When I teach infectious diseases (ID) to students in multiple health professions, I like to highlight how they are like a puzzle: Knowledge of the organisms that cause infections combined with knowledge of the pharmacology and spectrum of activity of antimicrobial agents leads to rational antibiotic choices. This is one of the areas of ID that I find most appealing because I am often in the scenario of having to choose agents for resistant infections based on in vitro data, pharmacokinetic/pharmacodynamic studies, logic, and—if I’m lucky&mdash;some retrospective studies. Although clinically interesting, this situation is not ideal. It is borne out of necessity, as resistant infections are difficult to study in controlled trials, and the epidemiology of antimicrobial resistance is constantly changing. 

® will print shortly after the publication of a long-awaited clinical trial that was 5 years in the making. The MERINO trial tested the hypothesis that a β-lactamase inhibitor combination is noninferior to a carbapenem for the treatment of bacteremia caused by Enterobacteriaceae resistant to third-generation cephalosporins.

 Previous retrospective studies examining the issue have had mixed results, and many clinicians have differing opinions. After screening over 1600 patients to find 391 to enroll, the investigators have an answer: Piperacillin/ tazobactam use was associated with higher mortality than meropenem. 

This is a result that few in ID wanted to see because it can be used to justify (often correctly) more use of carbapenems, which in turn can lead to selection pressure encouraging the growth of carbapenem-resistant organisms. However, unpopularity does not lead to invalidity. The single-best-designed study examining empiric regimens for presumed extended-spectrum β-lactamase—producing bloodstream infections has concluded that carbapenems save lives. 

ID practitioners were not the only group to receive an evidence-based wake-up call recently. The long-standing practice of using aspirin for primary prevention of cardiovascular events is being reevaluated after several recently published studies. More data in ID pharmacotherapy is emerging that reevaluates the need for intravenous therapy for several disease states, including endocarditis and osteomyelitis. As these and other prospective studies are reported, it is up to all of us in health care to evaluate the level of evidence in our own practices and continue to evolve, just like the organisms we work to treat. 

® features the latest on the Zika virus, which although absent from the media headlines, has not disappeared from our lives and remains a concerning threat to those who live in tropical climates where the disease’s vector, the 

 mosquito, is rampant. Keeping with the theme of zoonotic infections, we have included an interesting case study on Lyme neuroborreliosis presenting as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), making it the fourth documented case of Lyme-induced SIADH. A couple of other items of interest in this issue include an article on the necessity of globalized antibiotic stewardship programs in the fight against antibiotic resistance, by Debra Goff, PharmD, FCCP, and colleagues as well as highlights and pitfalls of the Infectious Diseases Society of America and the American Thoracic Society guidelines for hospital-acquired and ventilator-associated pneumonia, by Lucia Rosé, PharmD, and Dana Byrne, MD, MSCE. 

Continue to look for the latest infectious diseases news on our website and social media channels (

Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS 

Dr. Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia, 

 He is also the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple. 

Harris PNA, Tambyah PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10):984-994. doi: 10.1001/jama.2018.12163. 

Resistance Map. The Center for Disease Dynamics, Economics & Policy website. https://resistancemap.cddep.org/Antibiotic- Resistance.php. Accessed October 3, 2018. 

Articles

Editor-in-Chief Letter

Editor-in-chief, Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS, shares how it is up to all of us in health care to evaluate the level of evidence in our practices and continue to evolve, just like the organisms we work to treat. 

In the Ever-Evolving World of Infectious Disease, the Bottom Line Is Evidence Matters

A 79-year-old man with a medical history of coronary artery disease and hypertension presented to the emergency department (ED) with acute onset of ataxia and double vision in June 2018. Two days prior to his admission, he was seen at an outside ED for complaints of a headache. At the outside facility, he was found to have a blood pressure of 210/105 mm Hg, which was reduced with oral antihypertensives. Imaging at that hospital did not demonstrate any acute hemorrhage, and he was discharged with instructions to follow up with his primary care provider.  

On the morning of the current admission, he awoke feeling ataxic and weak and had diplopia. He attempted to ambulate and subsequently fell while getting out of bed. He denied syncope or any post&shy;ictal symptoms during this episode. The history was obtained from his daughter, who was at his bedside. The patient was unable to give a history secondary to his condition.  

Coronary artery disease, with a known drug-eluting stent placed in 2009; hypertension; hyperlipidemia; and gout.  

Norvasc 10 mg by mouth daily; losartan 100 mg by mouth daily; metoprolol 50 XL daily; atorvastatin 40 mg by mouth every night at bedtime; allopurinol 300 mg by mouth daily; aspirin 81 mg by mouth daily.  

The patient was sexually active with his wife of 50 years, a nonsmoker, and a nondrinker and denied any illicit drug use. His family denied any recent travel outside the Pennsylvania area over the 6 months prior to presentation. He and his family denied any recent illness or sick contacts. He also did not own any pets, and his family did not recall any obvious pet exposures.  

The patient’s vital signs were within normal limits. On physical examination, he was lethargic and unable to respond coherently and appeared very fatigued. His mucous membranes were moist, and he did not have any signs of volume overload (eg, jugular venous distention, edema). His pupils were equal, round, and reactive to light, but he could not abduct his eyes. His cardiovascular assessment did not reveal any murmurs or arrhythmias, and his thoracic examination was unremarkable. His neurological examination was remarkable for 2 out of 5 strength in his upper and lower extremities, bilaterally.  

Given his concerning physical examination, laboratory work was ordered to discern the etiology of his condition. Complete blood count was unremarkable; however, serum sodium was found to be 125 mEq/L (normal: 135-145 mEq/L). A chart review revealed a serum sodium level of 138 mEq/L 2 days prior to admission.  

Further laboratory evaluation of the patient’s hyponatremia demonstrated serum osmolality of 269 mOsm/kg (normal 275-295 mOsm/kg), urine osmolality of 688 mOsm/kg, urine sodium of 87 mmol/L, and uric acid of 3 mg/dL.  

