Jason C. Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS, is a clinical professor at Temple University (TU) School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital in Philadelphia, Pennsylvania. He also is director of the PGY2 Residency in Infectious Diseases Pharmacy at TU.

Jason Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS*

SARS-CoV-2 has taken us on a rollercoaster, and not just on graphs of case counts. The natural tendency to project linearity to trends makes each hill and dip feel unnatural. The media exacerbates perceptual changes with its hyperfocal attention on each new development, even expected ones like breakthrough infections. People feel they are being jolted around.

The early efficacy results of the mRNA vaccines from Pfizer-BioNTech and Moderna were positively stunning. Demonstrating more than 90% vaccine effectiveness against symptomatic infection when the goal was a 50% reduction in severe disease caught people off guard. It was the first bit of good news in quite a while, coming at a time when school buildings were shut in much of the country and we adapted to e-school, working from home, and the awkwardness of Zoom happy hours. When vaccines started to be given in December 2020, people began to envision a world without COVID-19.

Things have not turned out that way. Despite commanding the greatest portion of vaccine supply and getting a head start, vaccinations in the US have fallen behind that of most high-income countries; at this writing, 

the US is at the bottom of the G7 and 60th in the world in percentage vaccinated

. However, that is only part of the picture. The virus has not waited for us to vaccinate the world’s population- it keeps evolving towards more transmissible variants. In the Delta variant, SARS-CoV-2 has transformed into not just a highly transmissible variant, 

but one of the world’s most transmissible infectious diseases

. We are fortunate that Delta came to the US after vaccines became widely available or we would be looking at a very different society right now.

The combination of Delta and vaccine hesitancy has cost many lives, but it also highlights the need to reset expectations on the COVID-19 endgame. Herd immunity may never have been a realistic goal, but it seems clear it is an impossibility. Over the next several years, everyone is likely to be infected with SARS-CoV-2. With the attenuation that vaccination provides, most vaccinated people will have asymptomatic, mild, or moderate infection. Unvaccinated people with previous COVID-19 will have less severe reinfection, and the ever-decreasing number of unvaccinated people without previous COVID-19 will be susceptible to severe disease.

The continued spread of immunity, whether acquired by vaccination or infection, will drive overall cases down. However, the incomplete nature of immunity and future mutations in SARS-CoV-2 will allow it to remain a circulating human pathogen like other endemic human coronaviruses.

One of the most apparent issues that the pandemic has revealed is ineffective communication. To increase vaccine uptake, ‘get vaccinated and you’re good’ became the narrative. People listened. When Delta became pervasive and changed things again, momentum towards a ‘post-pandemic’ dream was harder to change. Therefore, it is time to prepare people for a future with endemic COVID-19 now. We won’t be masked forever, but we aren’t wiping the virus off the earth either.

Articles

Time to Prepare People to Accept COVID-19 Endemicity

The first antifungal medication, amphotericin B deoxycholate, was approved in 1958 for the treatment of fungal infections. It wasn’t until 15 years later that flucytosine was introduced and 15 years after that when azole antifungals were brought to market in the 1990s.

 Echinocandins, introduced in the 2000s, provided broad-spectrum antifungal coverage with minimal toxicity compared with the preceding agents. Since that time, the FDA has approved no new classes of antifungal agents. Although the current antifungals used in clinical practice provide sufficient coverage against a plethora of fungal species, resistant species and strains are evolving rapidly. The multidrug-resistant fungus 

 that is emerging as a serious global health threat; it has high rates of resistance to azoles and amphotericin B, correlating to poor clinical outcomes.

Ibrexafungerp (Brexafemme) is a first-in-class triterpenoid approved by the FDA on June 1, 2021, for the treatment of vulvovaginal candidiasis (VVC) in adult and postmenarchal pediatric females.

 In this article we review the agent’s mechanism of action, pharmacokinetic properties, safety and efficacy, and place in therapy.

Ibrexafungerp has a unique name that can be understood by breaking it down. “Ibrexa” is the fantasy prefix, “fung” refers to the mechanism of action targeting (1,3)-β-D-glucan synthase (similar to caspo

enoid. In 2019, the United States Adopted Names Council approved the use of the “-fungerp” stem for this new class of triterpenoid antifungals.

Similar to echinocandins, ibrexafungerp is an inhibitor of (1,3)-β-D-glucan synthase; however, it is structurally different and interacts with the enzyme in a different way. Due to this difference there is limited potential for cross-resistance with echinocandins, which has been confirmed in in vitro studies, as ibrexafungerp was shown to retain activity against echinocandin-resistant strains of 

It is also active against some other less common molds.

