand whether those on PrEP will engage in riskier behaviors because of perceived protection.

8. Rodger A, Bruun T, Cambiano V, et al. HIV transmission risk through condom-less sex if HIV+ partner on suppressive ART: PARTNER study. Conference on Retroviruses and Opportunistic Infections.

Boston, MA: March 3-6, 2014. Abstract 153LB.

Other Drugs for PrEP

10. Buchbinder SP, Glidden DV, Liu AY, et al. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial.

Lancet Infect Dis. 2014;14(6):468-475.

For now, PrEP is based on TDF/FTC. However, TDF alone has been proven effective in trials with heterosexuals and IVDUs and, according to guidelines from the Centers for Disease Control and Prevention, it could “be considered an alternative for these specific populations.”5 However, it has not yet been studied in MSM and thus is not recommended for this group. As already mentioned, recent data from the IPERGAY trial may eventually support intermittent dosing of TDF/FTC. In data presented at the HIV Research for Prevention (HIV R4P) meeting, the injectable integrate inhibitor cabotegravir (S/GSK1265744, GlaxoSmithKline) has been shown to achieve high serum levels in both macaques and humans for up to 16 weeks. In healthy humans, drug concentrations also were measured in genital tissues. Phase II clinical trials will be the next step for this possible candidate PrEP drug.25,26

Summary In the few years that PrEP has been studied and used for HIV prevention, it has proved highly effective when taken at least on a semi-regular basis. Resistance and clinically significant effects on kidney and bone health have not been found to be problematic thus far, nor has the issue of risk compensation (although “real-world” data is lacking).

All of these issues warrant further study with greater longitudinal follow-up data as widespread rollout of PrEP continues. PrEP will have the largest effect on the highest-risk subgroups, and will in this regard likely continue to provide a crucial additive tool to help stem the tide of new HIV infections worldwide, assuming it is implemented properly (Table).

References 1.

Johnson AS, Hall HI, Hu X, et al. Trends in diagnoses of HIV infection in the United States, 2002-2011. JAMA. 2014;312(4):432-434.

2. UNAIDS. Global Report: UNAIDS report on the global AIDS epidemic. http://www.unaids.org/en/media/unaids/contentassets/ documents/epidemiology/2013/gr2013/UNAIDS_Global_ Report_2013_en.pdf. Accessed January 8, 2015.

3. Kerrigan D, Wirtz A, Baral S, Decker M, eds. The Global HIV Epidemics Among Sex Workers. Washington, DC: World Bank; 2013.

4. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505.

5. US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States-2014. http://www.cdc.gov/ hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed January 8, 2015.

9. Supervie V, Viard J-P, Costagliola D, et al. Risk of HIV transmission under combined anti-retroviral therapy: toward risk zero? J Acquir Immune Defic Syndr. 2014 Dec 2. [Epub ahead of print]

11. Cohen SE, Vittinghoff E, Bacon O, et al. High interest in pre-exposure prophylaxis among men who have sex with men at risk for HIV-infection: baseline data from the US PrEP demonstration project. J Acquir Immune Defic Syndr. 2014 Dec 11. [Epub ahead of print] 12. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-422.

13. Marrazzo J, Ramjee, J, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine or vaginal tenofovir gel in the VOICE study (MTN 003). Conference on Retroviruses and Opportunistic Infections. Atlanta, GA: March 3-6, 2013. Abstract 26LB. 14. Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14(9):820-829.

15. Baxi SM, Liu A, Bacchetti P, et al. Comparing the novel method of assessing PrEP adherence/exposure using hair samples to other pharmacologic and traditional measures. J Acquir Immune Defic Syndr. 2015;68(1):13-20.

16. ANRS. A drug taken at the time of sexual intercourse effectively reduces the risk of infection. http://www.ipergay.fr/un-grand-succesdans-la-lutte-contre-le-vih-sida.html. Accessed January 8, 2015.

17. Corneli A, Wang M, Agot K, et al. Perception of HIV risk and adherence to a daily, investigational pill for HIV prevention in FEM-PrEP. J Acquir Immune Defic Syndr. 2014;67(5):555-563.

18. Martin M, Vanichseni S, Suntharasamai P, et al. Renal function of participants in the Bangkok tenofovir study-Thailand, 2005-2012. Clin Infect Dis. 2014;59(5):716-724.

19. Mandala J, Nanda K, Wang M, et al. Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial. BMC Pharmacol Toxicol. 2014;15(1):77.

20. Grohskopf LA, Chillag KL, Gvetadze R, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIVuninfected men who have sex with men in the United States.

J Acquir Immune Defic Syndr. 2013;64(1):79-86.

21. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423-434.

22. Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet.

2013;381(9883):2083-2090.

23. Liegler T, Abdel-Mohsen M, Bentley LG, et al. HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial. J Infect Dis. 2014;210(8):1217-1227.

24. Grant RM, Liegler T, Defechereux P, et al. Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women. AIDS. 2014 Dec 9. [Epub ahead of print]

6. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599.

25. Spreen B, Rinehart A, Smith K, et al. HIV PrEP dose rationale for cabotegravir (GSK1265744) long-acting injectable nanosuspension. HIV Research for Prevention (HIV R4P). Cape Town, South Africa, October 28-31, 2014. Abstract OA03.02LB.

7. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410.

26. Andrews CD, Spreen WR, Mohri H, et al. Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science. 2014;343(6175):1151-1154.

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Commentary:

Why Do Vac Disease Out The United JAMES D. CHERRY, MD, MSC Distinguished Professor of Pediatrics David Geffen School of Medicine University of California at Los Angeles Los Angeles, California

KATHLEEN H. HARRIMAN, PHD, MPH Chief, Vaccine-Preventable Disease Epidemiolog gy Section Immunization Branch California Department of Health Richmond, California

N

umerous outbreaks of vaccine-preventable diseases have been reported in the United veral years. These States over the past sev

outbreaks have occurred on nattional, regional, and local levels and have involved childre en, adolescents, and adults.

To increase understanding regarding ng vaccinepreventable diseases in the present era, 2 important concepts should be addressed: reproduction number (Ro) and community (“herd”) immunity. Reproduction numberr can be defined as the transmissibility of a particular pathogen and indicates the number of secondary cases that one infected person would produce in a completely susceptible population. Measles, for example, is an extremely infectious airborne disease with an estimated Ro of 12 to 18.1-3 Community immunity describes a condition that occurs when a significant portion of a population (or herd) is immune—either through immunization or previous infection—and provides a measure of protection for individuals who are not immune (Figure). It is directly related to the Ro as well as the duration of protection following infection or vaccination. The level of protection conferred to individuals and, by proxy, society after infection or vaccination varies based on the causative pathogen and the vaccine.

Pertussis Individuals who are infected by or vaccinated against Bordetella pertussis only acquire short-term immunity.4-6 In addition to the new birth cohort of susceptible infants, there is a gradually increasing cohort of both older children and adults who once again become susceptible to pertussis. Despite high pediatric immunization rates in the United States, pertussis infections continue to occur in unvaccinated, susceptible children as well as in previously vaccinated older children, adolescents, and adults, due to primary vaccine failure and waning immunity.

Pertussis is a markedly different disease than measles and mumps, and is far more complex. Although it has been known for more than 2 decades that pertussis circulates in adults, this knowledge is almost always overlooked.7,8 Reported cases of pertussis only represent the tip of the iceberg. Pertussis causes infection and illness in all age groups, from birth through age 90 years or older. Currently, the majority of pertussis cases

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Figure. The relationship between community immunity and transmission of infectious diseases.

Image courtesy of the National Institute of Allergy and Infectious Diseases.

in adults are not diagnosed despite the fact that they are an important cause of infections in infants.9,10 During the 2010 and 2014 epidemics in California, more than 9,000 and 10,000 cases of pertussis were reported, respectively. In 2014, the number of cases reported in the state was the highest in more than 70 years.11-15 However, it is possible that during the previous epidemic in 2005, when approximately 3,000 cases were reported, many more cases occurred but were undetected. Reasons for the higher number of cases detected in 2010 and 2014 may include an increased awareness by the public and clinicians, along with the nearly universal use of polymerase chain reaction (PCR) testing, a diagnostic method that is far more sensitive than traditional culture.15-17 In 2004, PCR became the predominant diagnostic method for pertussis in California; in 2005, 66% of laboratory-confirmed cases were diagnosed by this method and, by 2014, 94% were confirmed using PCR.15 As with any outbreak of a vaccine-preventable disease, the 2010 and 2014 outbreaks in California were

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caused in part by unvaccinated children; however, the contributions of this group were modest compared with the effects of vaccine failure and waning vaccinederived immunity. Vaccine failure and waning immunity have always occurred with pertussis, but the effects likely were exaggerated in this epidemic because acellular pertussis vaccines, which have been recommended for the entire 5-dose series since 1997, are not as efficacious as the whole-cell vaccines that they replaced and the first generation of children who received only acellular vaccines had reached adolescence.4,5 The efficacy of current pertussis vaccines ranges from 60% to 70%, and this protection decreases over time after vaccination.18,19 Data from the 2010 California epidemic and other recent studies suggest that this immunity may be waning more quickly than experts previously believed.20-25 Pertussis infection is endemic in both adolescents and adults. Although not widely recognized, pertussis occurred in adults even in the prevaccine era.6 The 2- to 5-year cycles of pertussis epidemics are caused by an accumulation of susceptible children in the population in whom pertussis is more easily recognized. The clinical manifestations of pertussis in older children, adolescents, and adults depend on the time interval since their last exposure to the pathogen. If they are exposed on an annual basis, they will likely have asymptomatic infections.4,5,26 If a longer period of time has elapsed since their last exposure, this will lead to waning antibody levels and, therefore, they will have symptomatic pertussis with varying degrees of severity.

Solving the pertussis problem (ie, obtaining sufficient community immunity to interrupt transmission) is complex and currently not possible. Unlike measles, neither pertussis vaccination nor infection confers lifelong immunity.4,5,27 Because the Ro for pertussis is similar to that for measles, a similar level of community immunity (ie, >90%) would be necessary to control its transmission.1-3 And because pertussis immunity is constantly waning, even if immunization rates greater than 90% could be achieved, it would not be possible to sustain high levels of immunity without regular revaccination of persons of all ages. However, revaccinating all adults, even at 10-year intervals, is extremely unlikely because the universal immunization of adults against influenza and pneumococcal disease has not been successful.28 A more realistic goal may be to focus on reducing the number of infant infections because young infants have the most severe disease and comprise most fatal cases.29 Several approaches can be used to reduce the incidence of infections in infants. Between 2006 and 2011, â&#x20AC;&#x153;cocooningâ&#x20AC;? was the recommended approach for the prevention of pertussis in young infants. This strategy involves the vaccination of anyone who will have contact with infants who are not yet old enough to be vaccinated. However, logistically it is difficult to vaccinate all people who might have contact with an infant, and information on the efficacy of this strategy is minimal.30

A promising approach is the vaccination of pregnant women because this method has the potential to provide direct protection to infants. Pertussis antibodies are transplacentally transmitted to the infant and will offer protection until the infant is old enough to be vaccinated.31 Studies have demonstrated that maternal immunization is safe and effective in preventing pertussis in young infants.31-33 In a recent study, maternal immunization was 93% effective in preventing pertussis in the first 2 months of the infantâ&#x20AC;&#x2122;s life.32 The current DTaP (diphtheria, tetanus, and acellular pertussis) and Tdap (tetanus, diphtheria, and pertussis) vaccines are less than optimal, so research should be directed toward new vaccines with more antigens and a better balance of those currently included.4,5 Alternately, there could be a return to whole-cell DTwP (diphtheria, tetanus, and pertussis) vaccines in which lipopolysaccharide (LPS) has been attenuated. LPS was the cause of most adverse reactions after DTwP vaccination, but LPS antibodies are likely important for protection. DTaP vaccines are less reactogenic than DTwP vaccines because virtually all LPS has been removed.

Measles Individuals infected with measles virtually always experience lifelong immunity.34 In the prevaccine era, approximately 98% of the US population (and other large-population countries) was immune by age 18. As a result, measles outbreaks only involved children and were caused by the annual introduction of a nonimmune birth cohort. The measles vaccine confers longterm immunity for most recipients; thus, although more than 90% (estimates range from 83% to 95%) of the population must be immune to measles to interrupt transmission,1-3 the United States achieved sufficient community immunity for measles to be declared eliminated in 2000.

Unlike pertussis vaccines, measles vaccines are highly efficacious; 2 doses of the current vaccine for MMR (measles, mumps, and rubella) confers long-term immunity to more than 99% of recipients.35 Nevertheless, measles remains a concern because of travel into the United States from areas where the disease has not been eliminated, which creates opportunities for outbreaks and sustained transmission. Since the elimination of endemic measles transmission in the United States in 2000, a median of 60 measles cases were reported annually between 2001 and 2010. However, 222 cases of measles were reported in 2011, the majority of which were associated with importation. Many of the patients were unvaccinated or had unknown vaccine status. Of note, nearly half of the measles importations in 2011 occurred among individuals who initially were infected in Europe.36 Single-dose coverage with the MMR vaccine among US children aged 19 to 35 months has been higher than 90% since 1996; however, many European countries do not have sufficient community immunity to control transmission due to declining MMR immunization

rates. Measles was nearly eliminated in much of Europe, but the disease has staged a comeback in recent years because safety concerns have stopped many parents from vaccinating their children. Although reported cases of measles declined in Europe in 2012,37 more than 30,000 cases were reported in 2011. Approximately 15,000 measles infections were reported in France alone, including 714 cases with pneumonia, 16 with encephalitis, and 6 measles-related deaths.38 In 2014, there were 20 outbreaks with 603 cases in the United States39; this included 58 cases in California, which occurred in the first 4 months of the year.40 The majority of cases occurred in the unvaccinated and most were importation related from Asia and Pacific regions. A large outbreak associated with Disneyland in Anaheim, California, began in 2014 and continued into 2015. As of January 22, 2015, this outbreak resulted in approximately 70 cases with a single chain of transmission.

