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Guideline Updates for Infective Endocarditis, HAP, and VAP

Along with a 1 reported case in Massachusetts, the

New Hampshire Department of Health and Human Services (DHHS) has confirmed a person infected with eastern equine encephalitis (EEE) has died. The public health agency said the person was hospitalized due to severe central nervous system disease. The last reported human EEEV infection in New Hampshire was in 2014, when DHHS identified 3 human infections, including 2 fatalities. In the same statement, DHHS mentions there has been 1 confirmed case in Vermont this summer.

On August 16, the Massachusetts Department of Public Health (MDPH) released a statement discussing the confirmation of the first human case of EEE in the state this year. The confirmed case was discovered in an 80 year old man who was exposed to the vector borne disease in Worcester County. As a result, the risk level in the local communities of Douglas, Oxford, Sutton, and Webster has been raised to critical, and in Dudley, Northbridge, and Uxbridge the risk is increased to high.

Additionally, the neighboring communities of Auburn, Charlton, Grafton, Leicester, Mendon, Millbury, Millville, Southbridge, and Upton are now considered at moderate risk according to MDPH.

“This is the first time we have seen a person infected with EEE in Massachusetts since 2020,” Public Health Commissioner Robbie Goldstein, MD, PhD, said in a statement. “EEE is a rare but serious disease and a public health concern. We want to remind residents of the need to protect themselves from mosquito bites, especially in areas of the state where we are seeing EEE activity.

Though very rare, EEE is serious and a potentially fatal disease that can affect people of all ages. EEE is generally spread to humans through the bite of an infected mosquito. There were 12 human cases of EEE in Massachusetts in 2019 with 6 deaths, and 5 human cases with 1 death in 2020. There were no human cases of EEE in Massachusetts in 2021, 2022, or 2023.

EEE has a fatality rate of 33% to 70%, with most deaths occurring 2–10 days after the onset of symptoms.

In addition to a high mortality rate, long-term physical and mental complications, including permanent neurological deficits have been identified in many people who survive EEE.

Plymouth is approximately 40 miles south of Boston along the coast, and Worcester County is in the middle of the state, so the 2 areas are not in close proximity, but due to the elevated risk locally, the town of Plymouth decided to take action in response to outdoor parks. As of last Friday, all town public parks and fields are close daily from dusk until dawn.

“As Mass DPH has now elevated Plymouth’s EEE risk status to high, it is important to take extra precautions when outdoors and follow state and local health guidelines to avoid unnecessary risk to exposure to EEE. The health and safety of our community, residents, and visitors remain our priority,” Plymouth’s Commissioner of Health and Human Services, Michelle Bratti, said in a statement.

According to the Centers for Disease Control and Prevention (CDC) most people who are infected with the virus do not develop symptoms; however, for those that do, the date from the bite to the onset of the illness is 4 to 10 days. EEE can also result in fever or neurologic disease. The type of illness will depend on the age of the person and other factors. Those who are infected can develop meningitis.

There are no FDA-approved treatments for EEE and for patients who develop severe cases, they can be hospitalized to receive supportive treatment.

Over the weekend, MDPH detailed plans of spraying for mosquitos including aerially in areas of Plymouth County, and truck-mounted spraying in parts of Worcester County. As of Saturday, 10 communities in Massachusetts were raised to high or critical risk for EEE virus.

“The risk from EEE is high in parts of Plymouth County and critical in parts of Worcester County,” State Epidemiologist Catherine M. Brown, DVM, said in a statement. “In addition to recommending that people use mosquito repellent with an EPA-registered active ingredient and clothing to reduce exposed skin, we also recommend that evening outdoor events be rescheduled to avoid the hours between dusk and dawn. The mosquitoes most likely to spread EEE are most active during the dusk to dawn hours.”

There are preventative strategies to avoid EEE, and the MDPH has listed such measures 

For those who live in Massachusetts and want more information on EEE, it can be found 

 or by calling the DPH Division of Epidemiology at 617-983-6800.