 Ibrexafungerp has demonstrated activity against biofilms produced by 

with similar activity to that of echinocandins but significantly higher than that of fluconazole (

Unlike the echinocandins, ibrexafungerp is highly bioavailable and can be given both intravenously and orally. Ibrexafungerp is available as 150-mg oral tablets and administered at 300 mg given 12 hours apart for 2 doses, which completes the regimen in a single day.

 Plasma concentrations peak around 4 to 6 hours after oral administration. Administration with a high-fat meal increased the maximum concentration and area under the curve by around 32% and 38% compared with fasting, respectively, but this is not considered clinically significant. Ibrexafungerp can be taken with or without food.3 Protein binding is 99.6% to 99.8% and the mean steady state volume of distribution is approximately 600 L.

 Tissue to blood ratios for several organs have been estimated in a single-dose pharmacokinetic analysis in rats, which found extensive distribution in vaginal tissue; the lung, kidney, liver, and spleen; bone marrow; muscle; and skin, but minimal distribution in central nervous system tissue and the spinal cord.

 Ibrexafungerp is hepatically cleared and mainly eliminated in the feces and bile (~90%), with approximately 1.5% urinary elimination. Dose adjustments are not required for renal or hepatic impairment. The half-life is approximately 20 hours, supporting the single-day dosing.

 Currently, no data exist on crushing or breaking the oral tablets.

Ibrexafungerp is extensively metabolized by the cytochrome P450 pathway and is affected by drugs that induce or inhibit this pathway. Because it is a substrate of cytochrome P3A4 (CYP3A4), coadministration of the drug with strong CYP3A4 inhibitors increases its concentration and a 50% dose reduction is recommended.

 Avoid coadministration with moderate to strong CYP3A4 inducers, such as rifampin, which may reduce concentrations of ibrexafungerp. Ibrexafungerp is also a CYP3A4, P-gp, and OATP1B3 transporter inhibitor, but the clinical significance of this is not of concern for the short duration of treatment for VVC.

 Concomitant use with pantoprazole for 5 days resulted in decreased ibrexafungerp exposure by 25%, though this was not considered clinically significant at the current approved dose.

Two phase 3 clinical studies evaluated the safety and efficacy of ibrexafungerp compared with placebo for the treatment of VVC. VANISH 303 and VANISH 306 (NCT03734991 and NCT03987620) were randomized, double-blind, placebo-controlled trials that included nonpregnant postmenarchal patients aged 12 and older with a diagnosis of symptomatic acute VVC.

 More than 90% of patients with baseline cultures were culture positive with 

. The investigators in both trials evaluated clinical cure, defined by the complete resolution of signs and symptoms, at test of cure at 8 to 14 days post treatment. According to the data, patients receiving ibrexafungerp showed complete response rates compared with those receiving placebo of 50% vs 28% (

 = .001) in VANISH 303, and 63.5% vs 44.9% (

 = .009) in VANISH 306. Adverse effects among patients were minimal and mainly gastrointestinal in nature.

Several other ongoing phase 2 and 3 clinical trials are being conducted to evaluate the role of ibrexafungerp in patients with recurrent VVC (CANDLE, 

), refractory invasive fungal infections (FURI, 

). Highlighting the CARES study in particular, investigators evaluated the safety and efficacy of ibrexafungerp 750 mg twice daily for 2 days, then 750 mg once daily for up to 90 days in hospitalized patients with documented candidiasis or candidemia caused by 

. Interim results have demonstrated a complete or partial response in 8 of 10 patients (80%).

 FURI has also shown positive results thus far, with investigators reporting that 46 of 74 patients (62%) experienced complete or partial responses and 18 of 74 (24%) had stable disease at the time of analysis.

Adverse Effects, Warnings, and Precautions

Based on data from clinical trials in patients with VVC, the adverse effect profile of single-day ibrexafungerp is generally favorable. Gastrointestinal adverse effects were the most common, including diarrhea (16.7%), abdominal pain (11.4%), nausea (11.9%), dizziness (3.3%), and vomiting (2.0%).

 A press release for the FURI and CARES studies stated that ibrexafungerp was well tolerated overall and that investigators had identified no safety signals warranting changes to the studies.

 In contrast to many azole antifungals, ibrexafungerp does not cause QTc prolongation.

The use of ibrexafungerp is contraindicated in pregnancy, as data from animal studies have shown a potential for fetal harm. During treatment with the agent, the use of effective contraception is advised. Concentrations in breast milk are unknown.

