In spring 2018, the United States Pharmacopeia (USP) announced plans to revise general chapters <795> and <797>, which set standards for compounding nonsterile and sterile preparations. The goal was to better align these 2 chapters with USP <800> (“Hazardous Drugs — Handling in Healthcare Settings”), which was published in 2016 and goes into effect December 1, 2019.

The USP unveiled its proposed revision to <795> on March 30, 2018, with a public comment period that ended on July 31, 2018. The proposed revision for <797> followed on July 27, 2018, with a public comment period that closed on November 30, 2018. Whether feedback was submitted before the deadlines, facilities that perform nonsterile or sterile compounding must understand the proposed changes and determine the potential impact if they take effect. Below are revisions that merit attention.

USP <795> PHARMACEUTICAL COMPOUNDING — NONSTERILE PREPARATIONS

One of the most notable changes introduced in this chapter is a redefinition of what constitutes “nonsterile compounding.” This could mean that facilities that previously did not consider themselves to compound drugs would now be subject to USP <795> standards. The introduction to this chapter specifies that the practice of reconstituting a powder to make a suspension, although not considered compounding if dispensed immediately to a patient, will now represent nonsterile compound- ing if the suspension is stored for future use. This will have numerous ramifications for pharmacists and facilities that previously stored suspensions without having to operate by the guidelines set for compounding pharmacies.

Section 4 of <795> expands upon a requirement that “compounding facilities must have a space that is specifically designated for compounding.” As written, this section is subject to interpretation because the USP provides no clear definition of what constitutes a “designated space,” only that such an area must be “separated from areas not directly related to compounding.” Although a simpler solution could be feasible, it is also possible that this revision mandates a separate room dedicated solely to nonsterile compounding. If facilities do not have such a room to spare, this could necessitate new and expensive construction.

Section 1 of <795> also newly states that any compounding facility must provide a staff member who is uniquely responsible for training on nonsterile compounding, assuring that competencies are done, record keeping, and conducting observational studies, among other duties. For smaller facilities, with a pharmacy staff of, say, 2 people, this new requirement could necessitate hiring new personnel or bringing in a third party for training, either of which would weigh on a facility’s budget.

USP <797> PHARMACEUTICAL COMPOUNDING — STERILE PREPARATIONS 

This chapter also brings fundamental change to the medication compounding model. The previous version of <797> outlined 3 categories of compounded sterile products: low, medium and high risk. The proposed revision to <797> consolidates that into 2: categories 1 and 2. This shift is likely to have the greatest impact on facilities that were formerly classified as medium-risk compounders, which describes most hospitals in the United States. Many of these facilities will now graduate to a higher level of compounding risk in category 2 and, as such, will have a higher bar to clear to remain in compliance.

Among the new rules of which facility managers must be aware is a greater investment of time. Previously, mandatory checks, such as glove fingertip testing and media fill testing, were done annually, but <797> will now mandate that these be performed semi-annually. Those responsible for this quality assurance will now effectively have their workload doubled. In a midsize facility, with 25 employees, for example, the process, including testing mechanics, training, and visual observations, could be estimated to take 2 hours per employee. That represents an additional 50 hours of work, not to mention a doubling in the cost of supplies.

Similarly, the requirement for surface sampling, which is wiping surfaces in various compounding areas to test for bacterial contamination, is mandated to be done monthly in the new version of <797>. The previous version required that this testing need only be done “periodically,” with that term defined loosely. For most facilities, then, this redefinition will result in additional time requirements.

USP <797> also introduces a new definition of what constitutes compounding. In the case of a bag-and-vial system, in which a medication vial is attached, with adaptor, to the bag that it needs to be mixed in for infusion, if a nurse attaches the bag and vial, that is not regarded as compounding. However, if a batch of bags and vials are being attached within the pharmacy, to be put into different automated dispensing cabinets, that process is now considered “sterile compounding” and would need to be done inside an International Organization for Standardization Class 5 hood.

