The trajectory of HIV has changed dramatically in just a few decades. Back in the early days of the epidemic, contracting HIV basically meant progressing to full-blown AIDS and death. Now, thanks to antiretroviral drugs and other therapies, individuals with HIV often can keep the virus at bay, avoid infecting others and live a normal lifespan. But while HIV has moved from a guaranteed death sentence to a chronic condition that can be kept at bay, a permanent cure has, thus far, eluded researchers.  

The first step toward figuring out how far we’ve progressed toward a cure, according to experts, is to define it. “What do you mean by a cure?” asked Anthony Fauci, MD, the director of the National Institute of Allergy and Infectious Diseases. “If by cure you mean eradicating the virus, there hasn’t been much progress made.”

However, Dr. Fauci spoke encouragingly about the gains that have been made just this past year in terms of long-term virus suppression. Researchers continue to develop long-acting therapeutics, such as broadly neutralizing antibodies, that enable those living with HIV to keep the virus undetectable and untransmissible for longer periods of time. Referencing ongoing 

 that demonstrate long-term suppression, these results “get into the cure range,” he told 

One recent study at Beth Israel Deaconess Medical Center in Boston involved rhesus monkeys infected with simian-human immunodeficiency virus (SHIV), which is related to HIV, and then put on antiretroviral therapy (ART) for roughly 2 years. Toward the end of this period, the monkeys were split into 4 groups: One group was given the broadly neutralizing antibody known as PGT121, another was given a selective TLR7 agonist known as GS-9620, the third was given both, and the fourth was given a placebo.

After a period of time, the animals stopped receiving ART, so the researchers could observe whether they experienced a viral rebound. Every monkey taking the placebo rebounded, with an average rebound time of 3 weeks. Nine out of the 11 taking only PGT121 rebounded, and 10 of the 11 taking only GS-9620 rebounded. However, of the 11 monkeys taking the combination therapy, 5 experienced no rebound after 168 days of monitoring. The other 6 did rebound but then experienced suppression of the virus.

This is an encouraging response that can hopefully be replicated in continuing animal trials and, one day, in humans. “We are organizing an ambitious human trial that should start this year,” Paul Volberding, MD, a professor at UCSF School of Medicine in San Francisco, told 

. “The field remains an exciting one to watch."

Roughly a decade ago, the so-called “Berlin patient” was given a stem-cell transplant to treat his leukemia, which had the unintended side effect of curing his HIV. He remains the only person in the world to have been cured, and scientists are trying to figure out how to replicate this success in other patients.

“These cells likely underwent graft-versus-host disease,” Scott Kitchen, PhD, associate professor of medicine at the David Geffen School of Medicine at UCLA, told 

. Graft-versus-host disease, which can occur after a bone-marrow transplant, involves the new donor cells attacking not only the cancerous cells but healthy cells as well. Dr. Kitchen explained that in the case of the Berlin patient, the donor was one of a very small number of individuals who are naturally resistant to HIV because of a mutation in the CCR5 gene. This donor’s cells may have targeted a dormant reservoir of HIV in the patient, killing it off and rendering him free of the disease.

Unfortunately, researchers have been unsuccessful in replicating this treatment in other HIV-positive subjects due to an extremely small pool of naturally HIV-resistant donors and severe side effects in the subjects. Going forward, scientists likely will focus on treatment that “involves combining approaches like ART with bone marrow transplantation,” said Dr. Kitchen. “Another approach is to use gene therapy and basically take the person’s own stem cells and modify them in a way that knocks out the CCR5 gene.”

Dr. Kitchen is currently working on gene therapy as a treatment for HIV. “There’s some promise, but at this point the studies are ongoing,” he said. “What we can say is that there are increasing signals that are being found in nonhuman primate studies. We are eager to evaluate whether these interventions may have an effect in humans.”

Treatment Breakthroughs, but Infection Rates Still High

“Can we and will we end the HIV epidemic?” asked Quarraisha Abdool Karim, PhD, associate scientific director of the Centre for the AIDS Programme of Research in South Africa (CAPRISA), speaking at a National Institutes of Health symposium earlier this month. “We really have no more excuses, because we have the tools.”

However, the reality is that the infection continues to spread worldwide, negating the very real advances in treatment. According to Dr. Karim, 5,000 new infections occur each day, 70% of them in sub-Saharan Africa. In many African communities, a significant portion of the residents have HIV. “A key driver of the epidemic is high rates of infection in young women,” she said, adding, “We’re talking about this in a continent where 65% of the population is under age 35.”

Several other symposium attendees agreed that infection in young women often occurs because of sexual contact—possibly nonconsensual&mdash;with older men who either don’t know they’re infected or are noncompliant with their medication regime. “We see young people in great danger,” said Linda-Gail Bekker, MBChB DTMH DCH FCP(SA) PhD, deputy director of the Desmond Tutu HIV Foundation at the University of Cape Town in South Africa. “Youth in Africa have a high rate of communicable diseases.”

It’s not just underdeveloped nations in Africa and Latin America that are dealing with out-of-control HIV: According to Dr. Bekker, the United States experiences 30,000 to 40,000 new infections yearly.