The patient presented to the hospital with concerning physical examination and metabolic derangements. Initially, the work-up and management concerned his hyponatremia. On presentation, his hyponatremia was classified as hypotonic and euvolemic. Given his high urine osmolality and high urine sodium, his hyponatremia appeared to be related to syndrome of inappro&shy;priate secretion of antidiuretic hormone (SIADH). The patient was placed on fluid restriction for initial management of SIADH and did not show much neurological improvement or correction of his hyponatremia. Because fluid restriction usually corrects underlying hyponatremia related to SIADH, additional etiologies were sought. Thyroid and adrenal studies were checked, as these functions are known to also mimic or confound a diagnosis of SIADH, but results were within normal limits.  

Given that the etiology of the patient’s SIADH remained a mystery, radio&shy;logical surveillance was undertaken to search for any possible lesions or malignancies. A chest x-ray was concerning for a possible lesion in the thoracic cavity, which led to further evaluation via bronchoscopy. It was thought that the patient may have had neuroendocrine sequelae of SIADH related to a possible thoracic malignancy. However, the results of the bronchoscopy proved to be fruitless and were simply demonstrative of a mucous plug, which had no clinical significance.  

The patient was not improving, so a reassessment of the history of the present illness was repeated with his family members. A careful and in-depth history revealed that 2 months prior to presentation, the patient had been hiking in the woods with his grandchildren and could have been bitten by a tick. This led to subsequent testing for Lyme disease, which was confirmed via a Western blot analysis.  

Once the appropriate diagnosis of Lyme disease was made, intravenous ceftriaxone therapy was initiated. There was a rapid improvement in the patient’s metabolic panel and his neurological status (

). On the day of discharge, the patient was more lucid, was answering questions appropri&shy;ately, and had full strength in his upper and lower extremities. He finished a 4-week course of ceftriaxone with resolution of his ataxia and diplopia.  

enzyme-linked immunosorbent assay with a reflexive Western blot demonstrating 6 confirmatory IgG bands: 18 kDa, 28 kDa, 30 kDa, 39 kDa (BmpA), 45 kDa, and 66 kDa.  

Hyponatremia is the most common electrolyte imbalance seen in clinical practice.

 In patients older than 65 years, SIADH was the main culprit in over half of all cases of hyponatremia.

 The most common etiologies of SIADH are malignancy, medications, and central nervous system (CNS) disorders.

 CNS infections are a rare but known cause of SIADH and include bacterial and enteroviral meningitis, tuberculosis, herpes simplex, St. Louis encephalitis, and La Crosse encephalitis. Management of SIADH involves treating the underlying etiology; however, management becomes more difficult when the cause of the SIADH is not identified and significantly affects the patient.  

This patient initially presented with vague neurological symptoms and hyponatremia, identified as SIADH. Multiple imaging modalities and invasive tests, including bronchoscopy, were performed, but a cause for the SIADH remained unknown. Eventually, a thorough discussion with the family revealed that the patient went hiking in the woods 2 months prior to presentation. Lyme disease was positive after testing but was not identified as an etiology for the SIADH. It was not until antibiotic treatment was initiated that the patient’s hyponatremia and symptoms resolved.  

Lyme-induced SIADH is a rare phenomenon, and only 3 case reports were found in the literature.

 A review of the cases revealed almost iden&shy;tical presenting symptoms and hospital course to the patient’s. In the case reports, the patients were eventually tested for Lyme disease, and after appropriate antibiotic treatment was initiated, complete resolution of all symptoms and hyponatremia occurred.  

This case identifies 3 major problems that affected the patient: a prolonged hospital course, a significant financial burden, and a delay in care. Our patient underwent multiple imaging studies, including invasive testing, but a clear cause for the SIADH could not be determined. In addi&shy;tion to having to wait for the diagnosis of Lyme disease, the patient was exposed to a prolonged hospital course and incurred unnecessary medical costs. A more thorough history and education about the lesser-known consequences of Lyme could have led to earlier diagnosis.  

In addition, further research is needed regarding the pathophysiology and sequela effects of Lyme-induced SIADH. Given that the hypothal&shy;amus secretes antidiuretic hormone, it is clear that CNS involvement of Lyme disease may be associated with endocrinopathies. Understanding this mechanism may broaden the understanding of not just Lyme disease but also the interplay between tick-borne illnesses and undiagnosed or perplexing endocrinopathies.  

SIADH is a common disorder that can be treated only by identifying the correct etiology. When practitioners are unable to determine the root cause, patients undergo a prolonged hospital course, incur significant medical costs, and experience a delay in care. Resolution of the patient’s SIADH ultimately occurred after discovery and treatment of Lyme disease via the least expensive modality: a more thorough history. This case report is the fourth documented case of Lyme-induced SIADH. All cases had similar hospital courses, including incidental diagnosis of Lyme and complete resolution of symptoms when antibiotics were administered. This case report is another piece of evidence to support this medical phenomenon and stresses the importance to the medical community of including Lyme disease as a differential for SIADH.

Dr. Karnik is a current PGY-2 resident in the department of internal medicine at Drexel University College of Medicine/ Hahnemann University Hospital and is interested in pursuing a career in academic gastroenterology. 

Dr. Rossi is a current PGY-3 resident in the department of internal medicine Drexel University College of Medicine/ Hahnemann University Hospital and is excited to pursue a career in infectious diseases. 

Dr. Parikh recently graduated from Drexel University College of Medicine/Hahnemann University Hospital residency program and is currently working as a hospitalist. 

Dr. Sangitha is a 2018 graduate of Drexel University College of Medicine/Hahnemann University Hospital (HUP) who is currently in an internship in internal medicine at HUP.

Soiza RL, Hoyle GE, Chua MPW. Electrolyte and salt disturbances in older people: causes, management and implications. 

. 2008;18(2):143-158. doi: 10.1017/S0959259809002822.

Anpalahan M. Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. 

Baylis, PH. The syndrome of inappropriate antidiuretic hormone secretion. 

Siddiqui N, Peter DMS, Marur S. Ticks and salt: an atypical case of neuroborreliosis

2017;7(6):358-362. doi: 10.1080/20009666.2017.1407209.

Syed W, Yeager J, Fariduddin M, Shah A, Dhamoon A. Tick bite causing water retention Lyme’s disease manifesting as acute hyponatremia from SIADH. 