Given the breadth of new likely requirements, it is incumbent on facility managers to assess their operations to determine what compliance issues might arise if USP <795> and <797> are implemented as written. In the case of <797>, they had an opportunity, before November 30, to write to the USP to request clarification or make a well-reasoned case for revisions to the chapter before it is formalized. In any case, this latest regulatory activity needs to be on the radar of any facilities that compound medication for patients.

Kenneth Maxik, MBA, MBB, FACHE, is the director of patient safety and compliance at CompleteRx in Lexington, Kentucky.

Articles

Safe Handling

Regardless of whether they suggested revisions to latest standards, they must prepare for new compounding regulations.

USP Ushers in Sweeping Changes to Rules for Hospital and Retail Pharmacies

The National Cancer Institute estimates there will be about 42,220 new cases and 30,200 deaths related to liver cancer in the United States in 2018, numbers that have been insidiously rising over the past 2 decades (figure 1).

 Liver cancer is more common in men than in women (figure 2

), and represents the fifth and ninth most common cancer, respectively, by gender, according to the World Health Organization.

Two major classifications of hepatic malignancies are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma.

 HCC originates from hepatocytes and excludes metastatic hepatic tumors. There are several risk factors implicated in the development of HCC, such as alcoholic liver disease, nonalcoholic fatty liver disease, and viral hepatitis. Most HCC cases are linked to hepatic cirrhosis. However, malignancy may also arise from elements unrelated to cirrhosis, such as hereditary hepatic diseases (figure 3

Chronic liver damage induced by the previously mentioned factors contributes to hepatic inflammation, oxidative stress, and, ultimately, the genetic mutations leading to tumor growth.

 The American Association for the Study of Liver Diseases published updated practice guidelines in 2018 regarding the diagnosis, staging, and management of HCC. The guidelines address patients with cirrhosis and make recommendations based on Child-Turcotte-Pugh classifications (table).

 Because of improved overall survival (OS), surveillance is recommended for adults with cirrhosis via ultrasound with or without alpha-fetoprotein every 6 months.

 When HCC is suspected, multiphasic computed tomography or multiphasic magnetic resonance imaging should be used for diagnosis.

HCC treatment is often influenced by the burden of disease at diagnosis. Although earlier stages may be managed with curative strategies, such as radiofrequency ablation or resection, patients with advanced disease may be limited to palliative therapies.

 The guidelines recommend against adjuvant therapy after successful radioablation or resection.

Until very recently, just 1 pharmaceutical option, sorafenib (Nexavar), was proven superior to placebo for patients with unresectable HCC.

 Sorafenib inhibits several intracellular and cell-surface kinases, halting angiogenesis and tumor growth.

 Evidence from the Asia-Pacific trial and the SHARP trial demonstrate the improved OS of patients treated with sorafenib versus placebo in the treatment of unresectable HCC with macrovascular invasion and/or extrahepatic disease. However, in clinical practice, some patients experience disease progression despite treatment with sorafenib.

 The undoubtedly grim outcome for patients with advanced disease, especially in the setting of primary therapy failure, is a resounding call for novel treatment strategies.

Strides have been made in the treatment of unresectable HCC over the past 2 years. In December 2016, results were published from the RESORCE trial, which examined the use of regorafenib (Stivarga) in patients who experienced HCC progression while on sorafenib. In this double-blind, placebo-controlled, phase 3 trial, 567 patients with CTP Class A cirrhosis who were not candidates for curative therapy and who demonstrated radiologic progression of tumors while on sorafenib were enrolled. The authors concluded that regorafenib improves OS in patients who fail initial therapy with sorafenib.

Since RESORCE, research has suggested many other medications may be effective and safe for use in patients with HCC who experience disease progression on sorafenib, including nivolumab (Opdivo),

In March 2018, the REFLECT trial findings were published. This trial investigated the use of lenvatinib (Lenvima) monotherapy versus sorafenib for first-line treatment of HCC. In this international, open-label, randomized, phase 3 trial, 954 patients with CTP Class A cirrhosis and unresectable HCC were enrolled. Results demonstrated that lenvatinib monotherapy is noninferior to sorafenib as first-line treatment of HCC.