Despite the high overall rate of measles immunity in the United States, pockets of under- or unvaccinated individuals, including school children whose parents apply for personal belief exemptions (PBEs), present a cause for concern. From 2000 to 2013 in California, the overall rate of PBEs for children in kindergarten quadrupled from 0.77% to 3.15%. The rate of PBEs declined to 2.54% in 2014 after the law was changed to require counseling by a health care professional before a PBE is taken. However, some schools reported PBE rates as high as 80% in 2014.14 As the cohort of unvaccinated children transitions into adulthood and travels to regions of the world where measles continues to circulate, the importation of the disease back into the United States will perpetuate. Immunization rates domestically are high enough to prevent the sustained transmission of measles when it is reintroduced into the country. But the pockets of underor unvaccinated individuals pose a threat to those in the community who cannot be vaccinated, such as infants and immunocompromised individuals. If the number of unvaccinated individuals in the United States continues to grow, the country could experience a resurgence of measles similar to that observed in Europe.

A resurgence of measles occurred in the United States between 1989 and 1991 and was primarily attributable to low vaccine coverage. During that period, more than 55,000 cases of measles and 123 deaths occurred; 17,000 cases and more than 100 deaths were reported in the state of California alone.

Mumps Although mumps has not been declared eliminated in the United States, there appears to be limited endemic transmission. The Ro for mumps is estimated to be between 4 and 12, and the level of community immunity needed to interrupt its transmission is estimated at 75% to 92%.1-3 The mumps vaccine, however, may not be as efficacious as previously estimated; therefore, achieving the elimination of mumps may be more

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difficult than anticipated.

Post-licensure studies conducted in the United States between 1973 and 1989 determined that the efficacy of a single dose of the MMR vaccine was between 75% and 91%. A study in the United Kingdom reported that the efficacy of 2 doses of the MMR vaccine was 88%.

Protection was considered to be long-term41; however, outbreaks of mumps recently have occurred among populations in which most individuals received 2 doses of the MMR vaccine, thus calling into question the longterm effectiveness of the vaccine.42-53 In 2006, the United States experienced a multistate outbreak of mumps that resulted in 6,584 reported cases.42 This outbreak primarily affected college students in the Midwest, with the highest incidences occurring in dormitories. Studies conducted on the campuses involved in the outbreak found that high rates of 2-dose MMR vaccine coverage were not sufficient to prevent the outbreak. In addition to primary vaccine failure, the protective effect afforded by the vaccine may wane over time.

Another large outbreak occurred in the northeastern United States during 2009 and 2010.45,46,48,51 The index case was an 11-year-old boy who was infected with mumps in the United Kingdom. There were 3,502 reported cases, primarily within Orthodox Jewish communities in New York, where prolonged, close contact between individuals in congregate settings facilitated its transmission. Among patients for whom vaccination status was reported, 90% had received at least 1 dose of mumps-containing vaccine, whereas 76% had received 2 doses. In 2011, a mumps outbreak that involved 29 people occurred on a university campus in California.48 This outbreak was sparked by an unvaccinated student who also had been infected in the United Kingdom. One of the infected individuals had received a single dose of MMR, 22 had received 2 doses, 2 had been vaccinated with 3 doses of MMR, and 1 was unvaccinated. One person had received a single dose of mumps-rubella vaccine and had documented serologic evidence of prior mumps immunity; 2 of the other infected individuals were unsure of their vaccination status.

Similar to measles, cases of mumps also have increased in frequency throughout Europe, secondary to declining rates of MMR vaccinations. In England and Wales, 4,035 cases of laboratory-confirmed mumps were reported by the Public Health England in 2013.44 As mumps cases continue to be imported, outbreaks are likely to occur in US settings where large numbers of adolescents and young adults have very close and prolonged contact, which facilitates transmission. [Editor’s Note: In fall 2014, several cases of the mumps were reported among ice hockey players in the National Hockey League, which includes among its ranks athletes from Europe and North America.] In the prevaccine era, mumps typically affected young children, a population in which complications are less common. A transition to cases of mumps in older individuals is likely to result in a greater percentage of complicated

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cases.41 Although the Centers for Disease Control and Prevention has not yet made this recommendation, a third dose of MMR was implemented in 2010 during outbreaks in both the northeastern United States and in Guam. The additional dose appeared to aid in the control of these outbreaks.47,51,52

Conclusion Outbreaks of vaccine-preventable diseases are occurring in the United States and will continue as long as these diseases circulate throughout the world. The epidemiology of each vaccine-preventable disease is different and vaccine efficacy varies based on the type of vaccine. Therefore, approaches to prevent and control these outbreaks must differ. Several approaches will be useful in the prevention and control of all vaccinepreventable diseases, including keeping immunization rates high, implementing effective control measures when cases and outbreaks are reported, striving to develop more effective vaccines, and working to reduce the incidence of vaccine-preventable diseases around the world.

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2. Anderson RM, May RM. Vaccination and herd immunity to infectious diseases. Nature. 1985;318(6044):323-329.

3. Anderson RM, May RM. Immunisation and herd immunity. Lancet.

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4. Cherry JD, Heininger U. Pertussis and other Bordetella infections.

In: Cherry JD, Harrison GJ, Kaplan SJ, et al. eds. Feigin and Cherry’s textbook of pediatric infectious diseases. 7th ed. Philadelphia, PA: Elsevier/Saunders; 2014;1616-1639.

5. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clinical Microbiology Rev. 2005;18(2):326-382.

6. Cherry JD. Adult pertussis in the pre- and post-vaccine eras: lifelong vaccine-induced immunity? Expert Rev Vaccines.

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7. Cherry JD. The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection. Pediatrics. 2005;115(5):1422-1427.

8. Cherry JD. The present and future control of pertussis. Clin Infect Dis. 2010;51(6):663-667.

9. Bisgard KM, Pascual FB, Ehresmann KR, et al. Infant pertussis: who was the source? Pediatr Infect Dis J. 2004;23(11):985-989.

10. Wendelboe AM, Njamkepo E, Bourillon A, et al. Transmission of Bordetella pertussis to young infants. Pediatr Infect Dis J. 2007;26(4):293-299.

11. Misegades LK. Winter K. Harriman K, et al. Association of childhood pertussis with receipt of 5 doses of pertussis vaccine by time since last vaccine dose, California, 2010. JAMA. 2012;308(20):2126-2132.

12. Winter K, Harriman K, Zipprich J, et al. California pertussis epidemic, 2010. J Pediatr. 2012;161(6):1091-1096.

13. Winter K, Glaser C, Watt J, Harriman K. Pertussis epidemic—California 2014. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2014;63(48):1129-1132.

14. Data on file. California Department of Public Health.

15. Cherry JD. Pertussis: challenges today and for the future.

PLoS Pathog. 2013;9:e1003418.

16. Cherry JD. Why do pertussis vaccines fail? Pediatrics. 2012; 129(5):968-970.

17. Cherry JD. Epidemic pertussis in 2012—the resurgence of a vaccine-preventable disease. N Engl J Med. 2012;367(9):785-787.

36. Centers for Disease Control and Prevention. Measles-United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(15):253-257.

18. Cherry JD. Comparative Efficacy of acellular pertussis vaccines: an analysis of recent trials. Pediatr Infect Dis J. 1997; 16(4 suppl):S90-S96.

37. European Center for Disease Prevention and Control. European monthly measles monitoring-May 2012. http://ecdc.europa.eu/en/ publications/Publications/1205-SUR-Measles-monthly-monitoring. pdf. Accessed January 16, 2015.

19. Cherry JD, Heininger U, Stehr K, et al. The effect of investigator compliance (observer bias) on calculated efficacy in a pertussis vaccine trial. Pediatrics. 1998;102(4Pt.1):909-912.

20. Klein NP, Bartlett J, Rowhani-Rahbar A, et al. Waning protection after fifth dose of acellular pertussis vaccine in children. N Engl J Med. 2012;367(11):1012-1019.

21. Witt MA, Katz PH, Witt DJ. Unexpectedly limited durability of immunity following acellular pertussis vaccination in preadolescents in a North American outbreak. Clin Infect Dis. 2012;54(12):1730-1735.

22. Baxter R, Bartlett J, Rowhani-Rahbar A, et al. Effectiveness of pertussis vaccines for adolescents and adults: case-control study.

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23. Klein NP, Bertlett J, Fireman B, et al. Comparative effectiveness of acellular versus whole-cell pertussis vaccines in teenagers. Pediatrics. 2013;131(6):e1716-e1722.

24. Koepke R, Eickhoff JC, Ayele RA, et al. Estimating the effectiveness of tetanus-diphtheria-acellular pertussis vaccine (Tdap) for preventing pertussis: evidence of rapidly waning immunity and difference in effectiveness by Tdap brand. J Infect Dis. 2014;210(6):942-953.

25. Sheridan SL, Ware RS, Grimwood K, et al. Number and order of whole cell pertussis vaccines in infancy and disease protection.

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26. Deen JL, Mink CA, Cherry JD, et al. Household contact study of Bordetella pertussis infections. Clin Infect Dis. 1995;21(5):1211-1219.

27. Wendelboe AM, Van Rie A, Salmaso S, et al. Duration of immunity against pertussis after natural infection or vaccination. Pediatr Infect Dis J. 2005;24(5 suppl):S58-S61.

28. Trust for America’s Health. Adult immunization: shots to save lives. http://www. heaIthyamericans.org/repo rt/73/adult-immuni zation-2010. Accessed January 16, 2015.

29. Murray EL. Characteristics of severe Bordetella pertussis infection among infants <90 days of age admitted to pediatric intensive care units—southern California, Septermber 2009-June2011. Pediatr Infect Dis Soc. 2013;2:1-6.

30. Skowronski OM, Janjua NZ, Tsafack EP, et al. The number needed to vaccinate to prevent infant pertussis hospitalization and death through parent cocoon immunization. Clin Infect Dis. 2012;54(3):318-327.

31. Munoz FM, Bond NH, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA. 2014;311(17):1760-1769.

32. Dabrera G, Amirthalingam G, Andrews N, et al. A case-control study to estimate the effectiveness of maternal pertussis vaccination in protecting newborn infants in England and Wales, 2012-2013. Clin Infect Dis. 2014. [Epub ahead of print] 33. Amirthalingam G, Andrews N, Campbell H, et al. Effectiveness of maternal pertussis vaccination in England: an observational study.

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34. Cherry JD. Measles virus.In: Cherry JD, Demmler-Harrison G, Kaplan S, et al. eds. Feigin and Cherry’s textbook of pediatric infectious diseases. 7th ed. Philadelphia, PA: Elsevier/Saunders; 2014;2373-2394.

35. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases-measles. http:// www. cdc.gov/vaccines/pubs/pinkbook/meas.html. Accessed January 16, 2015.

38. European Center for Disease Prevention and Control. European monthly measles monitoring-February 2012. http://ecdc.europa. eu/en/publications/Publications/SUR_EMMO_European-monthly measles-monitoring-February-2012. pdf. Accessed January 16, 2015.

39. Centers for Disease Control and Prevention. Measles cases and outbreaks. http://www.cdc.gov/measles/cases-outbreaks.html.

Accessed November 22, 2014.

40. Centers for Disease Control and Prevention. Notes from the field: measles—California, January 1-April 18,2014. MMWR Morb Mortal Wkly Rep. 2014;63(16):362-363.

41. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases-mumps. http://www. cdc. gov/vaccines/pubs/pinkbook/mumps.html. Accessed January 16, 2015.

42. Cortese MM, Jordan HT, Curns AT, et al. Mumps vaccine performance among university students during a mumps outbreak.

Clin Infect Dis. 2008;46(8):1172-1180.

43. Marin M, Quinlisk P, Shimabukuro T, et al. Mumps vaccination coverage and vaccine effectiveness in a large outbreak among college students—Iowa, 2006. Vaccine. 2008;26(29-30):3601-3607.

44. Public Health England. Confirmed cases of measles, mumps and rubella in England and Wales: 2012 to 2013. https://www. gov.uk/government/publications/measles-confirmed-cases/ confirmed-cases-of-measles-mumps-and-rubella-in-england-andwales-2012-to-2013. Accessed January 16, 2015.

45. Kutty PK, Lawler J, Rausch-Phung E, et al. Epidemiology and the economic assessment of a mumps outbreak in a highly vaccinated population, Orange County, New York, 2009-2010. Hum Vaccin Immunother. 2014;10(5):1373-1381.

46. Barskey AE, Schulte C, Rosen JB, et al. Mumps outbreak in Orthodox Jewish communities in the United States. N Engl J Med. 2012;367(18):1704-1713.

47. Ogbuanu IU, Kutty PK, Hudson JM, et al. Impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak. Pediatrics.

2012;130(6):e1567-e1574.

48. Zipprich J, Murray EL, Winter K, et al. Mumps outbreak on a University Campus—California 2011. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2012;61(48);986-990.