Investigators in in vitro studies have evaluated the potential for resistance to ibrexafungerp, finding an association with mutations in the 

2 gene. The clinical relevance of this is not yet known, but it has been established that ibrexafungerp retains activity against most echinocandin- and fluconazole-resistant strains of 

Although fluconazole is an inexpensive, well-tolerated, single-dose agent that is effective in the majority of VVC cases, ibrexafungerp is an option for patients who either fail fluconazole therapy or may be unable to receive it. Ibrexafungerp is available orally and has a favorable adverse effect profile.

Beyond VVC, ibrexafungerp has the potential to advance the care of patients with invasive fungal infections, including those caused by resistant 

 Clinical data evaluating inpatient use in more invasive and resistantinfections are pending. There is currently insufficient data to support the use of ibrexafungerp in patients with these infections, and clinicians should note that the dosing regimens under study are different from the approved VVC regimen. The drug interactions that are not clinically relevant with a single-day dosing regimen may warrant caution or necessitate dose modification for other uses.

Geena Kludjian, PharmD, is an infectious diseases clinical pharmacy specialist at Cooper University Hospital in Camden, New Jersey.

Nett JE, Andes DR. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. 

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Chaabane F, Graf A, Jequier L, Coste AT. Review on antifungal resistance mechanisms in the emerging pathogen 

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Brexafemme. Package insert. SCYNEXIS, Inc; 2021. Accessed June 22, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214900s000lbl.pdf

Boden J. How ibrexafungerp got its name. IDStewardship.com. April 22, 2021. Accessed June 21, 2021. 

https://www.idstewardship.com/ibrexafungerp-got-name/

Pfaller MA, Messer SA, Rhomberg PR, Borroto-Esoda K, Castanheira M. Differential activity of the oral glucan synthase inhibitor SCY-078 against wild-type and echinocandin-resistant strains of Candida species. 

. 2017;61(8):e00161-17. doi:10.1128/AAC.00161-17

Nunnally NS, Etienne KA, Angulo D, Lockhart SR, Berkow EL. 

 activity of ibrexafungerp, a novel glucan synthase inhibitor against Candida glabrata isolates with 

. 2019;63(11):e01692-19. doi:10.1128/AAC.01692-19

Jallow S, Govender NP. Ibrexafungerp: a first-in-class oral triterpenoid glucan synthase inhibitor. 

Marcos-Zambrano LJ, Gómez-Perosanz M, Escribano P, Bouza E, Guinea J. The novel oral glucan synthase inhibitor SCY-078 shows in vitro activity against sessile and planktonic Candida spp. 

. 2017;72(7):1969-1976. doi:10.1093/jac/dkx010

Wring S, Borroto-Esoda K, Solon E, Angulo D. SCY-078, a novel fungicidal agent, demonstrates distribution to tissues associated with fungal infections during mass balance studies with intravenous and oral [14C]SCY-078 in albino and pigmented rats. 

. 2019;63(2):e02119-18. doi:10.1128/AAC.02119-18

SCYNEXIS announces positive results from interim analyses of ongoing phase 3 studies (FURI and CARES), demonstrating oral ibrexafungerp’s ability to treat severe fungal infections in the hospital setting. Press release. SCYNEXIS. March 2, 2021. Accessed June 22, 2021. 

https://www.scynexis.com/news-media/press-releases/detail/233/scynexis-announces-positive-results-from-interim-analyses

Ibrexafungerp: A Novel Antifungal Agent That Is Easier to Pronounce Than Spell

As the US approaches the second half of 2021, amazing progress against 

 has been made. Most of the adult population has received at least one dose of vaccine and case rates have fallen substantially. Though the potential for seasonal spikes and new variants of concern remain as issues, it appears the worst of the pandemic is behind us in the US.

I feel that we were lucky. It seems wrong to write that for a disease that has claimed approximately 600,000 American lives, causes lingering effects in many people, and both harmed and altered the economy in ways that are still being assessed. 

However, it could have been much worse. An illness that combines the infectivity and asymptomatic spread of COVID-19 with the lethality of SARS-CoV-1 would have been beyond devastating.

Despite many missteps in our COVID-19 response, the US hit a grand slam with vaccine development. The widespread availability of COVID-19 vaccines across
the country makes it easy to forget that these agents became available only a few short months ago. 

Any one of the many steps in vaccine development could have gone wrong. Although not every vaccine that entered clinical trials was successful, multiple agents were, and they have efficacy that is well above the expected threshold to limit spread. Safety of our available vaccines is now well understood and severe adverse events are exceedingly rare, particularly for the mRNA vaccines.

The spike protein of SARS-CoV-2, which is the antigen targeted by every single one of the vaccines currently available, turned out to be an effective target for vaccine-induced neutralizing antibodies. The US government funding of several vaccine manufacturer programs led to useful vaccines (with others still possible), and the “go-it-alone” approach of Pfizer led to another success.