Sten Vermund, MD, PhD, dean of the Yale School of Public Health in New Haven, said, “We have some very profound structural inhibitions that make it very challenging.” He referred to difficulties such as financial problems and social stigma faced by those of color, individuals in lower socioeconomic groups, and the LGBTQ community when he said, “These structural underpinnings of risk are a backbone of why we’re kind of stuck in America.” There are bright spots, however: A report by the Centers of Disease Control and Prevention noted that 

 declined from 45,700 yearly to 37,600 yearly between 2008 and 2014. At the same time, 

 in recent years in certain communities in Europe, Asia, the Caribbean, and Africa

HIV experts note that it’s important for the medical community to pay attention to sexual and mental health issues to try to stem the tide of infection worldwide. Also critical is the need to provide job incentives for individuals so they don’t turn to sex work, which is a driver of HIV.

Finally, it’s incumbent on political leaders to prioritize a society’s health and well-being by making funds available for prevention and treatment as well as reducing poverty and its ill effects. “If you don’t have housing, if you’re starving, if you’ve got other things going on, you’re not going to stay in a[n HIV treatment] program,” Dr. Fauci said.

Ms. Saloman is a health writer with more than 20 years of experience working for both consumer- and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family. 

Articles

HIV / AIDS

Big advances in treatment can’t make up for an inability to stop new infections, which number 5,000 per day worldwide.

A Cure for HIV? An Update One Year Later

As the repeal of the Affordable Care Act remains stalled in the US government, action plans are being put into place to address other major areas that are affecting the health of the American public: namely healthcare-associated infections. A recent opinion piece in the online publication, 

, by medical affairs expert Stephen Littlejohn, calls our attention to this serious and growing problem

 which affects almost 750,000 Americans each year, and results in 75,000 deaths.

A member of the advisory board of the National Patient Safety Foundation (NPSF), Littlejohn highlights a "Call to Action" recently released by the foundation and suggests reframing, “the challenge of preventing healthcare harm as a public health crisis and proposes a national coordinated response [akin to the ways that we have previously tackled] smoking, highway accidents, and drunk driving.” However, we choose to confront the issue, Littlejohn and the NPSF bring our attention back to the true point/calling of healthcare: to improve patient health and “do no harm.”

, editorial advisory board member John Mohr, PharmD, and colleagues highlight the potential implications of 21st Century Cures Act on antibiotic drug development on page 8. The act aims to encourage the monitoring of antimicrobial resistance and increase stewardship efforts, which is particularly important in light of the fact that Centers for Disease Control and Prevention data reveal that each year at least 2 million Americans develop infections due to drug-resistant pathogens.

Calling attention to the increased focus on decreasing healthcare-associated infections, we feature an article which focuses on the latest updates to the Infectious Diseases Society of America and the American Thoracic Society guidelines for treating nosocomial pneumonia on page 14.

On page 12, experts discuss the new information that has come to light on direct-acting antivirals to treat hepatitis C, asking the reader to consider if patients who are infected with the virus should be, what the authors call “warehoused,” until newer, and safer treatments are made available. On page 10, we include interviews with the foremost experts in the field to learn how close we are to finally discovering a cure for another viral infectious disease: HIV.

Finally, tick-borne diseases continue to emerge and affect individuals in the United States. So much so that 

’s first Peer Exchange, coming in Summer 2017, will zero in on Lyme disease. In the article on page 18, we focus on the tick-borne diseases that are emerging in the United States and provide expert information on how to develop and deliver effective prevention and treatment methods for these diseases.

While we continue to focus on healthcare-associated infections, we will keep you informed of breaking news and updates through our website, 

, on social media (Facebook [@ContagionLive], Twitter [@Contagion_Live], and LinkedIn [@Contagion_Live]), and in our email newsletters (sign up at contagionlive.com/link/2). Stay informed!

LittleJohn SE. Patient safety: a public health crisis for a nation of patients. STAT news website. 

https://www.statnews.com/2017/04/10/patient-safety-crisis/

. Published April 10, 2017. Accessed April 10, 2017.

Centers for Disease Control and Prevention. Healthcare-associated infections. CDC website. 

. Updated October 5, 2016. Accessed April 10, 2017.

Centers for Disease Control and Prevention. Antibiotic/antimicrobial resistance. CDC website. 

. Updated March 8, 2017. Accessed April 10, 2017.

Centers for Disease Control and Prevention. Global HIV & tuberculosis. CDC website. 

https://www.cdc.gov/globalhivtb/index.html

. Updated March 23, 2017. Accessed April 10, 2017.

Chairman’s Letter

As the repeal of the Affordable Care Act remains stalled in the US government, action plans are being put into place to address other major areas that are affecting the health of the American public.

A Focus on Healthcare-Associated Infections Could Improve US Health

As the numbers of reported cases of tick-borne diseases (TBDs) continue to increase, so do the range of ticks that can carry these diseases, the amount of TBDs that have emerged, and the laboratory approaches to detect them, according to a panel of speakers in a March 21, 2017, webinar presented by the Centers for Disease Control and Prevention (CDC). 

