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

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, 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

Aminoglycosides date back to the 1940s, with the intro&shy;duction of streptomycin. Streptomycin was the first antibiotic available for the effective treatment of tuber&shy;culosis, netting its discoverer, Selman Waksman, a Nobel Prize. During the golden age of antibiotic development in the 1940s through 1960s, aminoglycosides continued to advance, along with many novel classes of antibiotics. Because of their potent activity against gram-negative organisms, aminoglycosides became mainstays of infectious diseases pharmaco-therapy, before eventually being displaced by broad-spectrum β-lactams, which became widely available in the 1980s and 1990s.

Inevitably, organisms developed resistance mechanisms to aminoglycosides. In Enterobacteriaceae, resistance is commonly due to plasmid-encoded aminoglycoside-modifying enzymes (AMEs). These enzymes cause a change in the chemical structure of the aminoglycoside compound, resulting in lower binding affinity for the bacterial ribosome and high-level resistance to the class. Plazomicin, which was approved by the US Food and Drug Administration (FDA) on June 25, 2018, for the treatment of complicated urinary tract infections (cUTIs), was developed with structural modifications to protect it from AMEs.

 On August 3, 2018, the Centers for Medicare & Medicaid Services granted plazomicin a new technology add-on payment for inpatient use.

Plazomicin is active against all aminoglycoside-modifying enzymes that confer resistance to older aminoglycosides, except N-acetyltransferase exhibited in 

 Compared with older aminoglycosides, it has more potent activity against extended-spectrum β-lactamase—producing and carbapenem-resistant Enterobacteriaceae (CRE).

 In an in-vitro comparison with CRE, plazomicin had a minimum inhibitory concentration for 90% of the isolates (MIC90) of 2 mg/mL compared with gentamicin (MIC90 64 mg/mL), tobramycin (MIC90 32 mg/mL), and amikacin (MIC90 32 mg/mL).

 The approved breakpoint for plazomicin is 2 mg/mL.

. The EPIC trial compared plazomicin with meropenem for the treatment of cUTIs, including acute pyelonephritis (AP), in 388 adults. Plazomicin demonstrated noninferiority in composite cure, defined as achieving micro&shy;biologic eradication and clinical cure, at the test-of-cure visit with a success rate of 81.7% compared with 70.1% with meropenem, a difference of 11.6% (95% CI, 2.7 to 20.3).

Interestingly, patients in the plazomicin arm also experienced a significantly lower rate of clinical relapse at late follow-up compared with those in the meropenem arm (1.8% vs 7.9%).

 The FDA granted plazomicin approval for the treatment of cUTI including AP in adults 18 years and older with limited or no available treatment options. The indicated dose is 15 mg/kg intravenously every 24 hours.

Plazomicin was also studied in the CARE trial, a prospec&shy;tive, randomized study of patients with CRE infections. Investigators compared plazomicin with colistin in 37 adult patients with bloodstream infections (BSIs), hospital-acquired pneumonia, and ventilator-associated pneumonia caused by CRE. Patients in the plazomicin arm had a 26.5% lower all-cause mortality or disease-related complication rate compared with those in the colistin arm (23.5% vs 50.0%; 95% CI, —0.7 to 51.2). Patients treated with plazomicin for a BSI demonstrated a survival benefit with a hazard ratio for death of 0.37 (90% CI, 0.15 to 0.91).

 In addition, patients with a BSI had a microbiologic response rate of 92.9% when treated with plazomicin compared with 53.3% for those treated with colistin.

Following a single 15-mg/kg intravenous (IV) dose, plazo&shy;micin achieved a maximum concentration of 73.7 mg/mL, a minimum concentration of 0.3 mg/mL, and an area under the curve of 257 mg/mL. The mean volume of distribution is 17.9 L, and protein binding is estimated to be 20%. Plazomicin has a half-life of 3.5 hours in patients with normal renal function and is primarily excreted renally unchanged. Therapeutic drug monitoring can be performed, with a goal trough level of less than 3 mg/mL prior to the second dose to minimize toxicity.

 Plazomicin lung penetration was measured at 13% after a single dose in healthy volunteers.

Warnings and precautions associated with plazomicin use are consistent with those reported for older aminoglycosides. Black box warnings include nephrotoxicity, ototoxicity, neuro&shy;muscular blockade, and teratogenicity. Adverse events most commonly observed in clinical studies include acute kidney injury, diarrhea, headache, nausea, vomiting, and hypertension or hypotension.

 In the EPIC trial, 3.7% of patients treated with plazomicin had a serum creatinine level increase of ≥0.5 mg/dL while on IV therapy compared with 3.0% of patients treated with meropenem.