. 2015;43(12):315. doi: 10.1097/01.ccm.0000475085.62436.71.

Perkins CMP, Shumway CN, Jackson MWL. Lyme neuroborreliosis presenting as the syndrome of inappropriate antidiuretic hormone secretion. 

Case Study

This case report is the fourth documented case of Lyme-induced syndrome of inappro&shy;priate secretion of antidiuretic hormone (SIADH).  

Salt, Ticks, and Lyme: A Case of Lyme Neuroborreliosis Presenting as SIADH

The Zika virus, which dominated mainstream headlines in 2016 with reports of infected women giving birth to babies with defects, has receded into the background. With the virus and its complications no longer front-page news, people might be forgiven for assuming the threat of this mosquito-borne plague no longer exists. But experts say Zika, which is transmitted by the 

 mosquito, still presents a clear and present danger to travelers and residents in certain parts of the world, especially those with a tropical climate.

First some numbers: As of September 5, 2018, just 41 cases of Zika had been confirmed in US states, all in individuals who were returning from travel to affected areas. In all US territories, which include Puerto Rico and the US Virgin Islands, there were 82 cases as of September 5.

Last year, there were 452 confirmed cases in US states, with 666 in all US territories.

 Given that 5168 cases were reported in the states and 36,512 in the US territories in 2016, it’s clear that the impact of the virus is much lower now.

 Still, virus activity continues in the Caribbean, most of Latin America, Central Africa, India, Indonesia, Malaysia, Cambodia, and Papua New Guinea, among other places.

Although Zika cases continue to be reported, the epidemic has been declared over in Puerto Rico, according to 

® Editorial Advisory Board member Carmen Zorrilla, MD, professor of obstetrics and gynecology at the University of Puerto Rico School of Medicine in San Juan. “We knew there was an epidemic when people presented with rash and symptoms, even nonpregnant ones,” Dr. Zorrilla told 

Other experts agree. “Because we have fewer cases now, our attention span is a little limited,” said Thais dos Santos, MS, advisor on surveillance and control of arboviral diseases in the Neglected, Tropical and Vector-Borne Diseases Unit of the Communicable Diseases and Environmental Determinants of Health Department, a division of the Pan American Health Organization, in an interview with 

®. “It’s kind of fallen off a lot of people’s radar. But the virus itself isn’t any less dangerous. The virus hasn’t become less aggressive.”

According to Ms. dos Santos, in the Caribbean and Latin America (Brazil was at the epicenter of the crisis), many individuals may have become naturally immunized against the Zika virus as it swept through these regions, contracting it without necessarily even knowing it. Because only 20% to 40% of infected people ever show symptoms,

Kate Fowlie, a spokeswoman for the US Centers for Disease Control and Prevention (CDC), agrees that natural immunity is the reason for the disease’s current low numbers. “We expect fewer Zika cases in 2018 because a proportion of the population was infected in 2016 and is no longer susceptible to infection,” she said. “However, mosquito-borne disease outbreaks are difficult to predict. There will be future outbreaks, including large ones, as well as years with reduced transmission, but it is impossible to know when or where these transmission patterns will occur.”

Dr. Zorrilla, however, is not sure widespread immunity is the reason for Zika’s quieting in Puerto Rico. “I calculated that about 10.5% of the pregnant women in Puerto Rico had a positive test for Zika,” she said. “That is not enough to cause herd immunity.” Her theory is that, much like dengue and other tropical diseases, Zika is following a natural cycle that ebbs and flows. “It seems that these vector disease epidemics...come in waves for periods of 3 to 5 years. The vector [the mosquito] is there. It’s a matter of time. We need to watch for the emergence of a new epidemic.”

But predicting when and if a Zika epidemic will hit is not simple. “This is a really difficult disease to do surveillance for,” Ms. dos Santos pointed out. According to her, of those who do experience the typical complaints of rash, fever, muscle weakness, and inflamed eyes (conjunctivitis), only up to half—and possibly significantly fewer&mdash;bother to seek treatment. “The signs and symptoms of people who have Zika are very nonspecific,” she said. In other words, the disease can easily be confused with something else, such as a cold or a mild case of influenza.

As we now know, Zika’s all-too-easily missed symptoms may give no indication of its potentially serious complications. Currently, there is no treatment for Zika. Women who contract the virus are, if they are of childbearing age, at risk of giving birth to children with severe health problems including microcephaly, eye problems (including vision loss), epilepsy, nervous system defects, and hearing defects. An August 2018 

 from the CDC revealed that of 1450 children born to mothers known to have the Zika virus during pregnancy, 1 in 7 had a birth defect associated with the virus or a neurological abnormality possibly linked to the virus (or both).

 Experts fear the true toll of the disease could be even higher as children age. “We’re only beginning to scratch at the surface of the impact of this,” Ms. dos Santos explained.

Although rare, Guillain-Barré syndrome (GBS) is also a known risk of Zika.

 This nervous system malady can strike anyone and causes muscle weakness or, in its most extreme form, complete paralysis that can last up to several months. According to Dr. Zorrilla, GBS can result from a number of diseases, including dengue and influenza, but when it results from the Zika virus, it appears to manifest in a more severe form.

Whether of childbearing age or not, individuals traveling to or residing in places that saw a lot of Zika activity in the past couple of years should not be lulled into complacency by the drop-off in the number of cases, say many experts. Although another large epidemic is unlikely in the short term, infections are still taking place. “The continental United States and Hawaii will continue to see some travel-related cases, and local transmission is possible because the types of mosquitoes that carry Zika virus are present across a large portion of the United States,” said the CDC’s Ms. Fowlie. “As travelers visit countries with risk of Zika, they can be infected and bring the virus back to the United States, where it could be spread to local mosquitoes or to others through sex.”

The possibility of sexual transmission means that individuals must be very careful in their intimate relationships. The CDC has issued updated guidelines, including the recommendation that any man who might have been exposed to Zika avoid conceiving for at least 3 months after his symptoms start.

 (Initially, men were told to wait 6 months before trying to conceive with a partner.) This is because women are at risk of getting the virus from their partner’s semen, which can harbor it for several months. Women who are already pregnant are also at risk if they engage in unprotected sex with a potentially infected partner, so the use of a condom or abstinence is encouraged until the birth. The exact amount of time someone remains infectious after acquiring the virus is unknown.