According to Rebecca Eisen, PhD, from the CDC in Fort Collins, Colorado, despite the rise in infected individuals, just 3 ticks transmit most cases of reported TBDs in the United States: 

“In recent decades, the numbers of many notifiable TBDs have steadily increased,” she said. “For example, the average number of reported Lyme disease cases has roughly tripled from 1992 to 2015. Likewise, the number of reported cases of anaplasmosis, ehrlichioses, and spotted fever group rickettsioses has steadily increased from 2000 to 2015.”

The geographic distribution of several TBDs is also expanding. From 1996 to 2015, the number of counties in which 

 was considered to be established more than doubled. Other factors also contribute to increases in the number of reported cases of TBDs and their distribution, she explained, including increasing human contact with ticks, landscape changes, a lack of effective prevention strategies, and improved diagnostics and clinical recognition.

No vaccines are available in the United States to prevent TBDs in humans. Current prevention strategies, such as personal protection measures, environmental modification, and tick suppression in animals, vary in efficacy and acceptability. “There is a need to develop effective approaches for preventing TBDs. But perhaps an even bigger challenge is how to deliver effective prevention strategies to large numbers of people and ultimately reduce the trend of increasing TBDs,” Dr. Eisen concluded. 

The etiologic spectrum of tick-borne rickettsioses in the United States has expanded during the past 15 years, said Christopher D. Paddock, MD, from the CDC in Atlanta, Georgia. Rocky Mountain spotted fever (RMSF), caused by 

, was the first recognized TBD in humans in the United States. The organism has a tropism for vascular endothelial cells, and the disease progresses rapidly to involve the skin, producing the characteristic maculopapular rash. Although RMSF can cause death when it involves the brain and lungs, Dr. Paddock stressed that doxycycline therapy has reduced the fatality rate to about 5%.

Most cases are reported from the central and southeastern United States, where 

 is the main vector of the RMSF agent. However, 

, the brown dog tick, more recently emerged as an unexpected vector of RMSF, noted Dr. Paddock. Epidemic levels of RMSF emerged in several American Indian communities in eastern Arizona between 2003 and 2012, with incidence rates approaching 150 times the national average.

 Large populations of these ticks have since expanded among free-roaming dogs in these communities. Fortunately, however, a 2-year pilot integrated tick prevention program was initiated in 2012 in one community with high rates of RMSF. This involved acaricide spraying of yards and placement of tick collars on more than 1000 dogs, and significantly reduced the number of ticks in this area and the number of cases of RMSF. Whereas about 51% of dogs in the community had visible tick infestations at the start of the tick control initiative in April 2012, fewer than 6% of dogs had visible infestations at the end of the project in September 2013.

RMSF was considered the only tick-borne rickettsiosis in the United States for more than 100 years, until 

, the Gulf Coast tick, and also causes a skin rash. However, the 

rash is typically sparser than that in RMSF and may involve small vesicles or pustules. 

 infection also produces a distinctive eschar, a small focus of necrotic skin, at the site of the tick bite. Eschars occur only rarely in RMSF, said Dr Paddock, and while RMSF is life-threatening, 

 is also greater than the percentage of ticks infected with 

, said Dr. Paddock. About 1 in every 2 to 4 Gulf Coast ticks have been shown to be infected with 

. However, estimates suggest that fewer than 1 in 2000 ticks in the eastern United States harbor the bacteria, he added.

“Most of us think of TBDs as fairly badly neglected in the current environment, and tick-borne viruses are neglected even among these neglected pathogens,” said Gregory D. Ebel, ScD, from Colorado State University, Fort Collins. According to Dr. Ebel, Powassan virus (a flavivirus) is the tick-borne virus about which scientists know the most. It is maintained in nature in 3 distinct transmission cycles that involve woodchucks, squirrels, and deer ticks. Recent cases in humans seem to be related to the deer tick-driven transmission cycle, and this is partly why it is considered an emerging health threat in the United States.

Since 2006, 68 cases of Powassan encephalitis have been reported, said Dr. Ebel. Cases have occurred in the northeastern United States and upper Midwest, consistent with transmission by deer ticks. Severe disease occurs due to neurological involvement which arises secondary to either inflammation in the brain or direct neuronal injury, he noted.

First recognized in 2009 in Missouri, the Heartland virus, a phlebovirus transmitted by the bite of an infected lone star tick, is another emerging tick-borne virus, said Dr. Ebel. And one case of infection with Bourbon virus, a thogotovirus, was also reported in 2015. This virus remains poorly understood, but is probably tick-borne.

Many knowledge gaps persist about how new tick-borne viruses emerge, and Dr. Ebel highlighted several factors that hinder tick-borne virus research. In particular, the tick’s long life cycle—which often exceeds the length of a research grant&mdash;is an extremely difficult barrier to overcome, he concluded. (Learn more about Powassan virus by reading, “Another Tick-Borne Disease Growing in the United States: Powassan Virus,” available at 

Bobbi Pritt, MD, MSc, DTM&H, from Mayo Clinic in Rochester, Minnesota, discussed testing methods for diagnosing TBDs. Indirect methods measure the host’s immune response to an infecting organism, she said, and detect IgM or IgG class antibodies in serum. Serology is the method of choice for detecting many TBDs, but Dr. Pritt stressed that it is also insensitive in the first few days of an infection before antibody levels begin to rise. But by the second or third week, its sensitivity significantly increases, she said.