49. Livingston KA, Rosen JB, Zucker JR, et al. Mumps vaccine effectiveness and risk factors for disease in households during an outbreak in New York City. Vaccine. 2014;32(3):369-374.

50. Kutty PK, McLean HQ, Lawler J, et al. Risk factors for transmission of mumps in a highly vaccinated population in Orange County, NY, 2009-2010. Pediatr Infect Dis J. 2014;33(2):121-125.

51. Fiebelkorn AP, Lawler J, Curns AT, et al. Mumps postexposure prophylaxis with a third dose of measles-mumps-rubella vaccine, Orange County, New York, USA. Emerg Infect Dis. 2013;19(9):1411-1417.

52. Nelson GE, Aguon A, Valencia E, et al. Epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella vaccine for outbreak control—Guam 2009 to 2010. Pediatr Infect Dis J. 2013;32(4):374-380.

53. Barskey AE, Glasser JW, LeBaron CW. Mumps resurgences in the United States: a historical perspective on unexpected elements.

Vaccine. 2009;27(44):6186-6195.

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Epidemiology of Infections After Solid Organ and Hematopoietic Stem Cell Transplantation RAYMUND R. RAZONABLE, MD Professor of Medicine, Mayo Clinic College of Medicine Division of Infectious Diseases William J. von Liebig Center for Transplantattion and Clinical Regeneration Rochester, Minnesota

I

nfections are common complications of transplantation. The risk for infection is determined by the epidemiologic exposures of the donor and the recipient, as well as the net state of immunosuppression.

In general, infections often follow a temporal pattern after solid organ transplantation (SOT; Table 1) and hematopoietic stem cell transplantation (HSCT; Table 2). However, this timeline has evolved in response to changes in prevention strategies. For example, the onset of cytomegalovirus (CMV) infection, which typically occurs during the first 3 months after SOT and HSCT, may be delayed by antiviral prophylaxis.1,2 Moreover, antimicrobial prophylaxis may have been selected for infections due to multidrug-resistant bacteria,3 and may have contributed to a rise in Clostridium difficile infection (CDI).4-6

This article reviews the epidemiology of infections after SOT and HSCT, with special focus on studies reported at Infectious Diseases Week (IDWeek).

Epidemiology of Infections in SOT Recipients The majority of infections after SOT are due to bacteria, although fungi and viruses account for a large proportion of cases (Table 1).7 These infections may be predicted by epidemiologic risks, time to onset, and net state of immunosuppression.

First Month Post-SOT. Infections during this period

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Table 1. Selected Infections After Solid Organ Transplantation Timeline

Clinical Syndromes, Major Pathogen Classes, or Risk Stratum

Specific Pathogens

Antimicrobial Prevention Strategies

Month 1

Surgical site infections

Staphylococcus sp.; Streptococcus sp; enterococcus; gram-negative bacterial infections; Candida sp.

Perioperative antibacterial prophylaxis for 24 h (eg, cefazolin; cefotaxime; cefepime; vancomycin; others) Perioperative antifungal prophylaxis in selected patients (eg, fluconazole; voriconazole; echinocandins)

Abdominal infections

Staphylococcus sp.; Streptococcus sp; enterococcus; gram-negative bacterial infections; Candida sp.

Not indicated (other than what is used for perioperative prophylaxis)

Urinary tract infections Escherichia coli; Klebsiella Not indicated pneumonia; Pseudomonas aeruginosa; enterococcus; coagulase-negative staphylococcus; Candida albicans

Months 1-6

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Pneumonia

Staphylococcus aureus; P. aeruginosa; K. pneumonia; Acinetobacter sp.; others

Not indicated (other than perioperative prophylaxis for lung recipients)

Diarrhea

Clostridium difficile

Not indicated

Bloodstream infections

S. aureus; coagulase-negative staphylococcus; enterococcus; E. coli; K. pneumonia; P. aeruginosa

Not indicated

Skin and mucosal disease

Herpes simplex virus

Acyclovir (Zovirax, Valeant) prophylaxis for 4-6 wk (for those not receiving valganciclovir [Valcyte, Genentech] prophylaxis)

Bacteria

Gram-positive bacteria such as S. aureus; coagulase-negative staphylococcus; and enterococcus; gram-negative bacteria such as E. coli, K. pneumonia, and P. aeruginosa as well as anaerobes such as C. difficile, Nocardia sp., and Mycobacterium tuberculosis

Not indicated

Viruses

CMV Epstein Barr virus Human herpesvirus 6 BK virus Parvovirus Hepatitis B Hepatitis C Enteroviruses Adenovirus

Valganciclovir prophylaxis (or CMV surveillance and preemptive therapy) for CMV prevention Lamivudine (Epivir, GlaxoSmithKline), entecavir (Baraclude, Bristol-Myers Squibb), other direct antivirals with or without hepatitis B immunoglobulin for HBV prevention Direct antiviral drugs with or without pegylated interferon and ribavirin for hepatitis C prevention

Timeline

Clinical Syndromes, Major Pathogen Classes, or Risk Stratum

Antimicrobial Prevention Strategies

Candida albicans; Aspergillus fumigatus; Mucor and Rhizopus; Cryptococcus neoformans; Histoplasma capsulatum; Coccidiodes immitis; Blastomyces dermatitidis; Pneumocystis jirovecii

Months 1-6 (continued)

Beyond 6 mo

Specific Pathogens

Parasites

Toxoplasma gondii

Trimethoprim-sulfamethoxazole

General risk patients (minimal immunosuppression)

Respiratory viruses such as influenza, respiratory syncytial virus Respiratory bacterial pathogens such as pneumococcus

No antibacterial agents, but encourage routine vaccination (but no live vaccine is allowed)

Over-immunosuppressed patient

Infections as per months 1-6

Prevention of infections as per months 1-6

CMV, cytomegalovirus; HBV, hepatitis B virus

are mostly related to surgical procedures, use of medical devices, and hospitalization. Although perioperative prophylaxis has reduced its incidence, surgical site infections due to Staphylococcus spp., Streptococcus spp., and other pathogens still occur. Intraabdominal infections, which often are polymicrobial, may occur in liver recipients who require abdominal reexploration (for hepatic artery thrombosis, bleeding, biliary leakage, or retransplantation).8 Some intraabdominal infections can present as liver abscesses, especially in patients with hepatic artery abnormality, primary biliary cirrhosis, and primary sclerosing cholangitis.8 Urinary tract infections (UTI), especially related to indwelling catheters, due to gramnegative bacteria such as Escherichia coli, gram-positive bacteria such as enterococcus, and fungi such as Candida albicans may be observed.9 Ventilator-associated pneumonia due to Pseudomonas aeruginosa, Acinetobacterr spp., Staphylococcus aureus, and others, and bloodstream infection (BSI) due to S. aureus, enterococcus, and coagulase-negative staphylococcus could complicate transplant hospitalization.10,11 Enterococcus is one of the most common bacteria to cause infection during the early period after SOT.7 It occurs at a median of 17 days after liver12 and 30 days after kidney transplantation.13 UTI is the most common presentation, but patients may present with abdominal abscesses and BSIs.12,13 The widespread use of antibacterial agents (for prophylaxis and treatment) has contributed to the increase incidence of CDI.4-6 More than 50% of CDI occurred within 2 weeks after liver,14 and within 30 days after heart and heart-lung transplantation.4 Risk factors for CDI in liver recipients included high Model for End-Stage Liver Disease score,

nonalcoholic steatohepatitis, and coinfections with HIV and hepatitis C virus (HCV).14 Sources of infections after SOT could be the recipient (latent and endogenous infection), the donor (donortransmitted infections), or the environment. Pretransplant colonization with S. aureus was a risk factor for S. aureus pneumonia after lung transplantation in patients with cystic fibrosis.15 During this early period, herpes simplex virus (HSV) may reactivate to cause localized ulcerative or disseminated disease; acyclovir (Zovirax, Valeant) prophylaxis (or valganciclovir [Valcyte, Genentech] for CMV) has decreased its incidence.16 Donor-derived infections such as an unrecognized virus (HIV, HCV, hepatitis B virus), fungi (due to Histoplasma capsulatum or Cryptococcus neoformans), and other pathogens such as West Nile virus, rabies virus, or lymphocytic choriomeningitis virus may be manifested clinically during this early period.17 A major clue to donor-derived infection is the occurrence of similar illness among recipients of organs from the same donor.17 Transplant donors often have prolonged hospitalization before organ harvest, and may have acquired nosocomial infections due to methicillin-resistant S. aureus, vancomycin-resistant enterococcus, P. aeruginosa, or Acinetobacter baumannii and could transmit the infections through transplantation.17 Second Period Post-SOT. Opportunistic infections classically occur during this period, with CMV as the most common pathogen.18 Without prophylaxis, CMV and herpesviruses reactivate to cause clinical disease during this period. The median time to onset of CMV was 90 days for kidney recipients who did not receive anti-CMV prophylaxis.19 CMV reactivation was especially high with the use of lymphocyte-depleting agents.19

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Table 2. Selected Infections and Associated Risks After Hematopoietic Stem Cell Transplantation Timeline

Risk Factors

Common Infections

Prevention Strategies

Preengraftment (1-4 wk)

Neutropenia Lymphopenia Hypogammaglobulinemia Mucosal defects (mucositis and vascular access devices)

Herpes simplex virus Gram-positive bacteria Gram-negative bacteremia Candida sp.

Aspergillus sp.

Respiratory viruses

Acyclovir (Zovirax, Valeant) prophylaxis Antibacterial prophylaxis Antifungal prophylaxis

Postengraftment (early: 4-26 wk; late: 26-52 wk)

Lymphopenia Hypogammaglobulinemia

CMV (early); human herpesvirus 6 (early); varicella zoster (late); Adenovirus; BK virus Aspergillus sp. and other molds; Pneumocystis jirovecii Toxoplasma gondii (early) Nocardia sp.

Streptococcus pneumonia and other encapsulated bacteria

Valganciclovir (Valcyte, Genentech) or foscarnet (prophylaxis or preemptive therapy) to prevent CMV; acyclovir prophylaxis for varicella zoster prevention (in patients not receiving valganciclovir); voriconazole (Vfend, Pfizer) or posaconazole (Noxifil, Merck) prophylaxis; trimethoprim-sulfamethoxazole prophylaxis for P. jiroveciii and T. gondii

CMV, cytomegalovirus

Because of the negative direct and indirect effects of CMV, antiviral prophylaxis is a standard practice, most commonly with valganciclovir, during the first 3 to 6 months after SOT.18 If antiviral prophylaxis is not provided, serial CMV surveillance should be performed and preemptive therapy provided.18 Other opportunistic infections that may occur during this second period include Listeria monocytogenes, Nocardia asteroides, Aspergillus fumigatus, and Pneumocystis jirovecii. Invasive aspergillosis may occur especially among patients with epidemiologic risks and exposures (ie, renal insufficiency, exposure to areas of construction, or previous colonization) and profound immunosuppression. Pneumonia is the most common clinical presentation of invasive aspergillosis, but it could disseminate to any organ, as a result of the vasculo-trophic nature of Aspergillus spp. Infections with endemic fungi (eg, H. capsulatum and Coccidioides immitis) and Cryptococcus neoformans may occur during this period.20-22 P. jiroveciii pneumonia traditionally occurs during this period but trimethoprim-sulfamethoxazole prophylaxis for at least 6 months after transplantation has made it uncommon.

Beyond Month 6 Post-SOT. By this period, the vast majority of SOT recipients will have good allograft function, and their level of immunosuppression reduced to minimal levels. These patients are primarily at risk for infections similar (or slightly higher) to those observed in nonimmunocompromised populations. However, a

24

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small group of SOT patients will have poor graft function as a result of recurrent rejection or chronic dysfunction, and are over-immunosuppressed and remain at high risk for opportunistic infections, including those due to P. jirovecii, L. monocytogenes, Cryptococcus neoformans, N. asteroides, CMV, Epstein-Barr virus (EBV), and Aspergillus spp. Persistent hypogammaglobulinemia increases the risk for pneumonia and bacteremia due to encapsulated organisms.