According to Ms. Fowlie, the CDC received $350 million from the 2016 federal budget and used it to “prevent, detect, and respond to Zika,” she said. “CDC’s funding was used to increase mosquito control and surveillance, laboratory capacity, public health studies, technical assistance to state and local governments, and diagnostic development.” Some of the money went toward preventive measures, such as the spraying of insecticides to reduce the insect population in locales that have had disease activity. In some tropical locations without air-conditioning, places where people rely on open or poorly screened windows for ventilation, officials distributed Zika prevention kits that contained bed netting to help keep mosquitoes away during sleep. The kits also included condoms, mosquito repellent, and standing-water treatment tablets that kill mosquito larvae in puddles.

But the one thing that might make a real impact on Zika transmission rates, a vaccine, has yet to be approved by the US Food and Drug Administration. The National Institute of Allergy and Infectious Diseases reports that several types of vaccines are in development and will potentially be used to prevent Zika infection.10 They include vaccines based on DNA, inactivated Zika, and live Zika. Also in development is a vaccine that should offer protection against a variety of mosquito-borne diseases, including Zika. Most are in the clinical testing phase right now, and the medical community hopes they will be available sooner than later.

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.

Zika Virus—2018 Case Counts in the US. https://www.cdc.gov/zika/reporting/2018-case-counts.html. Updated September 5, 2018. Accessed September 6, 2018.

Zika Virus—2017 Case Counts in the US. https://www.cdc.gov/zika/reporting/2017-case-counts.html. Updated August 2, 2018. Accessed August 20, 2018.

Zika Virus—2016 Case Counts in the US. https://www.cdc.gov/zika/reporting/2016-case-counts.html. Updated February 14, 2018. Accessed August 20, 2018.

Zika Travel Information. https://wwwnc.cdc.gov/travel/page/zika-travel-information.  Updated August 14, 2018. Accessed September 5, 2018.

Zika Virus. https://www.cdc.gov/zika/symptoms/index.html. Updated June 21, 2016. Accessed August 28, 2018.

Rice ME, Galang RR, Roth NM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection — U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep 2018;67:858-867. DOI: http://dx.doi.org/10.15585/mmwr.mm6731e1.

Zika in Babies in US Territories. https://www.cdc.gov/vitalsigns/zika-territories/index.html. Updated August 7, 2018. Accessed August 28, 2018.

Zika and Guillain-Barré Syndrome. CDC website. cdc.gov/zika/healtheffects/gbs-qa.html. Updated August 9, 2016. Accessed September 5, 2018.

Update: Interim Guidance for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus for Men with Possible Zika Virus Exposure—United States, August 2018. https://www.cdc.gov/mmwr/volumes/67/wr/mm6731e2.htm. Updated August 7, 2018. Accessed September 3, 2018.

Zika Virus Vaccines. https://www.niaid.nih.gov/diseases-conditions/zika-vaccines. Updated August 16, 2018. Accessed September 4, 2018.

Feature - Emerging & Re-Emerging Infections

The virus may be fading from mainstream headlines, but it is active and physicians must stay vigilant.

Zika: Where Are We Now?

Achieving antimicrobial stewardship programs’ primary goal of using antibiotics responsibly to optimize patient care and minimize development of resistant infections, requires education of and collaboration among multiple parties, including physicians, information technology (IT) specialists, hospital administrators, and patients, according to experts who participated in a 

Jason Pogue, PharmD, BCPS-AQID, said that implemen&shy;tation of a successful antimicrobial steward&shy;ship program requires support from hospital administrators and the developers and users of the stewardship policies. “If you’re going to have initiatives [and] optimize antibiotic use, you have to ultimately have support from the C-suite,” said Dr. Pogue.  

Debra Goff, PharmD, said that she uses “the 5 Ds” to ensure the responsible use of antimicrobials to offset antibiotic resistance and decrease adverse events: making the correct 

“If all you look at is antibiotic use, you’re missing the picture,” she said. “You have to have more than just the physician who might be labeled as ‘in charge of stewardship’. You need all physi&shy;cians engaged.”  

However, Dr. Goff pointed out that expecting all physicians to know the details of first-line therapy for various types of infec&shy;tions is impractical. “I don’t expect a surgeon to know what a [carbapenem-resistant Enterobacteriaceae] is,” she said. “I tell them, ‘That’s not your job. What I need you engaged with is to engage with us and follow the guidelines. We’ll give you the rationale. We’ll give you the guidance.’ We teach them how to use the drugs responsibly, [and] then when you get the call for an antibiotic on the protected list, all the newer agents, it’s a 2-second phone call.”  

Sandy J. Estrada-Lopez, PharmD, said that institutions are figuring out ways to use electronic health records (EHRs) to identify which patients get infected, the type of pathogen they are infected with, and the best drug match for the pathogen. To obtain this information, some institutions use add-on systems, such as TheraDoc or MedMined, whereas the makers of the Epic system—used at her institution (Lee Memorial Health System) and others&mdash;are developing more robust modules for infection prevention and antimicrobial stew&shy;ardship. Dr. Pogue also said that the IT depart&shy;ment at his institution (Sinai-Grace Hospital of Detroit Medical Center) implemented an alert in the EHR if a physician attempts to order an antibiotic when a patient has recently had an organism resistant to that antibiotic.  

Dr. Goff added that involvement of the hospital IT department is important for generating meaningful reports that can be used for justifying the use of expensive antibiotics for select patients or identifying patients at high risk for 

 infection. She noted that for the latter situation, the IT department could create an alert when a proton pump inhibitor (PPI) is prescribed to a patient already on antibiotics or when 3 antibiotics are ordered for a patient already taking a PPI. “There are ways you strategize to figure out who is the highest-risk patient to get 

 in your hospital instead of me trying to look at every antibiotic [and] every PPI,” she said. “That’s an extremely time-consuming way to approach it.”