1.NH DHHS Identifies Person Infected with Eastern Equine Encephalitis Virus in New Hampshire.The New Hampshire Department of Health and Human Services. August 27, 2024. Accessed August 28, 2024.
https://www.dhhs.nh.gov/news-and-media/nh-dhhs-identifies-person-infected-eastern-equine-encephalitis-virus-new-hampshire
2. State health officials announce season’s first human case of Eastern Equine Encephalitis in Massachusetts. MDPH. August 16, 2024. Accessed August 27, 2024.
https://www.mass.gov/news/state-health-officials-announce-seasons-first-human-case-of-eastern-equine-encephalitis-in-massachusetts
3.Plymouth to Close all Public Parks and Fields from Dusk to Dawn. Town of Plymouth. August 23, 2024. Accessed August 27, 2024. PDF.
4. Eastern Equine Encephalitis: Symptoms, Diagnosis, and Treatment. CDC. May 15, 2024. Accessed August 27, 2024.
https://www.cdc.gov/eastern-equine-encephalitis/symptoms-diagnosis-treatment/index.html
5. State officials announce plans to spray for mosquitoes in sections of Worcester and Plymouth counties due to EEE. MDPH. August 24, 2024. Accessed August 27, 2024. 
https://www.mass.gov/news/state-officials-announce-plans-to-spray-for-mosquitoes-in-sections-of-worcester-and-plymouth-counties-due-to-eee



The town of Plymouth decided to prohibit people from using the parks from dusk to dawn due to concerns over eastern equine encephalitis after a man contracted the rare disease in the state.

Concerns Over Mosquito-Borne Illness Causes Massachusetts Town to Create Curfew for Parks, Spraying in Counties

Jason Pogue discussed ceftolozane tazobactam’s effectiveness over Ceftazidime Avibactam, particularly in pneumonia patients, where it reduced the likelihood of recurrent infections.

Ceftolozane Tazobactam Linked to Increased Clinical Success in Pneumonia

The CACTUS study found a 10% improvement in clinical success with ceftolozane tazobactam (CT), which was linked to a 1.5-fold increased chance of clinical success. After adjusting for residual differences between the treatment arms, the likelihood of success was nearly twice as high with CT. Despite these findings, mortality rates were similar between the two arms, and both therapies, CT and ceftazidime avibactam (CZA) showed high rates of resistance development.

The study's primary outcome was clinical success at day 30, defined as the patient being alive, free from the initial infection (with no escalation of therapy), and without infection recurrence within 30 days.

with Jason M Pogue, PharmD, BCPS, BCIDP explained, "What we found in the study was that CT was associated with about a 10% absolute improvement in that variable of clinical success. They weren’t great rates of clinical success in either arm. It was about 61% in the CT arm and 52% in the CZA arm. And so, if you got CT you had about a one-and-a-half-fold increased chance of having clinical success. Once we adjusted for residual differences between the two groups, it was about a two-fold increased chance.”

Although this difference might seem modest, the results suggest that CT offered a 1.5-fold increased chance of success. After adjusting for residual differences between the two groups, the chance of clinical success was approximately twice as high for patients treated with CT. Pogue further emphasized, "I like the idea of a therapy being twice as likely to have a positive outcome, but I think it’s very fair to note that success rates still weren’t optimal. We still need to think about ways to further improve outcomes for these patients.”

Mortality rates were similar across both arms of the study. The 30-day mortality rates ranged between 20-25%, and 90-day mortality rates were around 35%. These rates align with findings from other studies on drug-resistant 

Regarding mortality, Pogue commented that there was no difference observed between the two treatment arms. “When we looked at mortality, we saw no difference between the two arms,” he said. “When we looked at resistance development, we saw high rates in both treatment arms. So neither therapy was perfect, but CT was associated with increased clinical success.”

The study’s findings were particularly notable in pneumonia patients, where CT showed a clear benefit in reducing recurrent infections. Pogue shared, “When we looked at the nitty-gritty of the data, it was really driven by pneumonia patients. That’s where you really saw the effect, and the biggest driver was actually being less likely to have recurrent pneumonia after therapy. And again, that’s very consistent with our hypothesis, because if there was a place we thought this PK/PD (pharmacokinetics/pharmacodynamics) was most likely to manifest itself as clinically meaningful, we would have thought it would have been in pneumonia patients.”

This observation confirms the importance of pharmacokinetics and pharmacodynamics in shaping treatment outcomes, particularly for infections that involve the lungs.

While the clinical success rates were not optimal, Pogue acknowledged limitations due to the severely ill patient population. Over three-quarters of the cohort were in the ICU, mechanically ventilated, and on vasopressors. The average age was over 60 years, and many patients had significant comorbidities, including solid organ transplants and immunosuppressive conditions.

Pogue explained, “This cohort was incredibly ill, complicated patients... you do, to some degree, just have a really complicated patient population. And you would expect for a hard outcome like mortality, infection is certainly a piece of the story, but there’s a lot of other things that are going on in this patient population as well.”