One of the most common late-onset opportunistic infections is varicella zoster virus (VZV) causing localized dermatomal or disseminated zoster. In endemic areas, human herpesvirus (HHV)-8 may cause Kaposiâ&#x20AC;&#x2122;s sarcoma, which could be the most common malignancy in these regions.23 EBV infection may occur at any time after SOT, and cause post-transplant lymphoproliferative disorder,16 especially those with persistent T-cell dysfunction.24 CMV disease is observed during the late period among high-risk patients who received antiviral prophylaxis.1,18,25 Late-onset CMV disease is associated with higher mortality after lung transplantation.1,18,25

Epidemiology of Infections Post-HSCT Reflecting the severity of immune dysfunction and the different phases of immune recovery, infections after HSCT also follow a traditional pattern (Table 2).26 Most infections occur during the first 3 months postHSCT, including those caused by bacteria, fungi, BK virus, CMV, and C. difficile.26 Patients who received

antithymocyte globulin (Thymoglobulin, Sanofi-Aventis) are at higher risk for infections.27 Preengraftment Period. The 2 major factors that increase the risk for infection during the first month after HSCT are neutropenia and lymphopenia and disruption of mucocutaneous barrier. HSV reactivation commonly occurs to cause mucosal ulcers; acyclovir prophylaxis prevents this.16 Severe chemotherapyinduced mucositis may lead to translocation of oral and gastrointestinal flora to cause BSI, which could result in severe septic shock due to viridans group streptococcus.28 S. aureus, coagulase-negative staphylococcus, E. coli, and P. aeruginosa may gain entry into the bloodstream through indwelling vascular catheters. Many of these pathogens have developed multidrug resistance,3 including carbapenem resistance.29 Risk factors for carbapenem-resistant gram-negative infections are β-lactam/β-lactamase inhibitor use, trimethoprimsulfamethoxazole use, and colonization with resistant organisms.29 Candida spp. is the most prevalent fungal infection during this period; fluconazole prophylaxis is used for its prevention.30 Prolonged (defined as more than 14 days) and severe (defined as less than 500 cells) neutropenia is a risk for Aspergillus spp. and other molds; posaconazole (Noxafil, Merck) or voriconazole (Vfend, Pfizer) prophylaxis is preferred in these situations. In a study of patients with prolonged neutropenia, the risk for invasive fungal infection was 10% to 16%.31 HSCT patients are commonly febrile during the preengraftment period, and prompt the administration of empiric or targeted broad-spectrum antimicrobial therapy. Knowledge of the resistance patterns of bacterial pathogens is essential for choosing effective empiric regimens. Infections with multidrug-resistant gram-negative bacteria are associated with a nonsignificant trend for higher risk for death,3 and use of effective empirical therapy resulted in a lower 30-day mortality.29 The widespread use of antibacterial prophylaxis and therapy increases the risk for CDI. Additionally, low albumin levels and certain genetic variants in chromosome 13 may predispose to CDI in HSCT recipients.32 Immediate Postengraftment Period. Following engraftment, the risk for graft-versus-host disease (GVHD) is increased and immunosuppressive drugs are given to prevent this complication. Hence, this period, which is generally during days 30 to 100 post-HSCT, is characterized by severe impairment in cell-mediated and humoral immunity (ie, lymphopenia and hypogammaglobulinemia), and consequently, is a high-risk period for opportunistic infections. CMV is one of the most common infections, and manifests as fever, diarrhea, and pneumonia.16 To avoid myelosuppressive effects of valganciclovir prophylaxis, HSCT recipients undergo CMV surveillance to detect CMV reactivation that can be treated preemptively.33 HHV-6 reactivation may occur and cause fever, rash, hepatitis, and delirium.34 HHV-6 viral load was directly correlated with

delirium.34 Other opportunistic pathogens that cause disease during this period are Aspergillus sp., Fusarium sp., Mucorr and Rhizopus sp., and P. jirovecii.

Late Phase. In some HSCT patients, such as those with chronic GVHD, this period (beyond 100 days) is characterized by persistent impairment in cell-mediated and humoral immunity. In these patients, infections with CMV, VZV, EBV, Aspergillus sp., and P. jiroveciii continue to occur.

The majority of HSCT patients will have adequate immune reconstitution, and the risk for infections will be lower. Infections with respiratory viruses such as influenza, parainfluenza, and respiratory syncytial viruses (RSV) may occur. There is variation in treatment approaches for RSV infections, with either oral or inhaled ribavirin.35,36 A recent study supported oral ribavirin for treatment.37 Infections with encapsulated bacteria such as Streptococcus pneumonia are particularly more common in patients with hypogammaglobulinemia. Vacccination has reduced the incidence of pneumococcal disease in HSCT patients.38 VZV is a common opportunistic infection during the late period post-HSCT.39,40 Acyclovir has reduced its incidence, but zoster continues to occur after cessation of acyclovir prophylaxis, at a median of 19 months post-HSCT.39,40

Conclusions A wide variety of infections complicate the clinical course of organ and tissue transplantation. Risks for infection vary depending on the type of transplant and the type and severity of immunologic impairment.

Some infections may be predicted, and be prevented preemptively with the use of vaccines, stringent surveillance, and antimicrobial prophylaxis. Despite these, infections still occur, and should be diagnosed promptly and treated aggressively. This article provided a review of the studies reported at the 2014 IDWeek. These newly reported clinical studies illustrate the dynamic nature of the field of transplant infectious diseases.

References 1.

Beam ELT, Kremers W, Razonable RR. Cytomegalovirus disease after lung transplantation is associated with increased mortality despite extended antiviral prophylaxis. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 454.

2. Marcelin JR, Beam E, Razonable RR. Cytomegalovirus infection in liver transplant recipients: updates on clinical management. World J Gastroenterol. 2014;20(31):10658-10667.

3. Larue R, Royo C, Alp S, Lu N, Shoham S. Multidrug resistant Gram negative bacteria in a cohort of hematopoietic stem cell transplant recipients. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 450.

4. Bruminhent JTC, Cawcutt K, Razonable RR. Epidemiology and outcomes of Clostridium difficile infections in heart and heart-lung transplant recipients. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 445.

5. Chong PKC, Hathcock M, Kremers W, et al. Clostridium difficile infection and mortality in lung transplant recipients: a single-center retrospective cohort review. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 461.

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6. Ramanan PCNW, Wilhelm MP, Razonable RR. Association of Clostridium difficile infection with excess mortality after liver transplantation for hilar cholangiocarcinoma. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 453.

25. Santos CBD, Yusen R, Olsen M. Incidence, risk factors and outcomes of delayed-onset cytomegalovirus disease in a large retrospective cohort of lung transplant recipients. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 444.

7. Lee SJ, Lee S, Park JY. Infectious complications and mortality after liver transplantation according to donor: comparison between cadaveric and living donor transplantation. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 447.

26. Alp SO, Shoham S, Lu N et al. Infections in recipients of haploidentical bone marrow transplant: a modified prospective cohort study.

Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 449.

8. Aldeiri A, Rupali P, Gonulalan M, et al. Incidence and risk factors for the development of liver abscesses in liver transplant recipients with intraabdominal infections—a 10-year retrospective review. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 441.

27. Pedevillano L, Kleiger S, Seif AE et al. Infection risk in pediatric stem cell transplant recipients for hemophagocytic lymphohistiocytosis versus acute leukemia. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 439.

9. Ariza-Heredia EJ, Beam EN, Lesnick TG, et al. Urinary tract infections in kidney transplant recipients: role of gender, urologic abnormalities, and antimicrobial prophylaxis. Ann Transplant. 2013;18:195-204.

28. Freifeld AG, Razonable RR. Viridans group streptococci in febrile neutropenic cancer patients: what should we fear? Clin Infect Dis. 2014;59(2):231-233.

10. Lee SO, Brown RA, Kang SH, et al. Toll-like receptor 4 polymorphisms and the risk of gram-negative bacterial infections after liver transplantation. Transplantation. 2011;92(6):690-696.

29. Satlin M, Cohen N, Ma KC et al. Prevalence, risk factors, and outcomes of bacteremia caused by carbapenem-resistant Enterobacteriaceae in neutropenic patients with hematologic malignancies.

Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 434.

11. Lee SO, Brown RA, Kang SH, et al. Toll-like receptor 2 polymorphism and Gram-positive bacterial infections after liver transplantation.

Liver Transpl. 2011;17(9):1081-1088.

12. Elbatta M, Rupali P, Hadid H et al. Enterococcal infections in liver transplant recipients—a 9-year retrospective review. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 455.

13. Patel T, Rupali P, Moreno D et al. Enterococcal infections in kidney transplant recipients—a 4-year retrospective review. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 458.

30. De Luca M, Kleiger SB, Damiano A et al. Incidence of candidemia in pediatric transplant patients. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 463.

31. Saxinger L, Pabani A. Patients with prolonged neutropenia displayed similar IFI rates regardless of hematologic diagnosis and chemotherapy status: a challenge to antifungal prophylaxis. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 430.

14. Sullivan T, Rana M, Patel G, Huprikar S. The epidemiology of Clostridium difficile infection in liver transplant recipients. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 448.

32. Apewokin S, Coleman E, Enderlin C et al. Genetic variants associated with the development of Clostridium difficile infection during autologous stem cell transplantation. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 438.

15. St Pierre J, Poirier C, Chalaoui J et al. Association between pre-transplant Staphylococcus aureus colonizartion and post-transplant S. aureus infection among cystic fibrosis lung transplant recipients.

Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 426.

33. Razonable RR, Hayden RT. Clinical utility of viral load in management of cytomegalovirus infection after solid organ transplantation. Clin Microbiol Rev. 2013;26(4):703-727.

16. Razonable RR, Eid AJ. Viral infections in transplant recipients.

Minerva Med. 2009;100(6):479-501.

17. Chong PP, Razonable RR. Diagnostic and management strategies for donor-derived infections. Infect Dis Clin North Am. 2013;27(2):253-270.

18. Razonable RR, Humar A. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013;13(suppl 4):93-106.

34. Hill J, Boechk M, Leisenring W et al. Human herpesvirus 6 reactivation, delirium, and the effect of antiviral prophylaxis strategies after cord blood transplantation. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 433.

35. Beard O, Freifeld A, Ison M et al. Diagnosis and treatment of respiratory syncytial virus in immuncompromised hosts in large midwestern transplant centers. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 429.

19. Chitasombat M, Watcharananan S. Incidence, burden and cost analysis of CMV reactivation after use of anti-thymocyte globulin in resource-limited setting. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 431.

36. Wollersheim S, Armann J, Khan K. Systemic ribavirin therapy for respiratory syncytial virus infections in pediatric solid organ transplant patients: a single center experience over 3 RSV seasons.

Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 465.

20. Sun HY, Alexander BD, Huprikar S, et al. Predictors of Immune Reconstitution Syndrome in Organ Transplant Recipients With Cryptococcosis: Implications for the Management of Immunosuppression.

Clin Infect Dis. 2015;60(1):36-44.

37. Marcelin JR, Wilson JW, Razonable RR. Oral ribavirin therapy for respiratory syncytial virus infections in moderately to severely immunocompromised patients. Transpl Infect Dis. 2014 Apr;16(2):242-50.

21. Sun HY, Alexander BD, Lortholary O, et al. Lipid formulations of amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system cryptococcosis. Clin Infect Dis. 2009;49(11):1721-1728.

22. Sun HY, Alexander BD, Lortholary O, et al. Cutaneous cryptococcosis in solid organ transplant recipients. Med Mycol. 2010;48(6):785-791.

23. Ariza-Heredia EJ, Razonable RR. Human herpes virus 8 in solid organ transplantation. Transplantation. 2011;92(8):837-844.

24. Paulsen G, Feig D, Fowler K et al. Epstein Barr virus load and lymphocyte subset number and function in pediatric renal transplant patients. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014.

Abstract 435.

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38. Lee YJ, Huang Y, Gonzalez V et al. Incidence and risk factors for pneumococcal disease in cancer patients: a 20 year single center study at Memorial Sloan Kettering Cancer Center. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 440.

39. Han SB, Lee JW, Lee D-G et al. Varicella zoster infection after allogeneic hematopoietic stem cell transplantation in Korean children under relatively short term acyclovir prophylaxis. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014. Abstract 442.

40. Sahoo F, Xie H, Liesenring W et al. Five year cumulative incidence of herpes zoster in autologous hematopoietic stem cell transplant recipients who received long-term acyclovir or valacyclovir prophylaxis. Presented at IDWeek; Philadelphia, PA: October 9-12, 2014.

Abstract 436.

DIFICID ® (fidaxomicin) tablets, for oral use BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for Full Prescribing Information.

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID® and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused

by Clostridium difficile.

Clostridium difficile-Associated Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD).

CONTRAINDICATIONS Hypersensitivity to fidaxomicin.

WARNINGS AND PRECAUTIONS Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections.

Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficilee infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.

Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.

Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials DIFICID (N=564)

Vancomycin (N=583)

n (%)

n (%)

Anemia

14 (2%)

12 (2%)

Neutropenia

14 (2%)

6 (1%)

System Organ Class Preferred Term

Metabolism and Nutrition Disorders:: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders:: drug eruption, pruritus, rash Post Marketing Experience Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible.

Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively.

The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman.

Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.

In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

OVERDOSAGE No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin.

Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay.

Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells.

Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC0-t) was approximately 100 times that in humans.

Blood and Lymphatic System Disorders

Distributed by:

Gastrointestinal Disorders Nausea

62 (11%)

66 (11%)

Vomiting

41 (7%)

37 (6%)

Abdominal Pain

33 (6%)

23 (4%)

Gastrointestinal Hemorrhage

20 (4%)

12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders:: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations:: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count

Cubist Pharmaceuticals U.S. Lexington, MA 02421 USA Made in Canada.

DIFICID® is a registered trademark of Cubist Pharmaceuticals in the United States. ©2014 Cubist Pharmaceuticals. All rights reserved.

Revised: April 2014 DIF-0161-1

In adult patients with Clostridium difficile-associated diarrhea (CDAD)

DIFICID® (fidaxomicin) tablets demonstrated comparable clinical response at 10 days and superior sustained clinical response through 25 days beyond the end of treatment vs vancomycin1* DIFICID (n=542) was studied vs vancomycin (n=563) in two large Phase 3 CDAD trials (N=1105)1 Outcomes of treatment with DIFICID1 100

88% 86%

DIFICID 200 mg twice daily (n=542) vancomycin 125 mg four times daily (n=563)

PATIENTS (%)

80

71% 57%

60

40

20

0

CLINICAL RESPONSE

SUSTAINED CLINICAL RESPONSE

Primary endpoint: clinical response at the end of 10-day treatment.1 Sustained clinical response: initial clinical response at 10 days + survival without proven or suspected CDAD recurrence at 25 days post treatment end.1 Study description: two Phase 3, randomized, double-blind, non-inferiority studies (N=1105) comparing the efficacy and safety of oral DIFICID 200 mg twice daily versus oral vancomycin 125 mg four times daily for 10 days in the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements in the 24 hours before randomization and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization). Enrolled patients received no more than 24 hours of pretreatment with vancomycin or metronidazole and had either no prior CDAD history or only one prior CDAD episode in the past 3 months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.1

Efficacy measured only at days 10 and 35.1

DIFICID was associated with a lower rate of CDAD recurrence vs vancomycin at 25 days post treatment end as measured by sustained clinical response (14% [67/474] vs 26% [127/488])2,3 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 DIFICID patients1 In patients infected with a BI isolate, DIFICID did not demonstrate superiority in sustained clinical response when compared with vancomycin1

Indications and Usage DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficileassociated diarrhea (CDAD) To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile

Important Safety Information DIFICID is contraindicated in patients with hypersensitivity to fidaxomicin DIFICID should not be used for systemic infections Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. In the event of a severe reaction, discontinue DIFICID Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%)

Please see brief summary of full Prescribing Information for DIFICID on adjacent page.