 In the CARE trial, 11.1% of patients who received plazomicin had serum creatinine level increases compared with 38.1% of those who received colistin.

With its activity against multidrug-resistant Enterobacteriaceae, plazomicin offers an alternative for patients at high risk for, or with a history of, infection caused by organisms such as CRE. Although plazomicin is indicated by the FDA to treat cUTI, there are limited prospective data supporting its use as a treatment for other infections caused by CRE, particularly BSIs. As such, plazomicin may be particularly useful in urosepsis, though its use should be reserved for instances including carbapenem resistance or elevated MICs to older aminoglycosides.

Dr. Heaney is a PGY2 resident in infectious diseases pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She completed her PharmD at the University of the Sciences Philadelphia College of Pharmacy and a PGY1 residency at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania.

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

Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. 

Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. 

Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. 

Haidar G, Alkroud A, Cheng S, et al. Association between the presence of aminoglycoside-modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin, and plazomicin against Klebsiella pneumoniae carbapenemase- and extended-spectrum-β-lactamase-producing Enterobacter species. 

Cloutier D, Miller L, Komirenko A, et al. Evaluating once-daily plazomicin versus meropenem for the treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP): Results from a phase 3 study (EPIC). Presented at: ASM Microbe 2017; June 4, 2017; New Orleans, LA.

Plazomicin [package insert]. San Francisco, CA: Achaogen, Inc.; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303Orig1s000lbl.pdf. Accessed 18 July 2018.

Daikos G, Connolly L, Jubb A, et al. Plazomicin (PLZ) associated with improved survival and safety compared to colistin in serious carbapenem-resistant Enterobacteriaceae (CRE) infections: Results of the CARE study. Presented at: ASM Microbe 2017; June 5, 2017; New Orleans, LA.

Cass R, Kostrub CF, Gotfried M, Rodvold K, Tack KJ, Bruss J. A double-blind, randomized, placebo-controlled study to assess the safety, tolerability, plasma pharmacokinetics and lung penetration of intravenous plazomicin in healthy subjects. Poster presented at: 23

 European Congress of Clinical Microbiology and Infectious Diseases; May 1, 2013; Berlin, Germany.

The drug presents a new option for patients at high risk of infections caused by organisms, such as carbapenem-resistant Enterobacteriaceae.

Plazomicin: A Novel Aminoglycoside

After years of sounding the alarm about the dangers of limited antibiotic development, infectious diseases clinicians have been rewarded with multiple new antibiotics in the 2010s. To my shock, the 

Infectious Diseases Society of America’s “10x20” goal

 (10 new antibiotics before 2020) may actually be achieved. Changed regulatory pathways and “push” incentives that assist antibiotic development are partially responsible for the increased antibiotic throughput that we are benefitting from now.

However, the number of major pharmaceutical companies that invest in antibiotic development continues to decline, with AstraZeneca, Novartis, and Allergan recently announcing that they are leaving the anti-infective space. 

 is particularly notable as the company markets several recently approved antibacterial agents that address critical needs. Antibiotics are a societal good that rely on private industry for production and the message that even selling approved, useful antibiotics that save patient lives is not enough to attract major drug developers to stay in the market is disheartening, to say the least.

What is going on? There are many issues, however, the main issue is that because private industry is for-profit, it gravitates toward therapeutic areas that make the most money. Antibiotics, which fulfill an acute need that most people do not have, are not one of those areas. Inexpensive generic antibiotics are currently effective for the majority of infections in the world, while branded, expensive antibiotics that fulfill a need, such as infections caused by carbapenem-resistant Enterobacteriaceae (CRE), are used in a very small number of patients. To put that in another context, 100% of the CRE market is smaller than 1% of the diabetes market.

And what happens when a new antibiotic is approved? We try not to use it to preserve its use for the patients who really need it, and shorten durations of therapy to decrease resistance, laudable goals that clearly do not incentivize further development. Life can be painfully ironic.

We need to hit the reset button on how antibiotics are developed and admit that our current model does not work. Push incentives are not enough. Although smaller pharmaceutical companies have picked up the pace of antibiotic development, without larger companies to partner with they may be headed for difficult futures, and new antibiotics that make it to the market and then fail are not helpful. “Pull” incentives are needed to encourage companies to get back in the game. Because antibiotics are not profitable, it is necessary to reward companies who develop these needed agents in ways that serve their interests.

