Top Infectious Disease News of the Week—June 2, 2019

#5: What's in the Pipeline?

Although advances in combination antiretroviral therapy (ART) have greatly reduced morbidity and mortality associated with HIV, the pipeline for development of novel drug mechanisms and new agents in the existing drug classes remains full. This article presents a review of investigational drugs furthest along in development with propitious results in human subjects.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NRTI)

GS-9131 is a prodrug of the nucleotide analogue GS-9148.¹ It inhibits reverse transcription by chain termination. GS-9131 was shown to have broad in vitro activity against HIV-1 and HIV-2 and was not significantly affected by the presence of reverse transcriptase mutations K65R, L74V, M184V, or their combinations.¹ In vitro resistance selection studies have shown a high barrier to resistance.¹ GS-9131 has low potential for mitochondrial toxicity and renal accumulation.² It is a promising candidate with once-daily dosing in combination with other ART in patients with NRTI resistance and limited treatment options.

NUCLEOSIDE REVERSE TRANSCRIPTASE TRANSLOCATION INHIBITOR (NRTTI)

MK-8591 (EFdA) is an adenosine analogue that both acts as a reverse transcriptase chain terminator and prevents DNA translocation.³ It has a prolonged half-life of 150 to 160 hours.⁴ In early clinical studies, single oral doses of 0.5 to 30 mg of MK-8591 resulted in >1.2- log viral load decline by day 7. This suggests the NRTTI’s potential for once-weekly dosing, with high potency, at a very low dose.⁵ However, because of its high intrinsic aqueous solubility, an injectable formulation is not considered feasible.⁵ Studies in rat models using nondegradable polymer implants have shown a plasma half-life of up to 100 days, so the possibility of human implants with a dosing interval of 1 year or longer is being explored.⁶

Read about the HIV/AIDS pipeline.

#4: Tick, Tick, Tick: Vector-Borne Diseases Ramp Up

Pathogens transmitted by ticks cause the vast majority of vector-borne diseases in temperate North America, Europe, and Asia. In the continental United States, more than 95% of reported human cases of vector-borne diseases are caused by tick bites.¹ Lyme disease may exceed 300,000 cases annually, about 10-fold higher than the number of reported cases,² ranking it among the most common infections in the United States, second only to sexually transmitted diseases.

In addition, other tick-borne infections account for more than 10,000 reported cases annually,¹ but the number of actual cases is likely much higher.^3,4

Ticks are the central link in the pathogen—host– environment triad of tick-borne diseases. Typically, tick-borne diseases circulate between ticks and suitable hosts, mostly rodents. Occasionally, ticks bite and transmit pathogens to humans; nonetheless, humans are dead-end hosts and do not play a role in the enzootic cycle of tick-borne pathogens.

Read about vector-borne diseases ramping up.

#3: More Than Surviving Sepsis: Everything Old Is New Again

Because of numerous failed attempts at novel or targeted therapies in sepsis over the past 20 years, investigators have been compelled to step back in time and repurpose old agents, including angiotensin II and ascorbic acid, for the treatment of sepsis and septic shock. Both medications have historically shown promise in animal shock models. However, it was not until the publication of recent clinical investigations in humans that investigators’ interest piqued regarding their use in refractory vasodilatory shock.

ANGIOTENSIN II

Management of distributive shock focuses on early and adequate fluid resuscitation, timely antibiotic administration, and initiation of catecholamine (eg, norepinephrine, epinephrine) and/or noncatecholamine (eg, vasopressin) vasopressor therapy.¹ Given the potential for dose-dependent adverse effects (AEs) from catecholamine-based vasopressor therapy (eg, tachycardia), noncatecholamine therapy has potential clinical benefits.

One promising therapeutic strategy involves using the renin-angiotensin-aldosterone system (RAAS) to generate noncatecholamine vasopressor effects. Angiotensin II binds a number of G-protein coupled receptors, including angiotensin II receptor type 1 (AGTR1), which notably results in vasoconstriction, aldosterone secretion, sodium and water retention, and vasopressin release.²

Read about more than surviving sepsis.

#2: Tackling Antimicrobial Resistance Through RN Involvement

The US Centers for Disease Control and Prevention (CDC) reports that every year more than 2 million Americans acquire antibiotic-resistant infections, leading to at least 23,000 related deaths. This growing threat is fueled by antibiotic use in multiple industries from agriculture to health care. One of the most challenging aspects of tackling antimicrobial resistance in health care is driving change within providers’ practice, and a resource that is often forgotten is that of the registered nurse (RN).

In the face of increasing regulatory focus on antimicrobial stewardship (AS), many are looking to ways of enhancing compliance and innovation within their medical facilities. While physicians and pharmacists play a vital role, a new article in the American Journal of Infection Control serves as a reminder of the critical role of RNs.

Pointing to the 2017 joint paper from the American Nurses Association and the CDC, the authors emphasize the role of RNs in hospital antimicrobial resistance practices, but also that of the infection preventionist in providing education to RNs. While RNs play a critical role in patient care, their role in AS needs further development. Therefore, it is important to get a baseline of their knowledge and attitudes towards antimicrobial stewardship, and that’s just where the authors began. To assess the current state of knowledge and attitudes, the investigators of this study surveyed 2000 RNs at 3 hospitals within an integrated healthcare system in Utah.

Read about the role of RNs in stewardship.

#1: FDA Approves Ceftolozane/Tazobactam for HABP/VABP

The US Food and Drug Administration (FDA) has announced the approval of ceftolozane/tazobactam for the treatment hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). The approval of this new indication was granted to Merck & Co., Inc.

Ceftolozane/tazobactam (Zerbaxa) is a combination treatment of an anti-pseudomonal cephalosporin, ceftolozane, and an extended-spectrum β-lactamase inhibitor, tazobactam. In the United States ceftolozane/tazobactam is indicated for the treatment of complicated urinary tract infections including pyelonephritis caused by certain susceptible Gram-negative microorganisms and also in combination with metronidazole for the treatment of complicated intra-abdominal infections. It was first approved by the FDA in 2014.

In February, the FDA accepted the sNDA of ceftolozane/tazobactam for priority review to treat patients with nosocomial pneumonia. The acceptance of the sNDA was based on the findings of the ASPECT-NP trial.

“The approval of Zerbaxa for hospital and ventilator-associated pneumonia is great news for clinicians who care for these types of patients, particularly for those clinicians who work in hospitals or acute-care settings," said Yoav Golan, MD, MS, of Tufts Medical Center, when speaking about the approval. "This is for 2 main reasons. The first is the activity of Zerbaxa against some of the most resistant pathogens that cause pneumonia like multidrug-resistant Pseudomonas. Another reason is that Zerbaxa has relatively balanced activity against resistant pseudomonas as well as another challenging group of gram-negatives known as ESBL producers.”

The study, which compared a new 3-gram dose regimen of ceftolozane/tazobactam with meropenem, enrolled patients who were mechanically ventilated with hospital-acquired/ventilator-associated bacterial pneumonia. A total of 726 participants were enrolled into the trial and were randomized 1:1 to 3 g ceftolozane/tazobactam or 1 g meropenem, both by intravenous (IV) infusion over 1 hour every 8 hours for 8-14 days, stratified by age and diagnosis (vHABP vs VABP).

Read about the new indication for ceftolozane/tazobactam.