For more information about DIFICID and the AccessDIFICID™ patient access support program, please visit DIFICID.com or call 844-CUBIST-CARES (844 -282-4782) (M-F, 8 AM-8 PM; SAT, 9 AM-1 PM, ET) *Confidence interval was derived using Wilson’s score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response data and were imputed using a multiple imputation method.1 References: 1. DIFICID [package insert]. Lexington, MA: Cubist Pharmaceuticals; April 2014. 2. Data on file. A multinational, multicenter, double-blind, randomized, parallel-group study to compare the safety and efficacy of 200 mg PAR-101 taken q12h with 125 mg vancomycin taken q6h for ten days in subjects with Clostridium difficile-associated diarrhea. Clinical study report 101.1.C.003. June 17, 2010. Optimer Pharmaceuticals, Inc. 3. Data on file. A multinational, multicenter, double-blind, randomized, parallel-group study to compare the safety and efficacy of 200 mg PAR-101 taken q12h with 125 mg vancomycin taken q6h for ten days in subjects with Clostridium difficile-associated diarrhea. Clinical study report 101.1.C.004. June 4, 2010. Optimer Pharmaceuticals, Inc.

www.cubist.com ©2014 Cubist Pharmaceuticals DIF-0136-1 September 2014 DIFICID® and AccessDIFICIDTM are trademarks of Cubist Pharmaceuticals.

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

Preventing HospitalClostridi Optimal Stra BRIAN CURRIE RIE, MD, MPH Vice Presiden nt, Medical Research Division of Inffectious Diseases Montefiore Med dical Center Assistant Dean for or Clinical Research Professor of Clinical al Medicine Albert Einstein College ge of Medicine New York, New York

T

he past 20 yearss have see en a dramatic d tic change in the epidemiology y of Clostridium difficile e infecttions (CDI (CDI) in the United States and on a global g basis. The frequency of infections infectio h

2000 to 2009 the number of US hospitalized diagnosis more than doubled, from approximate number with a primary CDI diagnosis more than tr

Overall incidence of infections has increased dramatically over the period from 2001 to 2012 (Table 1).1-3 Data from the Centers for Disease Control and Prevention (CDC) National Health Safety Network have identified a 28% increase in the number of reported acute care– onset CDI cases from 2010 to 2012.4 Simultaneously, there has been a significant trend toward increased severity of infections during the epidemic, which has been largely attributed to the emergence and rapid dissemination of a virulent strain of C. difficile—the NAP1/BI/027 strain. CDI-related deaths increased 400% from 2000 to 2007, and CDI now accounts for at least 14,000 patient deaths annually.5,6 Beyond the increased morbidity and mortality, CDIs are estimated to cost US acute care hospitals $800 million per year.7 CDIs now account for 12.1% of all hospital-acquired infections and C. difficile has become the most common nosocomial pathogen.8 Guidelines for controlling CDI prevalence in acute care settings were issued early in the epidemic and have been updated over the years. Although every acute care hospital in the United States has adopted and initiated

some compone that the CDI epid has been refractor been put in place to tial CDI control interven including the existing evid It focuses on primary CDI prevention pr activities.

Infection Control and Environmental vironmental Hygi Hygiene It is well established that the primary mode of C. difficile transmission within hospital facilities results from person-to-person spread by ingestion of spores shed by symptomatic infected patients. The process is mediated by transient colonization of health care workers’ hands with spores and from contact with environmental reservoirs of spores. C. difficile spores are extremely hardy and can survive in the inanimate environment for weeks.

Additionally, evidence has accumulated that C. difficile spores are resistant to alcohol-based hand products and most commonly used hospital disinfectants.

This has resulted in recommendation of the use of soap and water for hand hygiene and diluted bleach for

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Table 1. Acute Care Hospitalizations With CDI Discharge Diagnosis2,3 Year

Annual Rate/100 Hospitalizations

2001

5.6

2008

11.6

2009

11.3

2010

11.5

2011

12.4

2012

13.6

CDI, Clostridium-difficile Clostridium difficile infection; IM, intramuscular

environmental disinfection in C. difficile control efforts.

The existing evidence strongly suggests that targeted infection control and environmental hygiene interventions could prevent the transmission of C. difficile and reduce primary CDI rates.

Guidelines from the Association for Professionals in Infection Control and Epidemiology (APIC), Society for Healthcare Epidemiology (SHEA)/Infectious Disease Society of America (IDSA), and CDC have all recommended a series of infection control and environmental hygiene CDI control interventions for many years (Table 2).9-12 The CDC guidelines and the most recent SHEA/IDSA guidelines have recommended a tiered approach to the initiation of interventions until effective CDI control is achieved. There is currently no data on how individual hospitals have chosen which of these components to adopt and implement or how many of the options they have instituted, nor how, or if, they have adopted the recommendations to document compliance with the measures. As hospitals initiated infection control and environmental hygiene interventions, investigations began to document an “accumulating impact” of successively introduced prevention measures in reducing CDI rates. This conceptually resulted in a “bundled” approach to the initiation of infection control—the simultaneous initiation of key infection control and environmental hygiene interventions.13,14 Three reports in the literature demonstrate that the hospital-wide introduction of CDI-bundled interventions substantially reduced institutional CDI rates.15-17 In Salgado et al, bundle interventions included staff education, empiric placement of all patients with diarrhea into contact isolation, environmental disinfection with a bleach product, and soap and water for hand hygiene.15 Implementation was associated with a 45.3% decrease in the institutional CDI rate, which was sustained over a subsequent 3-year period. Abbett et al used a bundle consisting of staff education, soap and water hand hygiene, environmental disinfection with bleach, and enhanced communication strategies between caregivers, laboratory staff, and environmental services personnel to promote earlier diagnostic testing, earlier

30

W W W. I D S E . N E T

initiation of isolation precautions, and treatment. Theses interventions were superimposed on already existing policies regarding use of contact isolation. The bundle intervention was associated with a 40% reduction in the institutional CDI rate.16 Finally, Muto et al employed a bundle consisting of staff education, increased and earlier case finding, soap and water hand hygiene, bleach for environmental disinfection, development of a C. difficile management team, monitored compliance with hand hygiene and isolation protocols, and an antimicrobial stewardship program (ASP) targeting antibiotics considered high risk for CDI. Bundle initiation was associated with a reduction in the institutional CDI rate from 10.4 cases per 1,000 discharges to 2 to 4 cases per 1000 discharges.17 Koll et al described a 35-hospital study designed to evaluate the impact of instituting an infection control/ environmental services intervention bundle on primary CDI rates.18 Each participating hospital was required to develop an internal interdisciplinary team consisting of infection preventionists, physician and nursing champions, environmental support staff, and quality improvement personnel to drive the bundle intervention. A prebundle evaluation documented significant variability in CDI-directed infection control and environmental services interventions in place among hospitals, and only 52% measured compliance with adopted prevention practices. A standardized bundle was created including rapid initiation of contact isolation of all patients with diarrhea, soap and water hand hygiene with monitored compliance, standardized bleach-based environmental disinfection with a checklist, and patient-dedicated rectal thermometers. Contact isolation included use of single rooms and use of glove and gown personal protective equipment. Standardized CDI case definitions and case finding methodologies were also instituted.

Bundle initiation was associated with a 33% decline in CDI rate and the largest decreases were observed for hospitals that started the initiative with more elevated CDI rates.18 Existing evidence suggest that carefully designed and systematically implemented infection control/environmental hygiene intervention bundles targeting CDI prevention can substantially reduce CDI rates in acute care hospitals. Furthermore, studies have demonstrated that these interventions can be successfully implemented across large numbers of hospitals and that they will have maximal impact in institutions that have the highest CDI rates.

Antimicrobial Stewardship and Primary Prevention Given that the great majority of patients with CDI have had prior exposure to antimicrobial agents, it is almost intuitive to consider limitation or restriction of antibiotics associated with the development of CDI as a primary preventive measure. Current APIC, SHEA/ IDSA, and CDC guidelines recommend implementation of institution-wide ASPs as a measure to affect primary

Table 2. Recommended Infection Control/Environmental Hygiene Measures for CDI Prevention9-12 Infection Control • Rapid testing of symptomatic patients or empiric contact isolation until testing completed • Contact isolation • Room signage • Single room with private toilet or commode • Dedicated equipment • Gloves and gowns when entering room • Hand hygiene with soap and water when entering and leaving room • Monitor compliance with hand hygiene and isolation protocols Environmental Hygiene • Cleaning and disinfection of equipment, high-touch surfaces, and floor • Use bleach-based disinfectant • Monitor compliance/effectiveness with checklist CDI, Clostridium difficile infection

CDI rates, and the practice has been widely supported in the literature, although there has only been limited data regarding the efficacy of this approach and limited guidance as to how to accomplish desired outcomes.

Nearly all antibiotics have been associated with the onset of CDI, and a single dose of preoperative antibiotic has been demonstrated to be sufficient to cause infection.9,19 There are numerous investigations in the literature attempting to identify the CDI risk associated with specific antibiotics, but the widespread use of antimicrobial agents and polypharmacy have complicated the process of identifying them. Clindamycin and cephalosporin antibiotic therapy consistently has been identified with increased risk for CDI.9 Fluoroquinolone antibiotics have been suggested to carry increased risk for CDI infection based on the fact that the NAP1/BI/027 strain exhibits high-level fluoroquinolone resistance, but the evidence to support this association remains controversial.9 There are a number of reports in which antibiotic stewardship activities alone, or in conjunction with other infection control and environmental interventions, have been able to reduce primary CDI rates. Successful clindamycin restriction has been demonstrated to significantly reduce CDI rates in 2 studies.20,21 Two other studies were able to document significant reductions in CDI rates with reductions in broad-spectrum antibiotic prescribing (defined as second- and thirdgeneration cephalosporins, piperacillin/tazobactam, carbapenems, fluoroquinolones, and vancomycin) and

by targeting imipenem and piperacillin prescribing.22,23 Both of these studies used a prospective audit and feedback approach and activities in both studies were only ICU based. Three additional hospital-wide intervention studies targeted CDI high-risk antibiotics (defined as second- and third-generation cephalosporins, fluoroquinolones, and clindamycin), third-generation cephalosporin and aztreonam antibiotic prescribing, and cephalosporins and augmentin.24-26 All studies were able to significantly reduce targeted antibiotic prescription and primary CDI rates.

A recent multicenter “before-and-after” intervention comparative study sought to identify the potential additive contribution of C. difficile–targeted antimicrobial stewardship activities in preventing primary CDI among 6 intervention and 4 control hospitals that had already documented more than 80% compliance with a prior CDI infection control/environmental services prevention bundle.27 State CDI reporting was mandatory for all participating hospitals, ensuring uniform case definitions and case finding methodologies. A case–control study approach was developed to allow each intervention institution to identify which antibiotics appeared to be high risk for CDI.28 Statistically significant odds ratios and evaluation of prescription frequency identified piperacillin/tazobactam as a targeted antibiotic at all 6 hospitals, quinolone antibiotics at 3 hospitals, and cefepime at 2 hospitals. Each hospital developed its own hospital-wide intervention program, including components of audit and feedback, antibiotic restriction, institution of treatment algorithms, and physician education. Modest reductions in targeted antibiotics were documented and, although there was a trend toward a reduced CDI rate among intervention hospitals compared with controls, the difference was not statistically significant. Participating ASP staff noted that the development of successful interventions was a slow process and that the full impact of interventions may not have been captured in the 1-year study period. They also emphasized that the large volume of targeted antibiotic prescriptions presented a challenge that may have exceeded available resources for the task.28 Clearly, there is a continued need to identify the most effective ways to study, measure, and operationalize ASPs as a potential component of multipronged hospital CDI control activities.