In contrast, direct methods detect the organism itself or some component of it. These include nuclei acid amplification tests, such as polymerase chain reaction to detect the organism’s DNA or RNA. Although nucleic acid amplification represents one of the earliest methods for detecting some organisms, it can be insensitive if nucleic acid is no longer detectable when the patient presents for evaluation. Nevertheless, it is especially useful for such organisms as the 

 species because large amounts of their DNA and RNA are present during the symptomatic stage of infection.

Several next-generation technologies are also emerging, said Dr. Pritt. Multiplex molecular panels can detect multiple bacterial, viral, and parasitic pathogens in a single test. In addition, broad range sequencing uses common targets and allows targeted gene amplification with subsequent sequence identification. “The last category of emerging technologies that I find particularly exciting is metagenomics,” she said, which allows amplification of all nucleic acid in a specimen, whether bacterial, fungal, viral, parasitic or human in origin. “This is currently very expensive and time consuming, but I think this is bound to change in the future,” she concluded.

Dr. Parry, a board-certified veterinary pathologist, graduated from the University of Liverpool in 1997. After 13 years in academia, she founded Midwest Veterinary Pathology, LLC, where she now works as a private consultant. Dr. Parry writes regularly for veterinary organizations and publications.

Drexler N, Miller M, Gerding J, et al. Community-based control of the brown dog tick in a region with high rates of Rocky Mountain spotted fever, 2012-2013. 

Centers for Disease Control and Prevention. Bourbon virus. CDC website. 

. Updated February 19, 2015. Accessed April 3, 2017. 

Kosoy OI, Lambert AJ, Hawkinson DJ, et al. Novel thogotovirus associated with febrile illness and death, United States, 2014. 

. 2015;21(5):760-764. doi: 10.3201/eid2105.150150.

Emerging Diseases

Experts explore how to develop and deliver effective prevention and treatment methods.

Tick-Borne Diseases Continue to Emerge and Increase in the United States

 infection (CDI) due to antimicrobial therapy accounts for 20% to 30% of cases of antibiotic-associated diarrhea.

 is also one of the most common organisms that causes hospital-acquired infections: from 2000 to 2009, the rate of CDI more than doubled and although that rate has leveled, it remains high. The burden of CDI comes with an attributable mortality of 5% to 10%, an increase in hospital stay from 2.8 to 5 days, and a yearly management cost in the United States of $1 billion to $4.9 billion.

For surveillance purposes, CDI can be broken down into standardized definitions to allow for monitoring for a potential outbreak and ensure patient safety that include community-associated, community-onset healthcare facility—associated CDI, and healthcare facility–onset and –associated. Several methods are available to diagnose CDI either alone or in combination, usually by detecting the presence of 

 Because of the low sensitivity and/or specificity of rapid toxin detection tests, however, such as an enzyme immunoassay (EIA) for toxin A and B, a two-step approach can be utilized using EIA detection of glutamate dehydrogenase with confirmation of positive results by cell cytotoxicity assay, cell culture, or polymerase chain reaction (PCR).

 Alternatively, findings from a colonoscopy or histopathology that demonstrate pseudomembranous colitis with the presence of symptoms, usually diarrhea, can help diagnose CDI.

There are several risk factors for CDI: age, duration of hospitalization, and antimicrobial exposure (the most modifiable risk factor). Antibiotics modify the normal bowel flora and allow the 

 to flourish. During hospitalization, the risk for developing CDI is related to specific classes of antibiotics, such as fluoroquinolones, beta-lactam/beta-lactamase inhibitors, and cephalosporins; the number of different antimicrobials prescribed; and the duration of treatment.

 When appropriate, using the minimum number of antibiotics with the narrowest spectrum of activity for the shortest treatment duration may help reduce the rate of CDI. Antibiotic stewardship programs, in collaboration with infection control practices, have been shown to reduce incidence of CDI in hospitals. Different mechanisms can be utilized as part of the stewardship program, and these may include antimicrobial de-escalation based on culture and antibiotic susceptibility, formulary restrictions/prior approval for selected antimicrobials, standard guidelines for treatment and prophylaxis, and development of an antibiogram to guide empiric therapy.

The results of several studies have demonstrated the benefit of appropriate antibiotic utilization on the incidence of CDI as well.

 For instance, Valiquette and colleagues implemented guidelines for antibiotic use that incorporated recommendations for antibiotics and shortening antibiotic durations in a tertiary care center in Quebec. As a result, the incidence of CDI decreased by 60% between 2003-2004 and 2005-2006; total and antibiotic consumptions fell as well.

 Likewise, Muto and colleagues used a team-based approach toward appropriate antibiotic utilization, combining targeted antimicrobial restriction, education, and expanded infection control measures at the University of Pittsburgh Medical Center. The team observed a decrease in antibiotic-associated CDI of 41%, with the overall rate decreasing to 3/1000 discharges from 7.2/1000 discharges.