The pull incentive that I like the most is that of an awarded patent extension for an agent of the company’s choosing. A company that develops an antibiotic that offers a true advantage in the treatment of a resistant infection, such as CRE, is rewarded with a 12-month patent extension for another product that they market. If you wonder if this will work, just think for a minute: What would it have been worth to Pfizer to extend the patent for Lipitor (atorvastatin)? Billions.

, that suggests this pathway as a solution. In today’s challenging political environment, the bill faces an uphill battle, but it is an example of the type of out-of-the-box thinking we need to change the current paradigm of antimicrobial drug development. If the incentive is strong enough, it could be used to encourage many positive outcomes, such as deeply discounted anti-infectives, funding for antimicrobial stewardship, and developments in susceptibility testing that keep pace with approvals.

Whatever form our incentives take, it is clear that something radical is needed. Our unique system that relies on private companies to produce a public good is failing.

: We have combined coverage on viral hepatitis into other sections in our print publication. Continue to look for the latest infectious disease news on our website and social media channels (

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

Contagion® editor-in-chief, Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS, affirms that the health care industry needs to hit the reset button on how antibiotics are developed.

Antibiotic Development&mdash;We Gave It a Push, Now It Needs a Pull

I have always disliked that corny expression because I am not fond of forced motivational phrases. However, as I write my column for this issue of 

, I find myself thinking about this managerial catch phrase, given a recent white paper and the response it generated among the infectious diseases (ID) community.

“Antimicrobial stewardship” is obviously a hot term in ID at the moment. Authors find ways to mention terms like this in papers, hoping to catch an editor’s eye; speakers present graphs showing its prevalence in Medline searches by year; and fully integrated ID news resources create “

” sections to ensure that it is comprehensively addressed within their pages. The attention is justified, given the rise in antibacterial resistance and the fact that antibiotic development is not where we need it to be. Accrediting bodies and government organizations have responded with new standards and guidance for health care organizations, which have scrambled to get up to par.

A multitude of vested professionals need to be at the table for antimicrobial stewardship programs to work. Many of these programs have been started and led by ID pharmacists, often with the support of ID physicians, and vice versa. The push for widespread adoption of stewardship programs has come from both professions. Some stewardship pharmacists work in jobs to implement programs initiated by ID physicians, and some ID physicians are compensated for their stewardship activities through business plans driven by pharmacy departments looking for support. In the vernacular of ID, it really is a synergistic combination, sometimes both clinically and economically.

Although a few recent publications may have distracted from the focus on how this synergy works as groups advocate for their own professions,

 I expect that we will continue to see stewardship programs evolve and expand in ways that meet the needs of our patients regardless of what stakeholders put into print. The rise of ID pharmacy as a profession has been complementary to services uniquely offered by ID physicians, not in competition with them. Together, we lead stewardship programs,

Ostrowsky B, Banerjee R, Bonomo RA, et al; Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and the Society for Healthcare Epidemiology of American. Infectious diseases physicians: leading the way in antimicrobial stewardship. 

. 2018;66(7):995-1003. doi: 10.1093/cid/cix1093.

Dodds Ashley E, Davis SL, Heil EL, LaPlante KL, Chahine EB, Bosso JA. Best care for patients is achieved through multi-disciplinary stewardship [published online May 15, 2018]. 

Joint Commission on Hospital Accreditation. APPROVED: new antimicrobial stewardship standard. 

CDC. Core elements of hospital antibiotic stewardship programs. CDC website. cdc.gov/antibiotic-use/healthcare/implementation/core-elements.html. Updated February 23, 2017. Accessed May 23, 2018.

National Quality Partners Playbook: Antimicrobial Stewardship in Acute Care. National Quality Forum website. qualityforum.org/Publications/2016/05/National_Quality_Partners_Playbook__Antibiotic_Stewardship_in_Acute_Care.aspx. Published May 2016. Accessed May 23, 2018.

Bush LM, Kaye D. Optimizing antimicrobial utilization: job of a steward, or time for a pilot? 

. 2017;65(9):1595. doi: 10.1093/cid/cix530.

Pollack LA, van Santen KL, Weiner LM, Dudeck MA, Edwards JR, Srinivasan A. Antibiotic stewardship programs in U.S. acute care hospitals: findings from the 2014 National Healthcare Safety Network Annual Hospital Survey. 

. 2016;63(4): 443-449. doi: 10.1093/cid/ciw323.

Morgan JR, Barlam TF, Drainoni M. A qualitative study of the real world experiences of infectious diseases fellows regarding antimicrobial stewardship [published online May 3, 2018]. 

The rise of ID pharmacy as a profession has been complementary to services uniquely offered by ID physicians, not in competition with them.