 Since the publication of REFLECT, the use of lenvatinib in combination with pembrolizumab, an anti—PD-1 monoclonal antibody, has been investigated in a phase 1b trial. The authors noted promising results regarding safety and exploratory endpoints, such as survival, with this drug combination.

Finally, in July 2018, the FDA granted a breakthrough designation to bevacizumab plus atezolizumab (Tecentriq) as a first-line treatment for advanced or metastatic HCC based on unpublished data from a phase 1b clinical trial.

HCC has traditionally been refractory to medical, radiological, and surgical management. Since the advent of sorafenib and a succession of promising targeted biologic chemotherapy agents, a window of hope is opening for more successful pharmacological options in the treatment of HCC. As with most milestones in medicine, we often build upon our previous successes, thus providing a promising path to the future.

Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP, are clinical pharmacists in Pensacola, Florida.

Elizabeth Shald is a PharmD candidate at the University of Florida in Gainesville. 

U.S. Department of Health and Human Services. Adult primary liver cancer treatment (PDQ)—health professional version. National Cancer Institute website. cancer.gov/types/liver/hp/adult-liver-treatment-pdq. Updated February 6, 2018. Accessed October 29, 2018.

Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. Acute Myeloid Leukemia-Cancer Stat Facts. seer.cancer.gov/statfacts/html/livibd.html. Accessed November 14, 2018.

Tsai WC, Kung PT, Wang YH, Kuo WY, Li YH. Influence of the time interval from diagnosis to treatment on survival for early-stage liver cancer. 

. 2018;13(6):e0199532. doi:10.1371/journal.pone.0199532.

Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. 

 2018;68(2):723-750. doi: 10.1002/hep.29913.

Orcutt ST, Anaya DA. Liver resection and surgical strategies for management of primary liver cancer. 

. 2018;25(1):1073274817744621. doi: 10.1177/1073274817744621.

Llovet JM. Tumors of the liver and biliary tree. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. 

Harrison's Principles of Internal Medicine

. 20th ed. New York, NY: McGraw-Hill; 2018.

Dhanasekaran R, Bandoh S, Roberts LR. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. 

. 2016;5:F1000 Faculty Rev-879. doi: 10.12688/f1000research.6946.1.

Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. 

 2018;67(1):358-380. doi: 10.1002/hep.29086.

Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. 

Llovet JM, Fuster J, Bruix J, Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. 

Nexavar (sorafenib) [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; 2010. accessdata.fda.gov/drugsatfda_docs/label/2010/021923s008s009lbl.pdf. Accessed November 26, 2018.

Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. 

. 2009;9(6):739-745. doi: 10.1586/era.09.41.

Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. 

2009;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7.

Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.

El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. 

. 2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2.

Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. 

 2018;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6.

Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. 

. 2018;379(1):54-63. doi: 10.1056/NEJMoa1717002.

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. 

. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.

Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).

U.S. National Library of Medicine. A study of the safety and efficacy of atezolizumab administered in combination with bevacizumab and/or other treatments in participants with solid tumors - full text view. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/study/NCT02715531. Accessed November 14, 2018.

Oncology Focus

How to treat hepatocellular carcinoma is heavily influenced by the burden of disease at diagnosis. 

What Are Treatment Approaches to Liver Cancer?

Annual epidemics of influenza occur between late fall and early spring and may be caused by 2 strains: either influenza A (with varying subtypes) or B.

 primarily spread person to person via respiratory droplets,

 and the incubation period is typically 1 to 4 days.

 Uncomplicated influenza illness is characterized by a sudden onset of constitutional and respiratory signs and symptoms,

 while complications include exacerbation of underlying medical diseases, primary influenza viral pneumonia,

 or secondary bacterial infections, such as otitis media, pneumonia, or sinusitis.

To control and prevent influenza, a routine annual 

 is recommended for all those >6 months who do not have contraindictions.

 In years that the influenza vaccine is discordant with the circulating strains of influenza, multiple benefits have been observed. These benefits include reduced severity of influenza-associated illness

; a decrease in influenza-associated hospitalizations, including admission into the intensive care unit

; reduced complications of other health conditions, such as cardiac disease and diabetes

 For these reasons, annual influenza vaccines are recommended, even during years that the strains in the vaccine do not match the circulating ones.