 On January 1, 2017, new antimicrobial stewardship standards were implemented that mandate the reporting of CDI in every hospital. As previously mentioned, appropriate antibiotic utilization has significantly decreased the rate of hospital-onset CDI. With the current increased incidence of CDI, the reporting rate is an important outcome to monitor.

 Indeed, the majority of acute care hospitals are already reporting the incidence of CDI to the Centers for Disease Control and Prevention’s National Healthcare Safety Network as part of the Centers for Medicare & Medicaid Services reporting program.

The best approach to combat CDI is a collaborative one that combines an antimicrobial stewardship program and infection control practices. The identification of patients with suspected CDI should occur rapidly, with contact isolation being implemented immediately. In addition, hand hygiene and disinfection of all surfaces in the patient’s room should be completed to prevention transmission of the infection.

Ultimately, prevention of CDI is key. Efforts should include early identification of patients with CDI, testing of patients who are symptomatic only, and infection-control measures—specifically, contact precautions, environmental cleaning, hand hygiene, and antimicrobial stewardship. We continue to see an increasing incidence of CDI with a high mortality rate. Required reporting will assist in alerting institutions to changes in their CDI rates to help prevent any future outbreaks.

Dr. Amanda Binkley earned her doctor of pharmacy degree at Philadelphia College of Pharmacy. She completed her PGY-1 pharmacy practice residency and PGY-2 infectious diseases residency at the Hospital of the University of Pennsylvania. She is an active member of the Society of Infectious Disease Pharmacists (SIDP).

Dr. Shawn Binkley earned his bachelor of science degree at Pennsylvania State University and his doctor of pharmacy degree at Midwestern University College of Pharmacy—Glendale, Arizona. He completed his PGY-1 pharmacy practice residency and PGY-2 infectious diseases residency at the Hospital of the University of Pennsylvania. He is an active member of SIDP.

Dubberke E, Carling P, Carrico R, et al. Strategies to prevent Clostridium difficile in acute care hospitals: 2014 update. 

Centers for Disease Control and Prevention. Clostridium difficile infection. CDC website. www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html. Updated March 1, 2016. Accessed February 17, 2017.

Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). 

Stevens V, Dumyati G, Fine LS, Fisher SG, van Wijngaarden E. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. 

Valiquette L, Cossette B, Garant MP, Diab H, Pepin J. Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of 

-associated disease caused by the hypervirulent NAP1/027 strain. 

Muto CA, Blank MK, Marsh, JW, et al. Control of an outbreak of an infection with the hypervirulent 

 BI strain in a university hospital using a comprehensive "bundle" approach. 

Fowler S, Webber A, Cooper BS, et al. Successful use of feedback to improve antibiotic prescribing and reduce 

 infection: a controlled interrupted time series. 

Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. 

Joint Commission. Approved: new antimicrobial stewardship standard. 

Preventive Care

What can healthcare providers do to stop these infections before they start?

Preventing Clostridium difficile From Getting Loose

For the past several years, patients infected with hepatitis C virus (HCV) were virtually “warehoused” as clinicians awaited the introduction of newer and less toxic direct-acting antivirals (DAAs). Although the pipeline is rich with new DAAs, available agents, such as Harvoni (sofosbuvir/ledipasvir) and Epclusa (sofosbuvirvelpatasvir), are being used routinely since “cure” rates approach 100% with these medications in many cases. Without question, these drugs have revolutionized the therapeutic approach to patients infected with HCV.

Prior to approval by the US Food and Drug Administration (FDA) in November 2013, DAAs were already being touted as a panacea in many ways, highlighting their superior tolerability compared with older available agents and their significantly shortened treatment durations. Recently, however, safety precautions have begun to emerge that might cause concern for clinicians treating patients with HCV.

It is well known that drug—drug interactions (DDIs) and adverse drug reactions have a significant influence on the risk for hospitalization, morbidity, and mortality in all patients.

 Most clinicians recognize the DDIs present with many of the DAAs, especially in patients who are coinfected with HIV and receiving antiretroviral therapy (ART). Common interacting medications include proton-pump inhibitors, thyroid hormones, and dihydropyridine derivatives.

 While most of the interactions can be managed with monitoring or slight dose adjustments, some can be more detrimental to patient outcomes. For example, amiodarone was one of the first DDIs to be reported as clinically significant, garnering an FDA warning for the combination of amiodarone- and sofosbuvir-containing regimens. Concurrent use of these two agents yielded reports of life-threatening bradycardia, with 1 death and 3 other patients requiring a pacemaker.

 As a result, patients who are on these medications concurrently should be monitored in an inpatient facility for at least 48 hours, with outpatient monitoring for an additional 2 weeks.

More recently, concerns have emerged regarding reactivation of hepatitis B virus (HBV) in patients treated for HCV with DAAs.

 (It is worth noting this risk was not identified in clinical trials because patients coinfected with HBV and HCV were excluded.) The mechanism behind the reactivation of HBV is unknown; however, it is plausible that clearance of HCV could result in a resurgence of HBV replication since the DAAs have no activity against HBV.

 Furthermore, HCV has shown suppressive effects on HBV replication in coinfected patients.

At present, 24 cases of HBV reactivation have been reported to the FDA Adverse Event Reporting System, with 3 cases of acute liver failure. It should be noted 2 of these patients died and one required a liver transplant.