He noted that the severity of illness in these patients makes it difficult to show the impact of the drug on mortality, as a superior therapy can only significantly impact mortality rates in a “sweet spot” patient population. “The amount of mortality rates that can be impacted by a superior therapy is really going to be limited to a sweet spot patient population,” he explained. “They have to be sick enough where they are going to die if you don't effectively treat them, but not too sick, where they probably won’t get better either way.”

Pogue suggested that more patients are needed to truly test the mortality hypothesis and emphasized the importance of subgroup analysis for gaining insights into mortality differences. “If you take a look at the supplemental table 2, we actually look at mortality rates compared between the two arms for different subgroups of populations. There are some interesting little nuggets that I think are in there.”

Looking ahead, Pogue discussed the potential for more research in the area of resistant infections. While the current study provided valuable observational data, a randomized controlled trial would be ideal to further validate these results. “The key thing you want to do now is design a randomized control trial where you actually put patients in these two arms. Unfortunately, I think that’s probably pretty unlikely, just because you'd need someone to support such a trial. It’s a complex study to do, and the chances of that occurring are quite low, in my opinion.”

Pogue emphasized that the current evidence should still influence clinical practice. “I believe pretty strongly that this is probably the best evidence we’re going to get… and I do think it should influence how we treat these patients.”

Part 1 of our interview introducing The CACTUS study: 

CACTUS Study Compares Ceftolozane-Tazobactam vs. Ceftazidime-Avibactam for MDR Pseudomonas

Shields RK, Abbo LM, Ackley R, et al. 1109. A multicenter, observational study to compare the effectiveness of Ceftazidime-Avibactam versus Ceftolozane-Tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the United States (CACTUS). Open Forum Infect Dis. 2023;10(Suppl 2):ofad500.082. Published 2023 Nov 27. doi:10.1093/ofid/ofad500.082

Jason M Pogue, PharmD, BCPS, BCIDP  discussed ceftolozane tazobactam’s effectiveness over ceftazidime avibactam, particularly in pneumonia patients, where it reduced the likelihood of recurrent infections.

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, and his team discovered the klebsiella pneumoniae variant, KPC-31, 

Identifying a Novel Variant of Klebsiella Pneumoniae 

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, medical director for the microbiology laboratory at AdventHealth in Orlando, FL has a unique perspective. As someone who has been both a practicing physician in the past and a current laboratorian, he is able to utilize both his clinical and diagnostic experiences and apply them to individual cases. This dual professional experience helped him earlier this year when he and his lab team at AdventHealth were able to diagnose a novel variant of 

, called KPC-31, in a patient which was possibly the first case ever diagnosed in the state of Florida.

The detection of this mysterious and unusual pathogen was discovered utilizing various diagnostics tools including whole genome sequencing (WGS) as well as multi-locus sequence typing (MLST).

“We've been lucky enough in the last two years that we've been working with whole genome sequencing, which brings us a direct, rapid clinical tool for identification,” Alexander said. “But now we have it implemented as a clinical tool for identifying mycobacteria, fungi, and some bacteria,” Alexander said.

The case identifying the KPC-31 variant stems from a patient that they were familiar with at his institution who had previously battled 

After discovering the isolate, it was rapidly tested against ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam. Alexander and his team were surprised because the isolate was resistant to ceftazidime/avibactam, and susceptible to meropenem/vaborbactam, and imipenem/relebactam. He said they also found meropenem and imipenem were susceptible without inhibitors.

“We decided to do whole genome sequencing. And then after we did that, we started evaluating and the first thing that we did was ask what is the MLST of this strain? So, we found that it was strain 307 that is  hypervirulent, and has been reported both globally and in some regions in the US.”

Alexander sees the adoption of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) mass spectrometry in microbiology being an important tool because it can identify microorganisms within 24 hours. Along with identifying the pathogen, he stresses the importance of differentiating between the antimicrobial resistance and susceptibility in these cases. And knowing the organism before setting up susceptibility testing is a significant development.

“I seeing antimicrobial testing not only from the treatment perspective, but also from the perspective of having a more comprehensive screening. This is something that we've been talking with some of the manufacturers about to try to have this approach, because we want to make sure that we are able to account for those new challenges that constantly are arising.”

Lastly, he says it is important for good communication between pharmacists, other clinicians, and laboratory professionals to work together through challenging cases.