Dr. Pogue also emphasized that providing the IT department with data demonstrating the effectiveness of the technology shows them the value of their input, which encourages them to participate in the development of antibiotic stewardship. “You’ll see reporting come up as one of these core elements of stewardship,” he said. “It’s getting that data back. We asked for a lot at my institution of our pharmacists and physicians when we revamped vancomycin dosing. They had to do a whole lot of extra steps because we thought it would be safer, and it was safer. I go to the pharmacy meeting and I say, ‘Look at these numbers.’ That gets buy-in [from the C-suite] and reinforces the importance of what you’re trying to do, which is ultimately improve patient outcomes.”

However, Andrew Shorr, MD, cautioned that stewardship is a relatively new endeavor and the effectiveness of potential protocols need to be assessed using clinical trials that compare 2 approaches. “When we start having randomized controlled trial data and we really are focused on a tool for a better kind of approach, we can actually start to apply that and say [that] the no up-front strategy is a fail, and this is the cost. But an audited feedback approach clearly offers benefits, and it’s easier to change physician behavior because that’s what this is all about with evidence.”

The panelists agreed that the responsible use of antibiotics to optimize care of the patient is the primary goal of an effective stewardship program, and Dr. Pogue added that activities of the stewardship program should also work to minimize the unintended consequences of toxicity, antibiotic resistance, and 

Additionally, educating other physicians, such as surgeons and oncologists, on the consequences of prophylactic antibiotics is important, according to Dr. Goff. “The prescribing of antibiotics is often just in case they might have an infection because they’re perceived as benign drugs with minimal risk,” she said. “Now the risk is much greater than that perceived benefit, and that’s what we’re trying to change. Stewardship has to convey that.”

Dr. Estrada-Lopez agreed that the education of other physicians on the negative consequences of unnecessary antibiotic prescribing has been relatively poor and that the lack of education is particularly evident in the outpatient setting where antibiotic use is often driven by patient request.

“Many patients want antibiotics just in case,” she said. “We’ve done a lot with education [of physicians] on ‘Use this, this is the spectrum,’ but not as much on the ‘nothing at all’ because they don’t really have an infection or really think about the total risk-benefit.”

According to the panelists, the best, and most obvious, way to avoid antibiotic resistance is to prevent infections that require treatment with an antibiotic. Dr. Shorr added that widespread promotion of up-to-date vaccinations and implementation of everyday measures in the intensive care unit to prevent infection when possible, such as elevating the bed, using orogastric instead of nasogastric tubes, and decreasing sedation, can help prevent development of resistant bacterial infections.

Hand washing is also important for preventing infection, and Dr. Shorr noted that the compliance rates are appallingly low. He stated that hand hygiene compliance among health care providers may be improved by placing hidden cameras and ensuring the hand sanitizer dispensers are refilled regularly throughout the hospital.

The panelists concluded that treating multidrug-resistant infections and promoting antimicrobial stewardship requires collaborative efforts among health care providers, patients, and hospital administrators. Dr. Estrada-Lopez said, “Working together, educating each other, and understanding how the role that we play can make a difference for patient care will lead us to the next steps in the future of decreasing antimicrobial resistance.”

Dr. Pogue added that getting patients on the correct antibiotic is a key component of stewardship and involves taking patient-specific information and local epidemiology information and using new antimicrobials judiciously. “Think what’s best for your patient as well as the hospital and get your patients on the best therapy,” he said.

Dr. Shorr concluded that collaborating with policy makers, legislators, and pharmaceutical developers will be important to increase recognition of antibiotics as a public resource that requires public stewardship. “We really need to be appealing to our policy makers and our legislators to realign incentives so that quality payments reflect quality behavior as opposed to punishments for the hospital [and] that pharmaceutical developers have legitimate reasons to risk the capital to go in and develop antibiotics that don’t pay the way chronic cancer therapies do,” he said. “All of these things need to change at a national level if we’re going to have the tools we need.”

Peer Exchange

Key considerations when choosing a treatment for gram-negative nosocomial infections include the patient’s referring facility. 

Multidrug-Resistant Infections: Implementing Programs for Antimicrobial Stewardship

The clinical characteristics and outcomes of 

pneumonia (PcP) differ in immunocompromised patients with and without HIV.

 Although evidence suggests improved survival with early adjunctive corticosteroids in patients with HIV and PcP,

 limited data for HIV-negative patients with PcP suggest adjunctive corticoste&shy;roids might not improve outcomes.

Wieruszewski et al evaluated the impact of early cortico&shy;steroids as an adjunct to anti-PcP therapy in acutely ill immu&shy;nocompromised adults without HIV.

 Outcomes of patients who received early corticosteroid therapy (within 48 hours of PcP diagnosis or therapy) were compared with those who did not.

Among the 323 patients in the study (early steroids, n = 258; nonearly steroids, n = 65) the median age was 65 years; 63% were male; 92% were white; 97% had immunosuppressive disease (hematologic malignancy 50%), and 60% had a history of immunosuppressive therapy prior to hospi&shy;talization. Patients received appropriate anti-PcP therapy (primarily sulfamethoxazole/trimethoprim) and a median dose of prednisone 60 mg daily.

Severity-adjusted (for baseline hypoxemia) regression and propensi&shy;ty-matched analyses found that administration of steroids was associated with less improvement in the early group than the nonearly group at day 5, with a mean ΔSOFA

 difference of —0.47 (95% CI, –0.73 to –0.21; 

= .001) and —0.46 (95% CI, –0.84 to –0.08; 

= .017), respectively. No differences were observed in the odds of having at least a 1-point improvement in SOFA

 at day 5 compared with baseline between groups (adjusted OR, 0.76 [95% CI, 0.24-2.28]; 

= .61). No differences in mortality, length of stay, admission to the ICU, or need for mechanical ventilation were found between early and nonearly steroid recipients.

This is the largest study to date on HIV-negative patients with PcP. Although this study was nonblinded, nonrandomized, and retrospective, the use of multivariable adjustments and propensity-matched cohort analyses confirmed the results of previous studies that found no observable benefit of early steroids in patients with PcP who are HIV-negative. The authors speculated that differences in patients with PcP who are HIV-negative versus those who are positive “may be due to a reduced response among those with earlier exposure to corticosteroids immediately preceding PcP presentation.”