Probiotics for Primary Prevention of CDI? Probiotic administration for the prevention of primary CDI is a controversial topic. Although the practice has been advocated for many years, there are only a few studies that demonstrate efficacy.9 Adjunctive therapy with probiotics has been used widely for patients, with or without the guidance of physicians, and a recent study investigating probiotic prescriptions at an academic medical center found that the documented indication for 72% of the prescriptions was either antibiotic-associated diarrhea, primary CDI prevention, or CDI treatment.28 The use of probiotic therapy for primary

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Table 3. Vaccines and Biologics in Development for Primary Prophylaxis of CDI34-38 Product

Antigen

Delivery

Clinical Trial Status

ACAM-CDIFF (Sanofi-Pasteur)

Formalin-inactivated toxins A and B

IM injections days 0, 7, and 28-30

Phase III for primary prevention

PF-06425090 (Pfizer)

Molecular and chemically inactivated toxins A and B

3 IM injections

Phase II for primary prevention; FDA fast-track status

IC84 (Valneva)

Recombinant fusion protein of toxin A and B binding regions

IM injection days 0, 7, and 21

Completion of Phase I safety and immune response

Product

Agent

Delivery

Clinical Trial Status

VP20621 (ViroPharma)

Spores of nontoxogenic Clostridium difficile strain M3

Biologics

Oral suspension

Phase II for recurrent CDI

C , Clostridium-difficile CDI, C ost d u d c e infection; ect o ; IM,, intramuscular t a uscu a

CDI prevention is intended to mitigate the effects of antibiotic disruption of bowel microbiota and different mechanisms have been proposed to explain how specific probiotics can affect the microbiota and interfere with C. difficile.30 Most studies of CDI prevention have focused on secondary prevention (prevention of CDI recurrence) because the risk for recurrent infection (20%-30%) is much higher than primary CDI (<10%) and smaller sample sizes are required for investigation. Historically, there are only limited studies investigating probiotics for primary prevention of CDI and they have been poorly designed and underpowered because of small sample sizes.

Several recent reports, including 2 meta-analysis studies and a quasi-experimental prospective cohort study investigating the impact of adding probiotics to an already existing CDI prevention bundle, have suggested that probiotics may have some utility for primary prevention of CDI, but they are far from conclusive.30-32 The large number of probiotic agents and the numerous combination preparations available are an obstacle to preforming any type of definitive meta-analysis, and meta-analysis investigations often include studies investigating both primary and secondary prevention.

Finally, the FDA regulates probiotics as food supplements, not as pharmaceuticals; as such, there is lack of standardization of the available probiotic products regarding dosage, potency, shelf life, and purity.9 Manufacturing standards may even vary between commercial preparations of the same species of probiotic and these variations have been demonstrated to influence the properties of the final products.33 Although APIC and CDC practice guidelines do not address the use of probiotics, the 2010 SHEA/ IDSA update of the clinical practice guidelines for CDI addressed the issue and specifically did not recommend the administration of probiotics for primary CDI

32

W W W. I D S E . N E T

prevention, noting that there were limited data to support the practice and that there was a potential downside given the risk for acquiring a probiotic-related infection.9 Further research studies using well-designed, randomized, placebo-controlled clinical trials to investigate the potential of individual probiotic agents for primary CDI prevention are required, and until they are completed probiotic primary CDI prevention will remain controversial.

Vaccines and Biologics There are currently 3 toxoid-based C. difficile vaccines in development (Table 3).34,35 Two of them, SanofiPasteurâ&#x20AC;&#x2122;s ACAM-CDIFF and Pfizerâ&#x20AC;&#x2122;s PF-06425090, are currently in clinical trials for evaluation as primary CDI prevention agents. A third, IC84 (Valneva), is included in this discussion, although only Phase I safety and immune response studies have been completed. Although they are all toxoid-based vaccines designed to elicit antibodies directed at both C. difficile toxins A and B, they differ in the nature of the presented antigen. ACAMCDIFF uses a formalin-inactivated preparation of toxins A and B, PF-06425090 uses recombinant toxin A and B mutants that are chemically inactivated, and IC84 is based on the use of a recombinant fusion protein containing toxin A and B binding regions. All 3 are preparations for intramuscular injection, all have been shown to be safe and well tolerated, and all have been demonstrated to be immunogenic in healthy adults after 3 serial injections over a 3- to 4-week period. IC84 also has been demonstrated to be highly immunogenic in older patients. The Phase III trial of ACAM-CDIFF vaccine is projected to be completed by the end of 2015.

A single biologic agent, VP20621 (ViroPharma), is currently being developed as a biotherapeutic agent and is in Phase II studies for evaluation for use in treating recurrent CDI.34,36,37 VP20621 consists of an oral suspension of the spores of the non-toxogenic C. difficile

strain M3, which had been previously shown to be protective against challenge with toxogenic strains in hamsters. Completed Phase I trials have demonstrated safety and tolerability (no diarrhea or change in bowel habits) to either single or multiple doses and persistent colonization with VP20261 was detected in 44% of study participants at 21 to 28 days.38 To date, the actual mechanism of CDI protection accorded by VP20261 remains obscure.36 Should these agents become available in the near future, further research will be required to determine if they can be implemented in a cost-effective manner and to determine the extent to which they can contribute to reducing the total burden of primary CDI among hospitalized patients.

Conclusion The acute care hospital CDI epidemic has been refractory to hospital-directed control efforts to date.

These activities need to be revisited and optimized to provide maximal impact on this continuing urgent public health threat.

There is existing evidence that a bundled infection control/environmental hygiene intervention can significantly reduce acute care hospital primary CDI rates, with maximal impact evident in hospitals with more elevated CDI rates. Furthermore, there is now an existing validated footprint for these activities that describes an intervention that has been successfully introduced across a fairly diverse group of hospitals.

Implementation of this type of bundle is challenging.

The transmission of C. difficile in the acute care setting is a complex process and, thus, designed interventions are complex and multifaceted. They involve a wide variety of health care professionals (physicians, nurses, infection control practitioners, and environmental services staff), who must all take ownership of the problem and coordinate their efforts to achieve successful outcomes. It is noteworthy that successful programs documented in this review often included the formation of an interdisciplinary team as a key component to drive the interventions on an institutional level. Additionally, they have all incorporated programs to measure compliance, and were able to document that they had achieved exceptionally high levels of compliance with the infection control components by direct observation and with the environmental hygiene components by the use of checklists.

The evidence presented in this report suggests that many hospitals are not measuring compliance with the CDI control programs that they have initiated to date.

Measuring compliance is labor intensive, but iterative staff feedback about performance is required to change existing behavioral patterns. A team approach brings greater resources to the task, but the long-term sustainability of this type of intervention beyond a 2-year period remains to be established. Public health officials and regulatory bodies need to identify a way to motivate hospitals to take on the infection control/

environmental hygiene bundle and to provide explicit guidance, direction, and encouragement to maximize success and sustain the activity.

There is less firm evidence regarding the efficacy of ASPs designed to reduce CDI rates. It is clear that these types of activities will require both access to institutional pharmacy prescribing databases and an individual tailored risk assessment to identity high-risk antibiotics that should be targeted at each institution.

Changing complex and established prescription behavioral patterns is a slow process, and it is worth noting that reports of ASPs that have successfully reduced CDI rates usually document a cumulative effect that increases over a number of years. In large hospitals, the volume of targeted antibiotic use may overwhelm the ASP team. However, there is some evidence suggesting that ASPs can be used in a more limited way, such as targeting single hospital units that have a concentrated CDI burden. Future research will need to continue to refine this type of intervention and clearly document efficacy. Furthermore, even if found efficacious, it is not clear how widely these programs can be established across all US hospitals, given the financial and professional resources required to establish an ASP. Probiotic use remains controversial and definitive studies are still required to establish that they can reduce CDIs. Finally, although all aspects of the hostâ&#x20AC;&#x201C; pathogen relationship have not been clearly ascertained for C. difficile, there are 3 promising vaccines and a biologic in active development and clinical trials for the CDI prevention.

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29. Simkins J, Kaltsas A, Currie B. Investigation of inpatient probiotic use at an academic medical center. Int J Infect Dis. 2013;17(5):e321-324.

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32. Mazaide PJ, Andriessen JA, Pereira P, et al. Impact of adding prophylactic probiotics to a bundle of standard preventive measures for Clostridium difficile infections: enhanced and sustained decrease in the incidence and severity of infection at a community hospital. Current Med Res Opin. 2013;29(10):1341-1347.

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21. Pear SM, Willamson TH, Bettin KM, et al. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med. 1994;120(4):272-277.

22. Elligsen M, Walker SA, Pinto R, et al. Audit and feedback to reduce broad-spectrum antibiotic use among intensive care unit patients: a controlled interrupted time series analysis. Infect Control Hosp Epidemiol.2012;33(4):354-361.

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34. Gerding, DN. Clostridium difficile infection prevention: biotherapeutics, immunologics, and vaccines. Discovery Medicine.

2012;13(68):75-83.

35. Donald RG, Flint M, Kalyan N, et al. a novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology. 2013;159(7):1254-1266.

36. Gerding DN, Muto CA, Owens RC. Measures to control and prevent Clostridium difficile infection. Clin Infect Dis. 2008;46(suppl 1):S43-S49.

37. Merrigan MM, Sambol SP, Johnson S. et al. New approach to the management of Clostridium difficile infection: colonization with non-toxogenic C. difficile during daily ampicillin or ceftriaxone administration. Int. J Antimicrob Agents. 2009;33(suppl 1):S46-S50.

38. Villano SA, Seiberling M, Tatarowicz W, et al. Evaluation of an oral suspension of VP20621, spores of nontoxogenic Clostridium difficile strain M3, in healthy subjects. Antimicrob Agents Chemother.

2012;56(10):5224-5229.

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

P Pre-Travel Pre-Tr ra l Risk Assessment, Travel Trave v Health alt lth h Precautions, and an nd Post-Travel Postos T os Illnesses: Illness ses Ann Ov Overview v HARIHARAN HARAN REG EGUNATH UN NATH, M MD Clinicall Fello C Fellow Division of Infectious ctious Disea Diseases University of Missou Missouri Columbia, Missourri

WILLIAM SALZER R, MD Professor of Clinical Medicine Division of Infectious Diseases University of Missouri Columbia, Missouri

GORDON D. CHRISTENSEN, MD Professor of Medicine Division of Infectious Diseases University of Missouri Columbia, Missouri

B

ecause the spectrum of infectious diseases varies

widely across nations and

continents, the international traveler can acquire, and even disseminate, diseases unknown to their hometown physicians. These unfamiliar illnesses can be misdiagnosed and mistreated.

The United States is a major contributor to the growth of International tourism.1 In 2013 alone, more than 60 million Americans visited another country and approximately 70 million foreign travelers entered the United States.2,3 Increasing numbers of people are also immigrating to the United States, potentially bringing with them exotic infectious diseases.4 In the future, many members of this new American population will return to their country of origin to visit family and friends, further increasing the opportunities for the importation of diseases unknown to most US physicians.

Globalization is not only changing world economics and world communications, it is also changing the destinations for Americans traveling abroad. Increasingly, US travelers are visiting developing countries to sightsee, seek adventure, engage in trade, and volunteer their services. But travel to developing countries can be hazardous. Substandard public sanitation, poor personal hygiene, contaminated food, tainted water, and infectious arthropod vectors (eg, biting flies, mosquitoes,

INFECTIOUS DISEASE SPECIAL EDITION 2015

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Table. Travel Vaccinations13 Routine Vaccinations

Recommendations • All travelers should have documented tetanus and acellular pertussis vaccinations within past 10 y.

• 1 dose of Tdap recommended for all adults, followed by Tdap every 10 y.

Tdap

• Travelers born before 1956 are considered immune to measles.

• Adults born after 1956 must get ≥1 dose of MMR (2 doses 1 mo apart is ideally recommended)

MMR

TravelSpecific Vaccinations

Recommendations

Hepatitis Aa

• At risk: Travelers to areas of poor sanitation, with chronic liver disease, MSM, IV drug users • Single dose (alone provides 1 y immunity) followed by a booster in 6-18 mo.

• Given at least 1 mo before travel generates protective antibody in 2-4 wk.

• If departure date is within 2 wk then immunoglobulin may be given with vaccine.

Hepatitis Ba

• At risk: HCWs, adventurers, travel sex, MSM, acupuncture, tattoos/piercings • Schedule: 0, 1 (50%-60% protection) and 6 mo (full protection) • Rapid schedules (for quick, good protection and if follow with 12-mo vaccination results in long-lasting immunity): 0, 1, 2 mo or 0, 1, 2 wk.

• Interrupted schedules can be finished without restarting.

Typhoid (live and killed vaccine)

• Live vaccine as oral capsules, given ≥1 wk before travel. Avoided if pt has diarrhea, is taking antibiotics, or is unable to refrigerate the capsules. Booster every 5 y.

• Killed vaccine must be completed ≥2 wk before travel.

Booster every 2 y.

Rabiesb

• At risk: Long stay, in rural area or adventure travel and children traveling to Africa, Latin America, India, and Thailand.

Meningococcal disease

• At risk: HCWs traveling to Africa and all travelers to subSaharan Africa from December to June. Vaccination needed for Muslim pilgrimage–Hajj (required to get Visa) and Umrah.

• Effective for disease with serotypes A, C, Y, and W135.

Booster after ≥10 y.

Polio

• At risk: Travelers to Africa, India, Pakistan, Indonesia, Syria, Yemen.

• Adults: 1 dose as booster. If never vaccinated, then a full series is indicated (0, 1-2, and 6-12 mo).

Varicellac

• 2 doses 4-8 wk apart for nonimmune adult travelers

Japanese B encephalitis

• At risk: Traveler to Asia with long stay (>2 wk) or frequent stay in rural areas or adventure mission.

• Inactivated virus vaccine: JE-Vax: 3 doses on 0, 7, and 30 d (or Ixiaro: 2 dose) • Accelerated regimens: 0, 7, and 14 d (2 doses 1 wk apart provides 80% protection, ~1/200 have an immediate hypersensitivity reaction).

Influenza (live intranasal vaccine or inactivated injectable vaccine)

• All travelers to the tropics and cruise ship tourists.

• All unvaccinated travelers traveling to the other hemispheres.

• Live intranasal vaccine can be given to immune-competent traveler aged 2-49 y and results in a positive test for a few weeks.