 These reports led to the uncovering of an additional 524 reported cases of liver failure in conjunction with more than 1000 reports of serious liver injury.

 Mortality attributed to the liver failure in these cases exceeded 30%, which is unacceptably high if the current paradigm of treatment is to continue. Interestingly, over 700 cases of antiviral failure have also been reported, contrary to what has been seen in most clinical trials. Of the DAAs, paritaprevir-containing regimens (34.5%) and sofosbuvir-containing regimens (32.6%) were most commonly implicated in the 524 reported cases.

The signal of increased risk of liver injury in any capacity is troubling, and perhaps even more so as most recommended HCV regimens contain sofosbuvir. Further, according to data from the Institute for Safe Medication Practices, clinicians who reported cases were almost exclusively specialists in the management of hepatitis reinforcing the validity of the findings.

As the era of DAAs was ushered in, the possibility of the beginning of the end of HCV also seemed to be on the horizon. With the introduction of the DAAs came the pressure to treat most patients who were infected. This was a move made secondary to direct to consumer advertising; patient characteristics, such as HIV or HCV coinfection; or simply patient preference. Whereas the consequences of DDIs can be appropriately managed in the clinic, heightened awareness of liver failure should result in greater vigilance in who receives antiviral therapy and who does not.

Given that newer agents, such as glecaprevir/pibrentasvir, ruzasvir, voxilaprevir, and MK-3682 are currently in clinical trials, this begs the question of whether we should place patients back in the warehouse until newer and safer agents become available. At present, it is unknown if these agents will carry the same risks described above. At the very least, perhaps the door should be reopened.

Dr. Lindquist, PharmD, BCPS, is a clinical pharmacist at the University of Tennessee Medical Center in Knoxville, Tennessee, and holds a faculty appointment as an assistant professor in the Department of Clinical Pharmacy at the University of Tennessee Health Science Center. She is also an active member of SIDP.

Dr. Cluck, PharmD, BCPS, AAHIVP, is an assistant professor in the Department of Pharmacy Practice at East Tennessee State University (ETSU) Gatton College of Pharmacy. He maintains a clinical pharmacy practice in infectious diseases at Johnston Memorial Hospital in Abingdon, Virginia as well as a weekly outpatient HIV clinic with the ETSU HIV Center of Excellence. He is also an active member of SIDP, ACCP, ASHP, IDSA, and AAHIVM. 

Dechanont S, Maphanta S, Butthum B, Kongkaew C. Hospital admissions/visits associated with drug-drug interactions: a systematic review and meta-analysis. 

Höner zu Siederdissen C, Maasoumy B, Marra F, et al. Drug-drug interactions with novel all oral interferon-free antiviral agents in a large real-world cohort. 

 2015;62(5):561-567. doi: 10.1093/cid/civ973. 

US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral drug. FDA website. https://www.fda.gov/Drugs/DrugSafety/ucm439484.htm. Published March 24, 2015. Accessed February 6, 2017. 

US Food and Drug Administration. FDA drug safety podcast: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. FDA website. www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm524589.htm. Updated December 28, 2016. Accessed January 28, 2017. 

Yalcin K, Degertekin H, Yildiz F, Kilinc N. A severe hepatitis flare in an HBV-HCV coinfected patient during combination therapy with alpha-interferon and ribavirin. 

Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection.

Moore TJ, Furberg CD, Mattison DR, Cohen MR. ISMP QuarterWatch: perspectives from new adverse events reports Institute for Safe Medication Practices website. https://www.ismp.org/quarterwatch/pdfs/2016Q2.pdf. Published January 25 2017. Accessed February 6, 2017.

HCV / Hepatitis

Should clinicians be extra vigilant when deciding who receives antiviral therapy, or are the adverse effects few and infrequent?

Risks Associated With Direct-Acting Antivirals&mdash;Smoke or Fire?

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recently published a joint update to their nosocomial pneumonia guideline.

 About 11 years have passed since the first guideline was published, and so identifying key changes between the new guideline and the original might be difficult for some end users. In this article, I highlighted several key differences and updates related to antibiotic therapy.

First, the previous guideline included healthcare-associated pneumonia (HCAP) in the spectrum of hospital-acquired pneumonia (HAP) and ventilator-acquired pneumonia (VAP). This was done because patients with HCAP were thought to be at high risk for multidrug-resistant (MDR) pathogens due to exposure to pathogens within healthcare facilities. In the new guideline, HCAP is included under the guideline for community-acquired pneumonia because recent data

 showed that many patients are not at high risk for MDR organisms as previously thought and therefore should not be treated in the same manner as patients with HAP or VAP.

Second, additional risk factors for MDR pathogens are provided in the new guideline. These risk factors include the septic shock at time of VAP and acute respiratory distress syndrome or acute renal replacement therapy preceding VAP.  All risk factors for HCAP have been removed.