Clinicians should reevaluate routine adjunctive steroid therapy for patients with PcP who are HIV-negative in the absence of other compel&shy;ling indications for receiving steroids. Robust randomized prospective studies are warranted to further explain the pathophysiological differences in immune status that predispose patients who are HIV negative to intensified inflammatory response to PcP antimicrobial therapy and their ability to respond to anti-inflammatory agents.

Moon SM, KimT, Sung H, et al. Outcomes of moderate to severe 

 pneumonia treated with adjunctive steroid in non-HIV-infected patients. 

 2011;55(10):4613-4618. doi: 10.1128/AAC.00669-11.

Lemiale V, Debrumetz A, Delannoy A, Alberti C, Azoulay E. Adjunctive steroid in HIV-negative patients with severe 

. 2013;14:87. doi: 10.1186/1465-9921-14-87.

The National Institutes of Health—University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. 

. 1990;32(21):1500-1504. doi: 10.1056/NEJM199011223232131.

Ewald H, Raatz H, Boscacci R, Furrer H, Bucher HC, Briel M. Adjunctive corticosteroids for pneumocystis jiroveci pneumonia in patients with HIV infection. 

. 2015;(4):CD006150. doi: 10.1002/14651858.CD006150.pub2.

Injean P, Eells SJ, Wu H, McElroy I, Gregson AL, McKinnell JA. A systematic review and meta-analysis of the data behind current recommendations for corticosteroids in non-HIV-related PCP: knowing when you are on shaky foundations. 

. 2017;3(3):e137. doi: 10.1097/TXD.0000000000000642.

Wieruszewski PM, Barreto JN, Frazee E, et al. Early corticosteroids for 

 pneumonia in adults without HIV are not associated with better outcomes [published online April 26, 2018]. 

In the Literature

The clinical characteristics and outcomes of Pneumocystis jirovecii pneumonia differ in immunocompromised patients with and without HIV.

Early Adjunctive Corticosteroids Do Not Improve Outcomes in HIV-Negative Adults With PcP

The globalization of antibiotic stewardship programs is necessary in the fight against antibiotic resis&shy;tance.

 Individual countries must take meaningful actions to counter antimicrobial resistance, tailoring implemen&shy;tation according to their national circumstances. One of the key challenges is preventing the overprescription of antibiotics in hospitals. Every unnecessary dose of antibiotics contributes to the escalating rate of antimicrobial resistance. The unrestrained use of anti&shy;biotics is the main driver for the rise in drug-resistant infec&shy;tions, which now kill more than half a million people every year worldwide, including 50,000 in Europe and the United States combined. Despite efforts by the US Centers for Disease Control and Prevention, the World Health Organization, the United Nations (UN), and others to encourage more prudent use of antibiotics, an international team of investigators found a 65% rise in worldwide consumption of antibiotics from 2000 to 2015.

 The increase in 76 countries was driven almost entirely by rising use in low- to middle-income countries (LMICs). Of particular concern is the escalating global use of antibiotics of last resort, such as colistin. To address the overprescription of antibiotics in hospitals, we need a scalable and proven solution that can be implemented on a global basis.

The UN issued a call to action for countries to implement antibiotic stewardship to address antimicrobial resistance and overuse of antibi&shy;otics, although action to tackle antimicrobial resistance has not yet matched the scale of the threat. The problem is worse in LMICs. Building on current work supported by multiple organizations in the areas of surveillance and antibiotic resistance, implementation of antibiotic stewardship programs to assure optimal use of antibiotics is equally important. Documenting antibiotic resistance rates from surveillance programs will not result in any meaningful change in antibi&shy;otic use if hospitals do not have trained health care providers who know how to apply surveillance data to make an antibiotic stewardship intervention at the point of care.

ASPs are desperately needed in hospitals; however, a shortage of adequately trained pharmacists and physicians in infectious diseases creates a challenge. Pharmacy practice models vary significantly in developing countries, with barriers to effective practice models including acute shortages of qualified pharma&shy;cists, no implementation of dispensing separation practices, and weak regulatory enforcement of drug sales. Pharmacists, while not always clinically empowered, are present in point-of-care moments and can help change physician behavior. Antibiotic stewards from resource-rich countries such as the United States must help LMICs implement ASPs. Elements of successful anti&shy;biotic stewardship in hospitals in LMICs have been developed by investigators working with 15 experts (including Dr. Goff) from 13 countries on 6 continents. Led by Céline Pulcini, a professor of infectious diseases in France and a member of DRIVE-AB (Driving Re-investment in R&D and Responsible Antibiotic Use), the consensus-based process produced 7 core elements (leader&shy;ship commitment, accountability, drug expertise, action, tracking, reporting, and education) as well as 29 checklist items that are relevant in all settings, including those that are resource limited.

The slow implementation of antibiotic stewardship in LMICs means more patients die every day from untreatable infections. To guide the rational use of antibiotics in LMICs, standard treatment guidelines (STGs) have been developed by national thought leaders in several countries. These STGs, coupled with Essential Medicine Lists, are intended to promote equitable access to affordable medicines that are safe and effective and improve the quality of patient care and clinical decision making. Stricter oversight of antibiotics and compli&shy;ance to STGs are warranted to reduce the amount of anti&shy;biotics consumed in LMICs. However, extensive data on the reporting of antibiotic use, consumption, and compliance with guidelines among hospitals and clinics are currently lacking. Pharmacists can play a key role in the implementation of surveillance systems for antimicrobial resistance and antibiotic use. As custo&shy;dians of medicines, pharmacists are well placed to lead an antibiotic surveillance initiative, through not only audit and data collection but also relationship building and working in multidisciplinary teams. The 

provides 3 examples of US antibiotic stewardship programs that are working with LMICs to implement or advance antibiotic stewardship programs, along with suggestions on how US stewards can affect global stewardship initiatives.

The South African National Department of Health formalized and published a 10-year antimicrobial resistance national stra&shy;tegic framework (2014-2024) to align with international efforts aimed at curtailing the mounting rate of antimicrobial resistance.

 The strategy advocates for collaboration across multiple sectors and adopts a OneHealth approach in its methodology. Furthermore, it calls for strengthened global partnerships because the respon&shy;sibility to cocreate solutions to this crisis is universally shared.