Yellow Feverd

• At risk: Travelers to West Africa, South America with stay ≥2 wk.

• Single dose required 10 d before entering into infected country. Some uninfected countries require International Certificate of Vaccination (yellow card valid for 10 y) from travelers arriving from an infected country.

• Booster every 10 y.

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Figure. The pre-travel checklist.

• Age and sex • Past medical history o Comorbid illnesses o Immune suppression o Vaccination history and contraindication to vaccinations o Medications o Pregnancy and breast-feeding

• Risky behaviors • Full details on travel itinerary: dates, duration, and stopovers • Environmental and seasonal considerations at destinations • Styles of travel: rural or urban, budget or luxury • Accommodation: hotel or camping • Activities: business, tourism, adventure, safari, missionary, humanitarian, nongovernmental organization

etc) greatly increase the risk for communicable disease.

These risks can be minimized by preventive measures, such as getting vaccinations, taking prophylactic drugs, and adopting practices that limit exposure to infectious agents. The challenge is getting travelers prepared for international travel.

The first Conference on International Travel Medicine recognized this problem when it proposed in 1988 that “travel medicine” be a medical specialty. In 1991, the International Society of Travel Medicine (ISTM) was formed to foster research and education in travel medicine. ISTM also monitors the diseases acquired and transmitted by travelers and keeps both the medical community and the general public informed about the safe practices and the preventive and therapeutic strategies travelers should take before, during, and after travel.5 The Centers for Disease Control and Prevention (CDC) joined ISTM in 1995 to create GeoSentinel. GeoSentinel is a worldwide network of more than 50 travel medicine clinics that monitors and advises people departing for foreign destinations and those arriving from foreign locales, regarding travel-related health precautions.6 It is the largest compiler of travelrelated illnesses and prevention measures. It is also

continually expanding; there are now separate GeoSentinel databases for Canada (CanTravNet) and Europe (EuroTravNet). These networks track the preventive measures given to departing international travelers and monitor the health of arriving travelers. The resulting data analysis has provided timely insights into the changing epidemiology of travel medicine.6-13 This article offers a general overview of travel medicine, travel health precautions, pre- and post-travel assessment of travelers, and the current spectrum of travel-related infectious diseases in the United States.

The goal is to provide the basic medical information to prepare patients for international travel.

Pre-Travel Evaluation Ironically—and unlike international travelers from the rest of the world—most people leaving the United States for foreign destinations do not seek travel advice before they depart.14 Needless to say, such a timely medical encounter could significantly reduce post-travel illness.

With some guidance, primary care practitioners can provide good advice for the traveler or at least direct them to someone who can provide travel advice.

An easy-to-remember approach to counseling the traveler is to ask the 4 questions often asked by journalists covering the news: 1. Who is the traveler in terms of age, health, vaccination history, medication use, allergies, and behaviors?

2. What will the traveler do when he or she gets to the destination?

3. Where will the traveler go and what medicolegal requirements must the traveler satisfy to enter and leave the countries he or she intends to visit?

4. When will the traveler be leaving? Will there be enough time to schedule his or her vaccinations?

The CDC offers a comprehensive pre-travel evaluation that captures the details of who, what, where, and when in a detailed format in the “Yellow Book,” which is freely accessible online.15 The Infectious Diseases Society of America (IDSA) also has a detailed set of guidelines for the pre-travel visit, including immunizations and recommendations for maintaining health while traveling.14 The aim of the pre-travel evaluation is not just to prevent illnesses by immunization and prophylactic medications, it is also to advise the traveler on how to

KEY TO TABLE HCW, health care worker; MMR, measles, mumps, and rubella; MSM, men who have sex with men; pt, patient; Tdap, tetanus, diphtheria, and pertussis (acellular) a

Hepatitis A/B (Twinrix®): Usual schedule is 0, 1 and 6 mo; 0 and 1 mo provides adequate protection against Hepatitis A, 50% to 60% against hepatitis B. Repeat dose at 6 mo offers full protection against hepatitis B. Accelerated schedule: 0, 1, and 3 wk offers good protection, repeat at 12 mo offers full protection. b

Pre-exposure prophylaxis with 3 doses at 0, 7, and 21-28 d. Post-exposure prophylaxis after vaccination with 2 additional doses at 0 and 3 d. Post-exposure prophylaxis without vaccination needs rabies immunoglobulin injected locally into the wound with residual injected systemically and 5 doses of cell culture vaccine on days 0, 3, 7, 14, and 28 (last dose can be skipped in healthy patients). c

Zoster vaccine (Zostavax) is not a substitute for Varicella Vaccine (Varivax).

d

Attenuated, live vaccine: contraindicated for infants, age >60, HIV-positive, steroids, cancer, etc. Can provide a waiver letter if vaccination not possible because of health status. May cause “flulike” illness 5 to 7 d later.

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maintain their health. The Figure briefly summarizes the pre-travel checklist.

Some destinations, like the jungles of equatorial Africa, command notable immunizations (ie, Yellow Fever vaccination) and medications (ie, malaria prophylaxis). Usually, travelers to such places know this and will seek providers for such care. Often overlooked, however, is that travel—even to conventional destinations—exposes the traveler not only to the exotic but also to the commonplace, such as influenza and diarrhea. These common illnesses pose as much or even a greater hazard to the traveler than do the exotic. For example, in the GeoSentinel (2007-2011) compilation of illnesses affecting 42,000 sick travelers, Leder and colleagues counted 28 deaths: 6 were due to malaria and 6 were due to pneumonia (none were related to Yellow Fever); of the 42,000 sick travelers, 34% had diarrhea and 6.7% had malaria.16 Because the commonplace can be overlooked, the pre-travel evaluation is also an opportunity to ensure the traveler is up-to-date on routine vaccinations. In general, all inactivated vaccines can be given at the same time. There is a potential for most live-virus vaccines (such as yellow fever, MMR, varicella, and liveattenuated influenza virus vaccine) to interfere with each other if given simultaneously. For this reason, the CDC recommends spacing these vaccinations at least 28 to 30 days apart or giving booster doses.17 If a traveler has skipped a dose or booster dose, it is not necessary to start the series over; it can be continued as scheduled. A complete vaccine schedule is available in various formats from the CDC and in the guidelines from the IDSA.13,15 The Table provides a list of the important recommendations for routine and travelspecific vaccinations and is adapted from the 2006 IDSA guidelines.13

Malaria All travelers to malaria-endemic destinations, especially pregnant women, medical missionaries, and military personnel require malaria prophylaxis.18-21 These travelers should also be counseled about the symptoms and signs of malaria. It should also be emphasized that drug prophylaxis alone does not confer full protection; measures to prevent mosquito bites, such as bed nets, repellents, protective clothing, and avoiding outdoor activities at night are also important.

Malaria can manifest a few months after return due to ineffectiveness of the prophylactic regimens against the dormant virus (the hypnozoites seen with Plasmodium vivax x and Plasmodium ovale).1 Hence, it is essential for travelers to contact the travel clinic if they develop fever, chills, headache, and so forth, even if it has been months since returning home, as other health care providers may not recognize or suspect malaria. Prophylactic drugs commonly prescribed include any one of the following.

Atovaquone plus Proguanil: This is a synergistic combination drug (Malarone, GlaxoSmithKline) and is the

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drug of choice to prevent malaria in most of the world.

The recommended dose is 1 tablet (250/100 mg) daily from day 1 of travel until 7 days after exposure. Although it has less adverse effects than other antimalarials, it is expensive. There is also the unestablished potential for possible teratogenicity (Pregnancy Category C).22 Mefloquin (various generics): This drug is inexpensive and is safe in pregnancy. The recommended dosing schedule is 1 tablet (250 mg) on 3 Sundays before travel and then continue weekly for 4 weeks after exposure.

The common adverse effects are gastrointestinal (GI) upset and vivid dreams, but on rare occasion the drug can also cause neurologic illness; it should be avoided in travelers with psychiatric illness including severe anxiety and depression. The drug also has cardiac toxicity and should be avoided in patients with cardiac conduction abnormalities as it prolongs the QT interval.23,24 Doxycycline: The recommended dose is 1 tablet (100 mg) daily and continued until 4 weeks after exposure. The adverse effects are skin photosensitivity and esophagitis. The drug stains dental enamel, so it is contraindicated in pregnancy and childhood (<8 years). A problem with the drug, not seen with atovaquone plus proguanil or mefloquin, is that a missed or late dose can leave the traveler vulnerable to getting malaria.

Chloroquine: The recommended dose is 300 mg base (500 salt) weekly and continued until 4 weeks after exposure. This drug is effective only for travel to areas with chloroquine-sensitive malaria.

Primaquine: This drug is used for prevention of Plasmodium vivax x and Plasmodium ovale after prolonged exposure; at this time, it is the only drug active against the hypnozoites. The recommended dose is 30 mg base daily for 14 days after exposure. Use of this drug requires testing the traveler for glucose-6-phosphate dehydrogenase deficiency before starting, as primaquine causes hemolytic anemia in people with a genetic deficiency of this enzyme.

Travelers’ Diarrhea Approximately 20% to 60% of travelers will develop diarrhea; destinations with the highest risk are Latin America, the Middle East, Sub-Saharan Africa, and Southeast Asia.16,25-27 Host-specific risk factors include use of acid suppressants (H2 blockers, antacids, and proton pump inhibitors), immune suppression, diabetes, and inflammatory bowel disease.

The most common microbe causing travelers’ diarrhea is enterotoxigenic Escherichia colii (ETEC), followed by campylobacter, salmonella and shigella.

Viruses (rotavirus and norovirus) and parasites (notably Giardia lamblia) cause up to 25% of travelers’ diarrhea, depending on the destination.28-30 The diarrhea usually resolves in a few days without therapy, but may disrupt travel activities. Women are more likely than men to have a post-infectious irritable bowel syndrome, which is seen in 3% to 17% of patients who have had travelers’ diarrhea. The most common sources of infectious diarrhea are partially cooked or reheated foods, such

as quiches and casseroles, and contaminated water (including ice). The general advice for hygienic food consumption is: “Boil it, cook it, peel it, or forget it.” But, a recent review finds this advice may not be practical or effective for most travelers.30 The following summarizes the recommended drug therapy for travelers’ diarrhea.

It is important to remember at all times that hydration with electrolyte supplementation is essential.13 Prophylaxis: Bismuth subsalicylate 2 tablets 4 times a day while traveling. Disadvantages are that it produces a black tongue and stool. Antibiotic prophylaxis (ciprofloxacin 500 mg daily or norfloxacin 400 mg daily) is not routinely recommended unless the traveler has advanced HIV, uncontrolled inflammatory bowel disease, or active immune suppression (eg, malignancy, chemotherapy, hypogammaglobulinemia, end-stage renal disease, or diabetes).1,2,13 Treatment: Only indicated for moderate to severe diarrhea (illness lasts more than 3 days, temperature higher than 38.5°C, pus, mucus, or blood in the stool).

Drug of choice is a fluroquinolone: oral ciprofloxacin 500 mg twice daily or oral norfloxacin 400 mg twice daily or oral levofloxacin 500 mg daily or oral ofloxacin 200 mg twice daily. Duration of therapy can be 3 to 5 days depending on response. Oral azithromycin 1,000 mg once and oral rifaximin 200 mg three times daily are alternative agents.13

Altitude Sickness Travel destinations that are more than approximately 2,500 m (8,000 ft) high carry a risk for high altitude sickness, especially if there is a rapid ascent. Acute mountain sickness (AMS) is a self-limiting illness characterized by headache, dizziness, sleep disturbance, anorexia, and fatigue. Symptoms usually disappear in 1 to 3 days if there is no further ascent. Sometimes AMS progresses to encephalopathy and ataxia, known as high-altitude cerebral edema (HACE). This can be a rapidly fatal condition due to vasogenic edema of the cerebral white matter, especially the corpus callosum (T2 hyperintensity in the splenium of the corpus callosum on magnetic resonance imaging); this in turn can cause cerebral herniation.31-33 High-altitude pulmonary edema (HAPE) is another life-threatening complication where a multitude of host-maladaptive responses to hypobaric hypoxia at high altitudes (increased sympathetic tone, poor ventilation, pulmonary vasoconstriction, etc.) result in pulmonary edema.34 The best therapy for HACE and HAPE is immediate descent. Specific medical therapy to avoid and manage AMS is as follows: Preventive therapy: Acetazolamide, a carbonic anhydrase inhibitor, induces metabolic acidosis and hence increases ventilation at night, increases arterial oxygenation, and promotes bicarbonate diuresis after respiratory alkalosis. This is recommended for ascents higher than 8,000 to 11,000 feet with a dose of 250 mg orally twice daily beginning on the morning of ascent and continue through the day after ascent. If symptoms

persist, therapy should be extended an additional day.

Because it is a diuretic, patients should avoid taking it at bedtime. Some patients develop circumoral and distal extremity paresthesias, in which case, each dose is reduced by 50%. Other adverse effects include a temporary distaste for carbonated beverages. Because it is a sulfonamide, acetazolamide is contraindicated in those with allergy to sulfa-containing compounds.

Treatment: The recommended approach is avoidance of further ascent and acetazolamide 250 mg orally twice daily until symptoms abate.

With, HACE and HAPE, although experienced providers in consultation with mountaineer travelers can try hyperbaric chambers, dexamethasone, and nifedipine, there is no substitute for immediate descent; other medical measures are generally not recommended as these conditions are rapidly fatal.