Third, the previous guideline recommended the use of 2 empiric antipseudomonal agents for all patients at high risk for MDR pathogens. In contrast, the new guideline recommended two agents for patients with structural lung disease that increases the risk of gram-negative infection (ie, bronchiectasis or cystic fibrosis). In addition, the older guideline suggested considering two empiric antipseudomonal agents in patients with VAP with a risk factor for MDR pathogens, those in units where more than 10% of gram-negative isolates are resistant to an agent being considered for monotherapy, and those in an ICU where local antimicrobial susceptibility rates are not available. The authors believed that this would reduce patient harm, unnecessary exposure to broad-spectrum antibiotic coverage, and microbial resistance development. The guideline further recommends having a specific antibiogram for intensive care patients.

Fourth, the new guideline clearly recommends including empiric coverage for methicillin-susceptible 

 (MSSA) for VAP patients if coverage for methicillin-resistant 

 was not indicated. The antibiotics suggested for these infections include piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem.

Fifth, the new guideline recommends several therapeutic options and removes other options. For example, the new guideline does not include some antibiotics that were mentioned in the previous guideline as a possible option for empiric therapy, such as ampicillin/sulbactam, ceftriaxone, moxifloxacin, and ertapenem. This is because these agents do not have antipseudomonal activity, while all of the options included in the new guideline have activity against 

. In addition, the combination of both inhaled and systemic antibiotics is now recommended for patients with VAP because of gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins.

 Whereas the previous guideline did not discuss tigecycline and doripenem, the new guideline states that these medications were associated with worse outcomes in patients with VAP. Aminoglycosides were only recommended as adjunctive agents, not as the sole empiric antipseudomonal antibiotic, for patients with HAP. Interestingly, the new guideline states that it is acceptable to use aztreonam as an adjunctive antibiotic with another beta-lactam—based antibiotic in the absence of other options because of having different targets in the bacterial cell wall.

Sixth, the new guideline makes some changes regarding antibiotic dosing. Although the previous guideline did not provide a recommended dose for any polymyxin, the new guideline recommends dosing colistin as a 5-mg/kg IV as a loading dose, followed by a maintenance dose of a 2.5-mg 

 creatinine clearance + 30) IV every 12 hours, whereas it recommends dosing polymyxin B as 2.5 to 3 mg/kg/day divided in 2 daily IV doses. The cefepime and aminoglycosides doses were modified as following: the cefepime IV dose was changed from 1 to 2 g every 8 to 12 hours to 2 g every 8 hours; gentamicin and tobramycin IV doses were changed from 7 mg/kg/day to 5 to 7 mg/kg/day; and the amikacin IV dose was changed from 20 mg/kg/day to 15 to 20 mg/kg/day. Moreover, the new guideline recommends considering a loading dose of vancomycin for severe infections and extended IV infusion for piperacillin/tazobactam, cefepime, ceftazidime, imipenem, and meropenem, as well as basing antibiotic dosing on the pharmacokinetic/pharmacodynamic properties data rather than the manufacturer’s prescribing information.

Finally, the new guideline discusses the use of biomarkers to treat VAP and HAP. Procalcitonin, soluble triggering receptor expressed on myeloid cells, and C-reactive proteins were not recommended to be used to decide whether to initiate antibiotic therapy; however, procalcitonin was suggested in addition to clinical criteria to guide the antibiotic therapy discontinuation as it was associated with decreased antibiotic exposure without increasing adverse outcomes.

In conclusion, the new guideline for HAP and VAP no longer includes HCAP. One antipseudomonal agent is currently recommended for most HAP and VAP cases unless patients have high risk for MDR pathogens, while MSSA coverage is needed in patients with VAP. Various changes and additions were made to antibiotic choice, dose, route of administration, and duration of therapy. A summary of the changes is included in the 

Table: Updates to IDSA/ATS Guideline for Nosocomial Pneumonia Snapshot

HCAP was included in the spectrum of HAP/VAP

Suggest 2 empiric antipseudomonal agents only for selected patients

Recommend 2 empiric antipseudomonal agents for all

			patients at high risk for MDR bacteria

Recommend empiric coverage of MSSA in VAP

All patients need empiric antipseudomonal agent

Agents without antipseudomonal activity are acceptable

Suggest procalcitonin plus clinical criteria to guide antibiotic discontinuation

Gentamicin and tobramycin IV: 5-7 mg/kg/day

Gentamicin and tobramycin IV: 7 mg/kg/day

HCAP indicates healthcare-associated pneumonia; CAP, community-acquired pneumonia; VAP, ventilator-acquired pneumonia;

HAP, hospital-acquired pneumonia; MDR, multidrug resistant; MSSA, methicillin-susceptible 

Feature - Respiratory Infections

Contagion® Editorial Advisory Board member, Khalid Eljaaly, PharmD, BCPS, CAPP, discusses key updates in the Infectious Diseases Society of America and the American Thoracic Society recommendations.

Changes in Therapy Guideline for Nosocomial Pneumonia

21st Century Cures Act Measures Aimed at Combating Antimicrobial Resistance

Establishing the limited population antimicrobial drug regulatory pathway

Encouraging monitoring of antimicrobial resistance and increase stewardship efforts

Improving availability of contemporary susceptibility break points

The Centers for Disease Control and Prevention estimates that each year at least 2 million Americans develop infections due to drug-resistant pathogens, which result in approximately 23,000 deaths annually.