For the 2018-2019 influenza season, the influenza activity was too low at press time to determine if this year’s vaccine will closely match the circulating strains. As of November, influenza A(H1N1) was the most common circulating strain. However, both influenza A(H3N2) and influenza B are circulating in lower numbers. If this trend of circulating viruses continues, this year’s vaccination should be protective.

For those with confirmed or suspected influenza infections, antiviral treatment is recommended as early as possible for any patient who has complicated, progressive, or severe illness; is at higher risk of influenza complications; or is hospitalized. Patients not meeting these criteria may be treated if treatment is initiated within 48 hours of illness onset. There are 4 prescription influenza antiviral agents recommended to treat influenza: zanamivir, baloxavir marboxil, oseltamivir, and peramivir.

The neuramidase inhibitors (NIs), oseltamivir, peramivir, and zanamivir, are the primary antivirals that have been used to prevent and treat influenza in recent years. Despite FDA approval, amantadine and rimatidine are not recommended to treat influenza A because of a high level of resistance (>99%) and no activity against influenza B.

 Antiviral resistance and reduced susceptibility to baloxavir marboxil and the NIs are low but can occur sporadically. The NIs are considered similar in antiviral activity; however, they vary regarding administration route. Oseltamivir is available orally, peramivir is available intravenously, and zanamivir is available as an inhalation product. Baloxavir marboxil, which is newly FDA approved, blocks viral replication and RNA transcription via a cap-depended endonuclease inhibitor. In 2 controlled, double-blind, and randomized studies in otherwise healthy individuals with uncomplicated influenza, a statistically significant reduction in median time to alleviation of symptoms was observed in people treated with a single dose of baloxavir compared with a placebo (53.7 vs 80.2 hours, respectively; P <.001). Furthermore, no difference in median time to alleviation of symptoms was found between a single dose of baloxavir and oseltamivir given for 5 days (53.7 vs 53.8 hours, respectively). Additionally, baloxavir was observed to significantly reduce viral load at day 1 compared with oseltamivir or placebo. Despite these noted positive results, reduced susceptibility was found in 2.2% and 9.7% of baloxavir marboxil recipients in the 2 trials.

Although full results of another trial, CAPSTONE-2 have yet to be published, patients with a high risk of complications because of influenza had similar trends with a reduced time to improvement of symptoms compared with the placebo (73.2 vs 102.3 hours, respectively; P <.0001) and oseltamivir (73.2 vs 81.0 hours, respectively; P = .8347). Additionally, median viral shedding was reduced in those who received baloxavir marboxil compared with oseltamivir or a placebo (48 vs 96 and 96, respectively; P <.0001).13 The clinical relevance in these differences has yet to be studied.

Influenza is a potentially life-threatening infectious disease, and prevention via vaccination is essential to reduce morbidity and mortality. Annual vaccinations have been proven beneficial even in years that the covered strains are a mismatch to circulating viral strains. When influenza does cause illness, the NIs and newly FDA-approved baloxavir marboxil are the drugs of choice. The clinical significance of the median time to reduction in symptoms compared with the placebo has been questioned with each of these antivirals. However, a reduction in severity and time of symptoms are potentially life-saving. Baloxavir marboxil is a single-dose antiviral, which shows promise. Data show similar results to oseltamivir regarding median time to reduction in symptoms in both otherwise healthy individuals and those at high risk of complications, but a statis- tically significant reduction in viral shedding compared with either oseltamivir or the placebo was identified. The clinical significance in this reduction is unknown, but it has the potential to reduce spreading of the disease, and future studies will need to be conducted to elucidate this effect. Finally, close monitoring of antiviral resistance is imperative to ensure proper treatment of patients with influenza.

Rebecca A. Jayakumar, PharmD, is an assistant professor of pharmacy practice at Roseman University College of Pharmacy in Henderson, Nevada, and maintains an infectious disease clinical site at Valley Hospital Medical Center in Las Vegas, Nevada.

Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M. Transmission of influenza A in human beings. 