Jet Lag Travelers flying to destinations across multiple time zones (usually more than 2 time zones, particularly eastward travel) are at risk for jet lag, characterized by malaise, day-time sleepiness, loss of concentration, and poor performance.

Recommended therapy: Zolpidem 10 mg immediately before sleep. Can be used for 2 to 3 nights at each end of the trip. Should not be taken during air travel as sleeping while flying can promote the formation of blood clots. Resisting the temptation to nap during the day after arrival at the final destination helps by abbreviating the adjustment phase. Authorities do not recommend over-the-counter melatonin.

Additional Risks Adverse climatic conditions, traffic accidents, sunburn, drowning, animal bites, falls, and violence (political and criminal) are additional risks inherent to foreign travel. The US Department of State publishes destination-specific travel warnings and alerts as well as more general destination-specific travel information.

A recent review found that more than 20% of travelers engage in casual sex with a new partner while traveling, nearly half of these encounters are unprotected.35 Alcohol, social isolation, and anonymity promote this behavior; young, single men with a past history of sexually transmitted infections (STIs) appear to be at greatest risk.13,35-37 Such activities also expose the traveler to STIs with increased resistance to antimicrobial agents. For understandable reasons, sex workers are particularly hazardous. The best recommendation is abstinence. Otherwise, the traveler should use barrier protection because of the risk for HIV, hepatitis B virus, and other STIs. Antibiotic-resistance profiles of sexually transmitted pathogens vary greatly depending on the destination.

Long-distance travel (for more than 6-10 hours) whether by air or by land carries a risk for venous thromboembolism (VTE). This risk is in addition to any host-specific risk factors that might also be present

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(such as a prior VTE, hereditary thrombophilia, estrogen-containing oral contraceptives, recent major surgery, active malignancy, pregnancy, advanced age, and obesity).38-40 Prevention: The traveler should be counseled to avoid immobility by moving around and exercising calf muscles while sitting, to not wear constrictive clothing, to maintain adequate hydration, to limit alcohol intake, and to wear below-the-knee support stockings. Aspirin is not known to be effective and the value of low-molecular-weight heparin in at-risk travelers is also unknown.13

Post-Travel Illness A wide variety of illnesses afflict travelers. A focused discussion of these individual diseases is beyond the scope of this review. GeoSentinel (including CanTravNet and EuroTravNet), with its worldwide clinic-based surveillance (54 travel medicine clinics and 235 additional clinics, across 40 countries and 6 continents), serves as the major source of epidemiologic and clinical information regarding post-travel illness.8 Surveillance data for the period 1997 to 2011, from 22 such GeoSentinel sites in the United States reported 13,059 diagnoses from 10,032 patients after travel. The most common diagnostic groupings were acute diarrhea (22%), non-diarrheal GI (15%), febrile systemic illness (14%), and dermatologic disorders (12%). Most common destinations of exposure were Sub-Saharan Africa (23%), followed by Central America (15%), South America (12%), the Caribbean (9%), South Central Asia (8%), and Southeast Asia (7%). Other regions of exposure included western Europe (5%), northeast Asia (3%), the Middle East (2%), North Africa (2%), eastern Europe (1%), Oceania (1%), North America (<1%), and Australia and New Zealand (<1%). Of the 1,802 patients with a febrile illness, the most common diagnosis was P. falciparum malaria (19%).41 More recently, surveillance data from all GeoSentinel sites (US and non US) for the period between 2007 and 2011, reported that approximately 42,000 travelers became sick after visiting Asia (32.6%), Sub-Saharan Africa (26.7%), and Latin America and the Caribbean (19.2%).11 Only 10.9% of North American sick travelers had a pre-travel evaluation for health maintenance (vaccines, preventive therapy, and travel precautions), but overall, 40.5% of travelers worldwide had a pre-travel evaluation. Most of the illnesses fell into 3 categories: GI infections (34%), febrile illnesses (23.3%), and dermatologic diseases (19.5%). Of the GI illnesses, 40% had acute diarrhea (presumptive enterotoxigenic Escherichia coli), 20% had a specific parasitic cause (most

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commonly: Giardia; primarily from India and environs), 10% had a specific bacterial cause (most commonly: Campylobacter, Salmonella, and Shigella; primarily from Asia, Africa, and the Middle East).

Of those travelers with diarrhea lasting more than 2 weeks, 40% developed a post-infectious irritable bowel syndrome. In travelers with a febrile illness, 29% had malaria (primarily travelers to Africa), 15% had dengue (primarily travelers to Southeast Asia, Latin America, and the Caribbean), and the remaining portion included a variety of acute febrile illnesses, notably enteric fever (typhoid and paratyphoid), Chikungunya, rickettsial diseases, viral hepatitis, leptospirosis, tuberculosis, and acute HIV. Forty percent of cases with fever remained undiagnosed, but were presumed to be viral in etiology.

Only 8% of travelers sick with a respiratory infection, had influenza (0.9% of all sick travelers).11

Summary The GeoSentinel network has compiled and published extensive statistics on the health care preparation of travelers before departure and on the descriptive epidemiology of the illnesses travelers bring back with them. Although this is the best information we have on travel-related illness, the GeoSentinel studies do not provide data on the proportion of travelers who did and did not become ill. Nevertheless, it is evident that travel-related illness is common and the spectrum of illness ranges from the rare and exotic to the frequent and mundane. Most importantly, this burden of disease can be reduced by timely pre-travel evaluation, immunization, prophylactic and therapeutic medications, and counseling on how to maintain health.

Perhaps more important than documenting the importance of travel illness, is the finding by the GeoSentinel network that all too frequently the North American traveler has failed to obtain a pre-travel evaluation, a medical encounter that could have prevented illness and injury. As international travel continues to become more common, health care providers should emphasize the value of the timely pre-travel medical evaluation to minimize the health risks posed by international travel.

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International tourism shows continued strength Madrid: The World Tourism Organisation (UNWTO); 2014 [cited 2015 February 26]. http://media.unwto.org/press-release/2014-10-30/internationaltourism-shows-continued-strength. Accessed February 12, 2015.

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38. Lapostolle F, Surget V, Borron SW, et al. Severe pulmonary embolism associated with air travel. N Engl J Med. 2001;345(11):779-783.

39. Perez-Rodriguez E, Jimenez D, Diaz G, et al. Incidence of air travelrelated pulmonary embolism at the Madrid-Barajas airport. Arch Intern Med. 2003;163(22):2766-2770.

40. Ferrari E, Chevallier T, Chapelier A, et al. Travel as a risk factor for venous thromboembolic disease: a case-control study. Chest.

1999;115(2):440-444.

41. Harvey K, Esposito DH, Han P, et al. Surveillance for travel-related disease—GeoSentinel surveillance system, United States, 1997–2011.

MMWR Surveill Summ. 2013;62(3):1-23.

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PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

Lead author:

JOHN J. LOWE, PHD Assistant Professor Department of Environmental, Agricultural and Occupational Health University of Nebraska Medical Center Nebraska Biocontainment Unit Nebraska Medicine Omaha, Nebraska

Co-authors:

KATELYN C. JELDEN, BS Department of Environmental, Agricultural and Occupational Health University of Nebraska Medical Center Nebraska Biocontainment Unit Nebraska Medicine Omaha, Nebraska

SHAWN G. GIBBS, PHD Department of Environmental, Agricultural and Occupational Health University of Nebraska Medical Center Nebraska Biocontainment Unit Nebraska Medicine Omaha, Nebraska

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W W W. I D S E . N E T

PHILIP W. SMITH, MD Nebraska Biocontainment Unit Nebraska Medicine Department of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska

MICHELLE SCHWEDHELM, MSN

CHRISTOPHER J. KRATOCHVIL, MD Nebraska Biocontainment Unit Nebraska Medicine Office of the Vice Chancellor for Research University of Nebraska Medical Center Omaha, Nebraska

Nebraska Biocontainment Unit Preparedness and Infection Prevention Nebraska Medicine Omaha, Nebraska

KATHLEEN C. BOULTER, RN

PETER C. IWEN, PHD

ANGELA HEWLETT, MD

Nebraska Biocontainment Unit Nebraska Medicine Department of Pathology and Microbiology University of Nebraska Medical Center Omaha, Nebraska

Nebraska Biocontainment Unit Nebraska Medicine Division of Infectious Diseases University of Nebraska Medical Center Omaha, Nebraska

ELIZABETH BEAM, PHD Nebraska Biocontainment Unit Nebraska Medicine College of Nursing University of Nebraska Medical Center Omaha, Nebraska

Nebraska Biocontainment Unit Nebraska Medicine Omaha, Nebraska

PPE: A staff member in the Nebraska Biocontainment Unit dons personal protective equipment (PPE) before caring for a patient with Ebola virus.

The Nebraska Biocontainment Unit (NBU), the largest high-level isolation unit in the United States, was established in 2005 by Nebraska Medicine, the University of Nebraska Medical Center, and the Nebraska Department of Health and Human Services.

Designed for care of highly contagious patients— whether infected from an act of bioterrorism, an emerging infectious disease, or a laboratory accident— the NBU is equipped with a host of critical infection control features such as controlled air flow (negative pressurized patient rooms with HEPA-filtered exhaust air), an in-unit Bio-Safety Level 3 (BSL-3) laboratory, secured unit access, staff shower-out access, and a pass-through autoclave.1 In recent months, the NBU has treated patients evacuated from West Africa with highly infectious Ebola virus disease (EVD). The NBU attributes 9 years of preparation and training for its success in Ebola virus infection control and patient care, using meticulously developed practices in staffing, personal protective equipment (PPE), organization, transportation, waste management, laboratory, supplies and medications, and family care.

Here, we document what we see as the keys to the success of the NBU. Staffing. NBU personnel are volunteers trained to effectively work with highly infectious patients through quarterly drills and exercises. The staff includes registered nurses; respiratory therapists; and physicians chosen from diverse backgrounds in clinical research, critical care, and infectious diseases. This diverse mix of backgrounds has proved advantageous in creating a collaborative and cohesive team. Staff members are

Transport: A transport team at the Nebraska Biocontainment Unit receives a patient with Ebola virus.

encouraged to be stewards of safety, and are empowered to call out issues related to safety. Staff training, safety, and “buy-in” to the goals of the unit are essential to the NBU’s success.

PPE. The NBU selects PPE for care of patients with EVD in accordance with recommendations from the Centers for Disease Control and Prevention (CDC), emphasizing PPE adaptability to match the patient’s condition.2 Designated donning and doffing personnel assist the application and removal of PPE by staff.

Organization. The incident command structure is activated before patient arrival, and media relations are directed through Nebraska Medicine’s public information officer. NBU hosts daily internal staff briefings.

Nebraska Medicine coordinates public relations and mass communication with the patient’s family, as well as local and state health departments. Finally, reliable communication methods through videoconferencing are established with medical consultants, the patient, and the patient’s family.

Transportation. An NBU-designated coordinator communicates with local and national transport partners in planning and conducting the transport of a patient with EVD. NBU recommends full-scale transportation drills before the arrival of an infected patient with EVD. Ambulance preparation and post-transport decontamination protocols are defined, but with responsibilities designated in advance.3 Waste management. NBU staff autoclaves Ebola virus–contaminated waste material before removal from the unit, a procedure not widely available to US medical facilities. Caring for a single patient with EVD has

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produced more than 1,000 pounds of solid waste, and hospitals preparing for a patient with EVD will require a plan for handling this waste compatible with category A infectious substance regulations.4 For liquid waste, the NBU dispenses hospital-grade disinfectant into the patientâ&#x20AC;&#x2122;s toilet for twice the recommended contact time before every flushing.

Laboratory. A BSL-3 laboratory was relocated into the NBU for point-of-care testing and specimen processing. Before patient arrival, consultation among laboratory, medical, and biosafety personnel determine which tests could be performed safely and where testing would be performed.5 Family care. A hospital official is designated to coordinate and accommodate the needs of the patientâ&#x20AC;&#x2122;s family such as housing, communication, transportation, and media management.

The NBU is working with Emory University and the CDC to disseminate the lessons learned from its experiences in caring for patients with EVD to help others

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in preparing their policies. These educational and outreach components are another important aspect of the NBU Ebola response.

References 1.

Smith PW. Designing a biocontainment unit to care for patients with serious communicable diseases: a consensus statement.

Biosecur Bioterr. 2006;4(4):351-365.

2. Centers for Disease Control and Prevention. Guidance on personal protective equipment to be used by healthcare workers during management of patients with Ebola virus disease in US hospitals, including procedures for putting on (donning) and removing (coffing); c2014. http://www.cdc.gov/vhf/ebola/hcp/proceduresfor-ppe.html. Accessed January 12, 2015.

3. Lowe JJ, Jelden KC, Schenarts PJ, et al. Considerations for safe EMS transport of patients infected with Ebola virus. Prehosp Emerg Care. 2014 Nov 7. [Epub ahead of print] 4. Lowe J, Gibbs S, Schwedhelm S, et al. Nebraska Biocontainment Unit perspective on disposal of Ebola medical waste. Amer J Infect Con. 2014;42(12):1256-1257.

5. Iwen PC, Smith PW, Hewlett AL, et al. Safety considerations in the laboratory testing of specimens suspected or known to contain Ebola virus. Am J Clin Pathol. 2015;143(1):4-5.

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014

Expiration Date: November 11, 2015

Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia.

2 Describe the comorbidities and causes commonly associated with hyponatremia and their significance in treatment.

3 Summarize current evidence and best practices in the management of hyponatremia.

4 Explain how to mitigate adverse events secondary to treatment of hyponatremia.

5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

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