 Antibiotics are a critical medical resource with the potential to cure life-threatening infections. However, the ability of bacteria to evolve rapidly, which is exacerbated by the inappropriate use of antibiotics, often leads to the development of antibiotic resistance.

As resistance develops and spreads globally, healthcare providers are left with a limited ability to effectively treat multidrug-resistant infections.

 Therefore, it is important to continually replenish the armamentarium of antibiotics. Unfortunately, the development of new antibiotics has fallen far behind the rising incidence of antibiotic-resistant infections.

 Factors that contribute to the relative lack of new agents are complex, with one significant challenge being the lack of an existing approval pathway for antibiotics that are intended to treat serious and rare pathogens. The 21st Century Cures Act (Cures Act), signed into law in December 2016 by President Barack Obama, outlines such a pathway and proposes several additional measures to combat antibiotic resistance.

The Cures Act introduces the Limited Population Antibacterial Drug (LPAD) regulatory pathway, which builds on ideas presented in US Food and Drug Administration (FDA) 2013 draft guidance on developing antibiotics for patients with unmet needs, and provides the FDA flexibility in the approval of antibiotics intended for limited patient populations.

 For example, multidrug-resistant pathogens are relatively rare and primarily infect patients who are often too sick to be enrolled in trials, such that large clinical studies may prove infeasible. As a potential solution, LPAD may allow for smaller descriptive clinical datasets supplemented by robust nonclinical data. LPAD directs the FDA to consider the benefit—risk profile in the intended population, the availability of alternative treatment options, and the severity and rarity of the infection that the antibiotic is intended to treat. The LPAD pathway also requires specific language (“This drug is indicated for use in a limited and specific population of patients”

) in any antibiotic label or promotional material for a drug approved via this pathway to indicate that the safety and effectiveness have been demonstrated only with respect to a limited population. Moreover, promotional material will need to be submitted to the FDA at least 30 calendar days prior to distribution to the public. Although many of the details surrounding the FDA’s implementation of LPAD will not be available until a draft guidance is issued within the next 18 months, the overall vision, in the words of Robert Califf, MD, former commissioner of the FDA, is that the pathway “...will help streamline the development programs for certain antibacterials and antifungals intended to treat targeted groups of patients suffering from serious or life-threatening infections, where unmet need exists due to lack of available therapies.”

 In addition to LPAD, the Cures Act encourages widespread monitoring for antibiotic resistance and increased efforts to reduce inappropriate uses of antibiotics. The legislation establishes a mechanism for healthcare facilities at the Department of Defense, Department of Veterans Affairs, and Indian Health Services to routinely report and evaluate aggregate antibiotic resistance rates within each facility. Healthcare facilities, such as hospitals, nursing homes, and outpatient clinics will also receive educational materials and guidance to support implementation of antibiotic stewardship programs. Importantly, an annual public report will be issued that summarizes national and regional trends in antibiotic resistance, as well as progress on stewardship activities. The first report is expected this year.

Lastly, the Cures Act includes provisions to help improve the availability of information on pathogen susceptibility to a given antibiotic (interpretive susceptibility criteria or “breakpoints”) and keep breakpoints up-to-date. Specifically, any new or updated interpretive susceptibility criteria standards will be evaluated every 6 months. Such an infrastructure may better enable clinicians to select antibiotics that are most likely to lead to positive clinical outcomes for their patients, as well as ensure consistency in methodologies used to establish breakpoints across all antibiotics and antibiotic classes regardless of the date of approval. Furthermore, break-points will be posted to a website, which will be established this year, and a reference or hyperlink to the site will be included in the FDA-approved package insert.

 A deeper understanding of the antibiotic resistance landscape and more frequent review of breakpoints will position clinicians, drug developers, scientists, and the FDA to more appropriately address the rising tide of resistance and optimize patient care.

In summary, several key sections of the Cures Act impact antimicrobial development and clinical use. The language in the legislation supports more stringent resistance monitoring and stewardship activities aimed at combating resistance. Most notably, LPAD represents both a congressional acknowledgment of the public health crisis and significant progress in the formation of a clinical-regulatory pathway that enables drug companies to develop antibiotics for patient populations that currently have unmet medical needs.

Dr. Stork is a senior associate in Regulatory Affairs at Achaogen. She completed her PhD in molecular biology at Stanford University. 

Dr. Komirenko is a clinical sciences fellow at Achaogen. She completed her PharmD at the University of California, San Francisco. She is an active member of the Society of Infectious Disease Pharmacists (SIDP).

Dr. Mohr is vice president of Medical Affairs at scPharmaceuticals and president and founder of Medical Affairs Strategic Solutions. He is an active member of SIDP.

Dr. Boucher is associate professor of medicine at Tufts University School of Medicine and director of the Infectious Diseases Fellowship Program and Tufts Medical Center. She is an active member of SIDP.

Centers for Disease Control and Prevention. Antibiotic/antimicrobial resistance. CDC website. www.cdc.gov/drugresistance/. Updated March 8, 2017. Accessed March 10, 2017.

Experts weigh in on what Congress is doing to tackle the threat of antibiotic resistance.

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