The Ohio State University antibiotic stewardship train-the-trainer program was initiated in South Africa in 2014. The program accelerated the uptake of antibiotic steward&shy;ship through exposure and mentorship of pharmacists and allowed for trained pharmacists to implement antibiotic stewardship programs faster in their settings. Pharmacists (not formally trained in infec&shy;tious diseases) decreased antibiotic use in 47 private hospitals across South Africa by 18% through implementation and moni&shy;toring of defined “low-hanging fruit” stewardship interventions including the prospective audit with intervention and feedback of antibiotic duration greater than 7 and/or 14 days, redundant duplicate antibiotic cover, cultures taken prior to antibiotic therapy, and the coadministration of 4 or more antibiotics.

 The train-the-trainer program shows potential to accelerate the global growth of antibiotic stewardship in every hospital.

In addition, the Wellcome Trust in London, England, produced a video (wellcome.ac.uk/news/three-pioneering-ways-stop-superbugs) in 2018 titled 

South Africa: Empowering Hospital Pharmacists,” highlighting the work of South African pharmacists, some of whom completed the US train-the-trainer antibiotic stewardship mentoring program and are taking pioneering action to tackle antimicrobial resistance. By promoting pioneers in this way, national and global leaders in antimicrobial resistance now have the opportunity to identify how replicable, scal&shy;able best practices can form the foundations of a successful, coordinated global response.

Although formalized antimicrobial stewardship is in its infancy in Zambia, the country has taken major steps in response to the World Health Organization’s Global Action Plan for Antimicrobial Resistance, which calls on countries to develop their own action plans on antimicrobial resistance.

 In the fight against antimicrobial resistance, Zambia also adopted a OneHealth approach that includes the human, animal, agriculture, and environmental sectors with the release of its National Action Plan (NAP) in 2017. Afterward, a kick-off summit for antimi&shy;crobial stewardship was held and included leadership from the Ministry of Health along with physicians and pharmacists from local hospitals to begin implementation of the NAP. Speakers included representatives from South Africa and Uganda who shared their respective country’s experiences with stewardship implementation. The workshop was spon&shy;sored by the Zambia National Public Health Institute and ReAct Africa. ReAct is an independent global network for antimicrobial resistance led by pharmacist Mirfin Mpundu that provides support to national governments implementing antimicrobial resistance action plans.

University Teaching Hospital, the highest-level hospital in Zambia, has begun to gather baseline antibiotic usage and resistance data with physicians and pharmacists from the University of Maryland, Baltimore. The hospital will pilot stewardship interventions discussed at the summit, including some of the tools used in South Africa. Given the success and scalability demonstrated by the South African pharmacists, this initiative will likely serve as an important model for other countries in Africa.

Aristotle said, “The whole is greater than the sum of its parts.” That is, when individual parts are connected to form 1 entity, they are worth more than if they had remained in silos. This quote reminds us that what 1 person can do, many can do better. There is something special that happens when antibiotic stewardship programs from resource-rich countries work together with LMICs toward the common goal of decreasing antibiotic use and resistance.

Dr. Goff is an associate professor and a founding member of the Antimicrobial Stewardship Program at The Ohio State University (OSU) Wexner Medical Center and leads the OSU—South Africa Train-the-Trainer antibiotic stewardship mentoring program. Follow her on Twitter @IDPHarmD or contact her for more information at debbie.goff@osumc.edu.

Ms. Messina is a pharmacist and the quality systems and innovation manager of the Netcare Hospital Group. Her scope includes the management and implementation of antibiotic stewardship across the 56 Netcare hospitals in South Africa.

Dr. Heil is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Medicine. She serves as an infectious diseases pharmacy specialist and antimicrobial stewardship pharmacist at the University of Maryland (UMD) Medical Center.

Goff DA, Kullar R, Goldstein E, et al. A global call from five countries to collaborate in antibiotic stewardship: united we succeed, divided we might fail. 

. 2017;17(2):e56-e63. doi: 10.1016/S1473-3099(16)30386-3.

Sample I. Calls to rein in antibiotic use after study shows 65% increase worldwide. 

theguardian.com/science/2018/mar/26/calls-to-rein-in-antibiotic-use-after-study-shows-65-increase-worldwide. Published March 26, 2018. Accessed July 12, 2018.

Pulchini C, Binda F, Lamkang AS, et al. Developing core elements and checklist items for global hospital antimicrobial stewardship programmes: a consensus approach [published online April 3, 2018]. 

South African National Department of Health. The South African antimicrobial resistance strategy framework 2014—2024. https://www.health-e.org.za/wp-content/uploads/2015/09/Antimicrobial-Resistance-National-Strategy-Framework-2014-2024.pdf. Published October 16, 2014. Accessed July 23, 2018.

Brink A, Messina A, Feldman C, et al. Antimicrobial stewardship across 47 South African hospitals: an implementation study. 

. 2016;16(9):1017-1025. doi: 10.1016/S1473-3099(16)30012-3.

World Health Organization. Global action plan on antimicrobial resistance. who.int/antimicrobial-resistance/publications/global-action-plan/en/. Published 2015. Accessed July 23, 2018.

Stewardship & Prevention

Globalization of Antibiotic Stewardship Programs: The World Is Waiting

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) updated the hospital-acquired and ventilator-associated pneumonia (HAP, VAP) guidelines in 2016. Hospital-acquired pneumonia is defined as pneumonia not associated with mechanical ventilation that develops 48 hours or more after admission to a hospital. Ventilator-associated pneumonia is defined as pneumonia that develops 48 to 72 hours after endotracheal intubation. hospital-acquired pneumonia and ventilator-associated pneumonia account for 22% of all hospital-acquired infections and lead to significant morbidity, mortality, and health care costs. Major differences between the 2005 and 2016 guidelines include removal of health care—associated pneumonia (HCAP), the addition of biomarker (eg, procalci&shy;tonin) usage recommendations for assisting with duration of therapy, and redefinition of duration for most patients from between 8 and 15 days to 7 days. In addition, Grading of Recommendations Assessment, Development and Evaluation methodology was instituted in the new guidelines. In terms of double coverage for 

, fewer risk factors to warrant combination were mentioned in the 2016 guidelines. Unit antibiograms, instead of just general local antibiograms, were highlighted as more reliable tools for empiric antibiotic choice because units can vary so drastically within 1 institution. Lastly, new diagnostic recommendations were included in the 2016 guidelines.