Nicholson KG. Clinical features of influenza. 

Dawood FS, Jain S, Finelli L, et al; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. 

. 2009;360(25):2605-2615. doi: 10.1056/ NEJMoa0903810.

Ho YC, Wang JL, Wang JT, et al. Prognostic factors for fatal adult influenza pneumonia. 

. 2009;58(6):439-445. doi: 10.1016/j.jinf.2009.03.007.

Bautista E, Chotpitayasunondh T, Gao Z, et al; Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. 

. 2010;362(18):1708-1719. doi: 10.1056/NEJMra1000449.

Fiore AE, Uyeki TM, Broder K, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010 [erratum in MMWR Recomm Rep. 2010;59(31):993] [erratum in MMWR Recomm Rep. 10;59(35):1147]. 

Thompson MG, Pierse N, Sue Huang Q, et al; SHIVERS investigation team. Influenza vaccine effectiveness in preventing influenza-associated intensive care admissions and attenuating severe disease among adults in New Zeeland 2012- 2015. Vaccine. 2018;36(39):5916-5925. doi: 10.1016/j.vaccine. 2018.07.028.

Udell JA, Zawi R, Bhatt DL et al. Association between influenza vaccination and cardiovascular outcomes in high risk patients: a meta-analysis. 

. 2013;310(16): 1711-1720. doi: 10.1001/jama.2013.279206.

Colquhoun AJ, Nicholson KG, Botha JL, Raymond NT. Effectiveness of influenza vaccine in reducing hospital admission in people with diabetes. 

CDC. Influenza antiviral medications: summary for clinicians. CDC website. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Updated November 28, 2018. Accessed December 12, 2018.

Hayden FG, Sugaya N, Hirotsu N, et al; Baloxavir Marboxil Investigators Group. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. 

. 2018;379(10):913-923. doi: 10.1056/NEJMoa1716197.

Ison MG, Portsmouth S, Yoshida Y, et al. Phase 3 trial of baloxavir in high risk influenza patients (CAPSTONE-2 Study). Presented at: IDWeek 2018; October 3-7, 2018; San Francisco, CA. Abstract LB16. idsa.confex.com/ idsa/2018/webprogram/Paper74204.html.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit

Infectious Diseases Focus

The newly FDA-approved drug blocks viral replication and RNA transcription via a cap-dependent endonuclease inhibitor.

Baloxavir Marboxil Treats Acute Influenza in Otherwise Healthy Patients

The CDC has categorized extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae infections, such as those caused by 

, as a serious threat, associated with 26,000 infections and 1700 deaths annually.

At most institutions, carbapenems are traditionally the preferred treatment for ESBL infections. Unsurprisingly, the resulting increase in carbapenem consumption has contributed to an increase in the selective pressure of carbapanem-resistant Enterobacteriaceae.

 Because of the negative impact of carbapenem overuse, noncarbapanem antibiotics have become an attractive treatment modality for combating ESBL infections.

 Promising results have emerged from several studies that used a beta-lactam/ beta-lactamase combination drug as the compar- ator to the carbapenems, because of the in vitro activity of clavulanate and tazobactam against ESBL enzymes.

Piperacillin/tazobactam (PTZ) has been compared with carbapenems in observational and retrospective studies for both definitive and empiric use in treatment of ESBL-producing Enterobacteriaceae bloodstream infections. Its use is considered controversial, given conflicting evidence from 6 studies.

 Four of the studies found no difference in mortality.

 Their results suggest that for infections with a low inoculum (bacteremia because of a binary or urinary source), those caused by ESBL-producing 

, and those in noncritically ill patients, PTZ offers similar outcomes to a carbapenem-based regimen. The other 2 studies found a difference in mortality outcome favoring carbapenems, including patients with a higher percentage of inoculum infections (bacteremia because of intra-abdominal infections or pneumonia), a higher percentage of infections caused by ESBL-producing 

, and a higher percentage who were critically ill.