Imagine some scenarios where things went differently. In one, multiple vaccines were not efficacious, and the one that succeeds in a trial has a measured efficacy of 50% but only for severe disease and only mildly blunts asymptomatic disease, leading to a limited effect on decreasing transmission. Vaccine availability is low due to high demand and limited production capabilities. Deaths decrease, but the pandemic rages.

Or, an approved vaccine is effective, but has a less-safe adverse effect profile that causes severe adverse effects in 1000 times as many people as the current vaccines. The adverse effects are still much rarer than deaths from COVID-19, but due to a different risk-benefit balance, only older adults and health care practitioners receive it. Deaths decrease, but the pandemic rages.

Or, imagine if the spike protein ended up being a poor target after all. Every single vaccine currently on the international market would fail. The pandemic rages.

None of these scenarios occurred. We are on track to control a rapidly emergent pandemic through vaccination for the first time in our history. It has not been easy, and because we have not implemented the more basic tenets of public health for infectious diseases well, we are fortunate. Humans have a tendency to forget history’s lessons as crises abate, and this is where I fear we are learning the wrong lesson now.

A process that began many years ago with vaccine development on multiple fronts culminated in the amazing therapeutics that we are putting into arms now. It is an enormous success. We cannot assume that the next challenge will be addressed successfully with technology at the same pace. The time to fund disease surveillance, bolster scant public health infrastructure, and develop our ability to respond to novel viruses is now, before the next shiny object takes our focus away.

Learning the Wrong Lessons

As exhausting as the pandemic has been, hope is amassing in the form of vaccinations. Millions of 

coronavirus disease 2019 (COVID-19) vaccine

 doses, as once promised, were not immediately available upon US Food and Drug Administration authorization, but much has improved since then. Manufacturing capacity has increased, distribution has improved, and vaccination infrastructure has scaled.

The (conservative) goal of achieving 100 million vaccinations in 100 days of the Biden administration was achieved quickly, and as of this writing, the US has vaccinated over 3 million people daily the past few days.

The rapid pace of vaccination has not yet been matched by decreases in infection rates. In fact, as I write this, the US is in danger of a fourth surge. Cases in regions including New York City, New Jersey, and Michigan have been increasing. Variants are spreading as well, and experts have been particularly concerned about the more contagious B.1.1.7 variant that led a surge in cases in the United Kingdom.

Concurrently, governors in some states have been loosening restrictions on public health measures including mask wearing and limits on indoor dining, gym capacity, movie theaters, and others. This reaction to the rapid decline of cases in late winter has created a concerning overlap with rapid variant increases and pandemic fatigue.

We find ourselves at the odd juxtaposition of hope and despair. Even with the concerning trends occurring, I think it is time to buttress the positive and be straightforward with people about what being vaccinated enables them to do.

Messages in the media of potential decreased effectiveness of vaccines against some variants have a negative impact on the perception of vaccine utility. I have only anecdotal experience to support this, but I hear both vaccine advocates and skeptics saying that they probably will not work anyway, whether they are on the side that wants to receive it or not. The message that vaccines are effective against the majority of variant strains, including the B.1.1.7 strain set to take over in the US, is being lost.

How can we improve this? Let’s tell people the truth about how vaccination can change their daily lives. We can do this starting with the most low-risk situations and work our way through others, allowing people to make their own decisions based on their risk tolerance. People who are vaccinated can safely mingle indoors and unmasked with other vaccinated people. Indoor dining and gym attendance are much safer for vaccinated people. Really, any event is safer for the vast majority of vaccinated people, and we should be honest about that.

Gray areas are coming into better focus, and I believe we should tell the public what we are learning and allow people to make assessments independently. Several studies have shown lower rates of asymptomatic infection in vaccinated individuals and populations, implying that they are unlikely to infect others. It seems that many public health officials are afraid that telling people this will discourage mask use and distancing, but I believe that people have the bandwidth to process that mask mandates are necessary since there is no way of knowing who is vaccinated and who is not.

Of course, some vaccinated people will develop COVID-19, and that fact needs to be broadcast as well. Instead of a series of black-and-white, this-or-that scenarios, the model of degrees of risk and protection that public health authorities espouse needs reinforcement.

The Centers for Disease Control and Prevention took a step forward in March with updated guidance for what vaccinated people can do safely. It is important that this continues to be updated as new evidence emerges and not stay too conservative. Let’s tell people the truth about what vaccination represents. It is not just the path toward a safer society, it is the way to individual normalcy.

Our editor-in-chief writes on the role caregivers play in informing the public on the perks of a more vaccinated population.