The elimination of HCAP from inclusion in these guidelines was due to 2 main reasons: (1) Many patients presenting from nursing homes or other health care facilities still have community-acquired pneumonia (CAP) with nonresistant pathogens, and (2) these patients are from the community and present to emergency departments, and their management is thus better managed using the CAP guidelines, which we are still anxiously awaiting.

The 2005 guidelines suggested that patients who were exposed to any health care environment (eg, nursing homes, rehab centers) were at risk for multidrug-resistant organisms (MDROs). However, the supporting studies were poorly designed and highly biased (ATS/IDSA 2005).

 Since then, studies assessing true risk of acquiring MDROs have concluded that patient characteristics (eg, presence of indwelling urinary catheters, recent antibiotic usage in the prior 90 days, previously known 

colonization, or prolonged prior hospital admission) likely play a much larger role in predicting MDRO risk.

The 2016 IDSA HAP/VAP guidelines place an emphasis on noninvasive respiratory sampling, but it is important to consider these cultures in clinical context, given that the specificity of semiquantitative respiratory cultures is around 50%.

 This is obvious in the guideline setting but not always considered in real practice, where cultures may be obtained as part of a fever work-up but not out of clin&shy;ical concern for HAP/VAP specifically. In clinical practice, we know that many of our critically ill and chronically ill patients may have abnormal chest imaging at baseline for reasons other than pneumonia, making the distinction of respiratory colonization versus true infection more difficult. However, the consideration of other clinical factors such as oxygen requirement changes, hemodynamic instability, and changes in secretions may help a discerning clinician.

The 2016 guidelines suggest the benefit of using procalci&shy;tonin in addition to clinical criteria to guide duration of therapy (but not to aid in diagnosis of pneumonia).

 The major benefits in limiting duration of therapy, when appro&shy;priate, include reduced antibiotic-related adverse effects; sooner reconstitution of gut flora, thereby reducing risk of 

associated diarrhea and other superin&shy;fections; and cost reduction.

The 2016 guidelines recommend 7 days for both hospital-acquired pneumonia and ventilator-associated pneumonia treatment unless there are complicating factors or slow clinical improvement.

 The evidence behind this new duration recommendation came primarily from 2 large systematic reviews assessing patients with HAP/VAP treated with short courses of antibiotics (7-8 days) versus long courses (10-15 days) and found no differences in mortality, recurrent pneumonias, length of stay, or duration of mechanical ventilation.

For ventilator-associated pneumonia due to nonfermenting gram-negative rods, there was no difference in pneumonia recurrence or mortality. Thus, longer durations based solely on microbiologic species were not supported.

The 2016 guidelines highlighted the need to empirically treat all HAP/VAP patients with antibiotics that are active against both 

(MRSA) coverage is necessary, vancomycin or linezolid should be used. Empiric MRSA treatment should be started if MRSA rates are more than 10% to 20% of all 

isolates in the specific unit or hospital at which the patient is being treated.

 For gram-negative coverage, β-lactams are preferred, although the specific agent of choice depends on local susceptibilities, ideally based on the unit antibiogram. Aminoglycosides should never be used as monotherapy for pneumonia because of increased mortality shown in prior studies.

The 2016 guidelines recommend 2 antipseudomonal antibi&shy;otics from different classes if patients have MDRO risk factors or are in a unit where more than 10% of gram-negative isolates are resistant to the preferred agent (usually a β-lactam). MDRO risk factors are different for ventilator-associated pneumonia and hospital-acquired pneumonia; however, prior antibiotic use is significantly associated with acqui&shy;sition of MDRO for both types of pneumonia. Additional factors specific to ventilator-associated pneumonia may predispose patients to MDRO (see the 2016 guidelines for details).

Regardless, the double coverage suggestion is a weak recommendation, based on low-quality evidence. Therefore, in our opinion, it should be taken with a grain of salt. In fact, to our knowledge, there has never been a study whose results have shown a mortality benefit with addition of a second antipseudomonal agent. The second agent recommended is either a fluoroquinolone or an aminoglycoside because the two are the only non—β-lactam antibiotics currently available for the treatment of pneumonia. Aside from a low quality of evidence used to make this recommendation in the guidelines, many institutions face high rates of quinolone resistance, making the benefit of the addition of fluoroquinolones to β-lactam regimens for patients with HAP/VAP at hospitals with more 30% to 40% gram-negative fluoroquinolone resistance essentially nil but with the higher risk of toxicity and 

infection. Combinatorial antibiograms are useful to identify whether quinolones or aminoglycosides remain active for β-lactam—resistant isolates. Although aminoglycosides, particularly amikacin, will likely target many β-lactam–resistant gram-negative strains, higher dosing is warranted for pneumonia. Even with higher dosing, aminoglycosides do not have optimal lung penetration and are not always feasible to initiate in older patients or those with renal dysfunction. However, in patients with concurrent gram-negative bacteremia or in septic shock, it may be prudent to add an aminoglycoside pending susceptibility results. The guidelines do not take into account the clinical stability of the patient.

Hospital-acquired and ventilator-associated pneumonia account for 22% of all hospital-acquired infections.

October 2018

In the Ever-Evolving World of Infectious Disease, the Bottom Line Is Evidence Matters

Salt, Ticks, and Lyme: A Case of Lyme Neuroborreliosis Presenting as SIADH

Zika: Where Are We Now?

Multidrug-Resistant Infections: Implementing Programs for Antimicrobial Stewardship

Early Adjunctive Corticosteroids Do Not Improve Outcomes in HIV-Negative Adults With PcP

Globalization of Antibiotic Stewardship Programs: The World Is Waiting

Hospital-Acquired and Ventilator-Associated Pneumonia: Highlights and Pitfalls of the 2016 IDSA / ATS Guidelines

Guideline Updates for the Treatment of Adolescents and Adults With HIV

Improving Antimicrobial Stewardship in the Management of Respiratory Infections

Plazomicin: A Novel Aminoglycoside