 Less than half of the patients in the studies that found a difference in outcomes received the recommended PTZ dose of 4.5 g every 6 hours. Thus, most patients in these 2 studies were underdosed, which may have been an underlying factor driving the differences seen between the 2 treatment groups. Based on all of these studies’ findings, the effectiveness of PTZ for treating bacteremia because of ESBL-producing Enterobacteriaceae remains unclear.

The MERINO trial offered to overcome some of the discrepancies seen in the previous studies.

 This study was an international, multicenter, open-label, randomized noninferiority trial of PTZ 4.5 g every 6 hours versus meropenem 1 g every 8 hours for the definitive treatment of 

bloodstream infections resistant to ceftriaxone. Subjects enrolled had at least 1 blood culture positive for 

 spp that was resistant to ceftriaxone but susceptible to meropenem and PTZ. Patients who had an allergy to either study drug, had a polymicrobial bacteremia, or were not expected to survive beyond 96 hours were excluded. The investigators divided patients by the infecting species (

 spp), severity of illness (Pitt bacteremia score ≤4 or >4), and source of bacteremia (urinary source or elsewhere). Individuals with a nonurinary source of infection and a Pitt score >4 were designated high-risk.

Three hundred and seventy-eight patients were evaluated for the primary endpoint of all-cause mortality at 30 days. Prespecified subgroup analyses of the primary endpoint included bacterial species (

), Pitt bacteremia score (≤4 or >4), and source of bacteremia (urinary versus nonurinary source). Noninferiority in 30-day mortality was not achieved (12.3% vs 3.7%; P = 0.90) when comparing PTZ with the meropenem treatment arms.

Several aspects of this trial resonate with previously observed data. For instance, although PTZ minimum inhibitory concentration (MIC) for 

 was similar across treatment groups, the median MIC was significantly greater for 

 species (4 mg/L vs 2 mg/L; P <.001). This could explain why PTZ had poorer outcomes in previous studies with a greater number of 

 infections. Similarly, the baseline characteristics for the MERINO trial illustrate that more patients in the PTZ treatment group had nonurinary sources of bacteremia, which was shown in 2 previous studies to lead to worse outcomes for PTZ-based regimens. Finally, although Pitt bacteremia scores were similar between the 2 groups, there were more immunocompromised and neutropenic patients in the PTZ group than the meropenem group. Also, whereas both groups had a similar number of patients in the intensive care unit, the APACHE II study scores were higher in the meropenem group, indicating a higher severity of illness. Given these differences, the investigators used subgroup analyses to further evaluate the outcomes. PTZ continued to fail to achieve noninferiority compared with meropenem.

The MERINO trial results do not support using PTZ as a carbapenem-sparing treatment option for ESBL-producing Enterobacteriaceae bloodstream infections. Pharmacists should encourage the use of a carbapenem. More studies are needed to shed light on the role of other beta-lactam/beta-lactamase combination drugs as a means to replace carbapenems as the panacea for ESBL-producing Enterobacteriaceae bacteremia.

US Department of Health and Human Services. Antibiotic resistance threats in the United States, 2013. CDC website. Accessed November 21, 2018.

Chastain DB, White BP Cretella DA, Bland CM. Is it time to rethink the notion of carbapenem-sparing therapy against extended-spectrum β-lact- amase-producing 

 bloodstream infections? A critical review. Ann Pharmacother. 2018;52(5):484-492. doi: 10.1177/1060028017748943.

Tamma PD, Rodri&#769;guez-Ban&#771;o J. The use of noncarbapenem β-lactams for the treatment of extended-spectrum β-lactamase infections. 

. 2017;64(7):972-980. doi: 10.1093/cid/cix034.

Bouxom H, Fournier D, Bouiller K, Hocquet D, Bertrand X. Which non-carbapenem antibiotics are active against extended-spectrum β-lactamase-producing 

Enterobacteriaceae? Int J Antimicrob Agents

. 2018;52(1):100-103. doi: 10.1016/j.ijantimicag.2018.03.014.

Rodri&#769;guez-Ban&#771;o J, Navarro MD, Retamar P, Pico&#769;n E, Pascual A&#769;; Extended- Spectrum Beta-Lactamases—Red Espan&#771;ola de Investigacio&#769;n en Patologi&#769;a Infecciosa/Grupo de Estudio de Infeccio&#769;n Hospitalaria Group. β-Lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing 

: a post hoc analysis of prospective cohorts. 

. 2012;54(2):167-174. doi: 10.1093/cid/cir790.

Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteremia due to Enterobacteriaceae producing extended-spectrum β-lactamase: a systemic review and meta-analysis. 

 2012;67(12):2793-2803. doi: 10.1093/jac/dks301.

Ng TM, Khong WX, Harris PN, et al. Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteremia due to extended-spectrum beta-lactamase-producing 

. 2016;11(4):e0153696. doi: 10.1371/journal.pone.0153696.

Gutie&#769;rrez-Gutie&#769;rrez B, Pe&#769;rez-Galera S, Salamanca E, et al. A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treat- ment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae. 

. 2016;60(7):4159-4169. doi: 10.1128/AAC.00365-16.

Ofer-Friedman H, Shefler C, Sharma S, et al. Carbapenems versus piperacillin-tazobactam for bloodstream infections in non-urinary source caused by extended-spectrum beta-lactamase-producing 

Enterobacteriaceae. Infect Control Hosp Epidemiol

. 2015;36(8):981-985. doi: 10.1017/ice.2015.101.

Tamma, PD, Han JH, Rock C, et al; Antibacterial Resistance Leadership Group. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. 

. 2015;60(9):1319-1325. doi: 10.1093/cid/civ003.

Harris PNA, Tambyah PA, Lye DC, et al; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of piperacillin-tazobactam vs meropenem on 30-day mor- tality for patients with 

bloodstream infection and ceftriaxone resistance: a randomized clinical trial. 

. 2018;320(10):984-994. doi: 10.1001/jama.2018.12163.

Clinical Care Focus

Is piperacillin/tazobactam an effective carbapenem alternative to treat bloodstream infections caused by ESBL-producing enterobacteriaceae.
 

What Are the Implications of the MERINO Trial?

LeAnn B. Norris, PharmD, FCCP, BCPS, BCOP, Clinical Associate Professor, University of South Carolina College of Pharmacy, Columbia, South Carolina

At the completion of this activity, the participant will be able to:

Identify the treatment options for patients with advanced melanoma

Examine the latest clinical data for patients with advanced melanoma

Explain the role of the pharmacist in supporting optimal treatment strategies in advanced melanoma management

Continuing Education

In the United States, about 13% of patients present with advanced melanoma (9% with regional disease and 4% with distant metastatic disease).

Progress in Treating Advanced Melanoma: Pharmacists

Pain is one of the most frequent reasons that patients seek medical care.

However, the complexity of pain can make strategizing for treatment difficult. It takes more than 1 approach and specialty to effectively manage pain. Beyond the physical, pain causes emotional, mental, and social burdens that can reduce quality of life.

 Practitioners must become skilled in collaborative and strategic pain management across the health care system.

A comprehensive approach to pain management requires that the patient with pain have an active role in determining the balance of biofeedback, counseling, medication, nutrition, physical therapy, and other adjunct nonpharmacologic treatments required to maintain a functional lifestyle and quality of life. Patients with persistent pain should be well informed about the modalities of pain management, and they should have a regimen specific to them and their pain. Education allows patients to set realistic goals and be skillful in managing their pain. A multidisciplinary team of occupational therapists, pharmacists, physicians, physical therapists, and psychologists can provide additional support for quality treatment.

A collaborative approach incorporates active interventions (those that require patients to exert energy) and passive interventions (those that do not require activity by the patient). Some active interventions are management of medication regimens, deep breathing, meditation, self-distraction, tai chi, and yoga. Many active interventions are self-directed and do not require professional health care supervision after initial instruction.

 Passive interventions include acupuncture, injections, massage, medications, and surgery.

ALTERNATIVE, COMPLEMENTARY, AND INTEGRATIVE MEDICINE 

Alternative and complementary medicine include nonmainstream modalities, such as chiropractic medicine, but differ in that complementary medicine also includes mainstream modalities, such as medications. Integrative medicine requires the coordination of complementary medicine with a patient-centered approach that addresses the emotional, functional, physical, social, and spiritual aspects of the patient’s life.

The jury is out on the efficacy of acupuncture, massage, relaxation, and other complementary therapies. Although benefits have been seen with these approaches in disease states such as back and neck pain, fibromyalgia, migraine, and osteoarthritis, many studies are negated by conflicting data,

 and some are simply anecdotal. Yet, these approaches are important because strategies should be individualized. Patients must help determine what interventions work.

CONVENTIONAL MEDICINE AND THE ROLE OF HEALTH CARE PROVIDERS 

Time spent with patients is an invaluable part of pain management. Motivational interviewing and shared decision making improve a patient’s ability to take control over the pain. Demonstration of compassion and knowledge are crucial to establishing a long-term relationship in which frequent follow-up is encouraged.

Although therapeutic emphasis is shifting from analgesic medications to an integrative approach, pharmacists and prescribers still have critical roles as educators and providers of the medications in the toolkit. Consideration of overall medical history, pain type, and severity is important when determining which medications should be a part of the pain management strategy. A patient with pain in 1 or 2 areas is likely suffering nociceptive pain, whereas a patient with a dermatomal region or stocking-glove distribution likely has neuropathic pain. Multifocal pain is often chronic and extends beyond physical sensations to alterations in energy, memory, mood, and sleep.

 When selecting the best agent, it is crucial to work with the patient to consider the role of analgesics in the management strategy. Consistent follow-up allows providers to determine not only efficacy and safety of medications but also whether they are bearing too little or too much weight in a patient’s overall pain management strategy.

Some common pain states include chronic low back pain, complex regional pain syndrome, diabetic neuropathy, fibromyalgia, myofascial pain syndrome, postherpetic neuralgia, and radicular pain. Acetaminophen, monoamine reuptake inhibitors, local anesthetics, membrane stabilizers, muscle relaxants, nonsteroidal anti-inflammatory drugs, opioids, and topical capsaicin have varying levels of success in these conditions.

 With the continuing opioid epidemic, American Society of Interventional Pain Physicians guidelines recommend a high level of involvement on the part of the provider in identifying true candidates for opioid therapy and monitoring efficacy and safety.

Pharmacologic pain management via a collaborative strategy alleviates symptomatic pain. Patients should be encouraged to report pain to their providers.

 After initial self-care therapies, prescription management has a role that should be in addition to appropriate complementary methods, such as spinal manipulation in back pain.

 Counseling, follow-up, and reevaluation of strategy efficacy are important in all cases but should be increased in patients with severe chronic pain who require strong analgesics with increased addiction potential.

Pharmacists can have a huge impact in guiding patient decisions and reinforcing follow-up. When a patient presents with symptomatic pain from a chronic condition, ask questions regarding aggravating and relieving factors, determine what methods are being used, and suggest the right medication for the type of pain. Providers should be skillful in working with patients to create a collaborative pain management strategy that balances complementary medicine, pharmacologic therapies, and self-care. Empowered patients with chronic pain conditions can live quality lives through frequent follow-up, modifications to suit their individual conditions, and well-rounded care.

Sarah B. Sanchez is a PharmD candidate at the Ernest Mario School of Pharmacy at Rutgers, the State University of New Jersey, in Piscataway.

Deepali Dixit, PharmD, BCPS, BCCCP, FCCM, is a clinical associate professor at the Ernest Mario School of Pharmacy and a clinical pharmacy specialist, critical care, at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. 

Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and high-impact chronic pain among adults - United States, 2016. 

. 2018;67(36):1001-1006. doi: 10.15585/mmwr.mm6736a2.

Feinberg S. ACPA resource guide to chronic pain management: an integrated guide to medical, interventional, behavioral, pharmacologic and rehabilitation therapies. American Chronic Pain Association website. theacpa.org/wp-content/uploads/2018/05/ACPA_Resource_Guide_2018-Final_ Feb.pdf. Published 2018. Accessed December 13, 2018.

A comprehensive approach requires that patients play an active role in determining medication and nonpharmacologic treatments.

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