“If we know that we have a problem with a specific antimicrobial resistant organism, let's say 

being able to understand it phenotypically— what are the best agents that in vitro we know have clinical activity or indicated for, having that cumulative data can actually drive antimicrobial therapy before susceptibility tests are available,” Alexander said. “I think using cumulative data to create a laboratory algorithm can be triggered just by a specific pattern. We can also alleviate the over calls to the laboratory asking for additional testing, asking for confirmation, and the pharmacy and the physician can escalate treatment immediately.”

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, and his team discovered the klebsiella pneumoniae variant, KPC-31, in a patient by sequencing the entire genome through a series of different diagnostics, which not only led to identifying the strain, but to a greater understanding of its antimicrobial susceptibility. 

From Pathogen to Infectious Disease Diagnosis: Identifying a Novel Variant of Klebsiella Pneumoniae 

This week the panel weighs in on monoclonal antibodies in this patient population as well as important overall takeaways about COVID-19 therapies. 

COVID-19 Roundtable: Prophylaxis for the Immunocompromised  

For the immunocompromised there is limited efficacy to vaccines. In a mid-sized study published in the journal, 

, investigators found decreased COVID-19 vaccination seropositivity amongst immunocompromised populations vs nonimmunocompromised healthcare workers (HCWs).

“Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01),” the investigators wrote. 

In a Centers for Disease Control and Prevention (CDC) 

report, a study showed vaccination in this population was significantly reduced in terms of protection against hospitalization. “VE against COVID-19–associated hospitalization was 38% in the first 7–59 days after receipt of an updated COVID-19 vaccine dose and 34% in the 60–119 days after receipt of an updated dose,” the investigators wrote.

With limited efficacy in these populations, the development of other prophylactic modalities such as monoclonal antibodies have been advanced as a potential alternative.

Earlier this year, Invivyd’s monoclonal antibody, pemivibart (Pemgarda), received an FDA emergency use authorization for the pre-exposure prophylaxis (PrEP) of COVID-19 for both adults and adolescents at least 12 years of age, and weighing at least 40 kg (88.1 lbs) who are immunocompromised.

“I cared for a patient who had COVID for over a year, who was heavily immunocompromised, and I couldn't help thinking at the time, if we had something like this [monoclonal antibody] for them, it really would have changed their entire life,” said roundtable panelist Scott Roberts, MD, associate medical director of Infection Prevention, Yale School of Medicine. “I think providers and patients need to be aware that this is an option right now.”

Roundtable panelist James Wilson, DO, FACP, FAWM, CTropMed, continues to stress the importance of COVID-19 vaccination for everyone, but says these FDA-approved treatments have certainly helped in both the inpatient and outpatient settings. “The reason COVID seems so much better now is we can treat it.”

This is the fourth and final episode of our series. To view the whole series, go 

1.Haidar G, Agha M, Bilderback A, et al. Prospective Evaluation of Coronavirus Disease 2019 (COVID-19) Vaccine Responses Across a Broad Spectrum of Immunocompromising Conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS). 

. 2022;75(1):e630-e644. doi:10.1093/cid/ciac103
2. Link-Gelles R, Rowley EAK, DeSilva MB, et al. Interim Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccines Against COVID-19-Associated Hospitalization Among Adults Aged ≥18 Years with Immunocompromising Conditions - VISION Network, September 2023-February 2024. 

. 2024;73(12):271-276. Published 2024 Mar 28. doi:10.15585/mmwr.mm7312a5
3.Invivyd Announces FDA Authorization for Emergency Use of PEMGARDA (Formerly VYD222) for Pre-exposure Prophylaxis (PrEP) of COVID-19. Invivyd press release. March 22, 2024. Accessed August 27, 2024.
https://investors.invivyd.com/news-releases/news-release-details/invivyd-announces-pemgardatm-pemivibart-demonstrated-84-relative

the panel discusses therapies and care around inpatients including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and remdesivir.

COVID-19 THERAPY Roundtable: Addressing Inpatient Clinical Care

According to the Centers for Disease Control and Prevention, the week ending November 30, 2024, there has been a rate of 0.8 hospitalizations per 100,000 people, and this shows a good downward trend over the last few weeks.

Although the number of hospitalizations have decreased significantly since the beginning of the pandemic, there are waves where incidence rates increase and a number of people who are contracting severe cases of COVID-19 need to be hospitalized.

During the height of the pandemic and before the development of vaccines and therapies, there were therapeutic limitations and patients could be put on mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

ECMO was utilized more frequently in a time when there was not other treatments. And in some select cases, roundtable panelist James Wilson, DO, FACP, FAWM, CTropMed, says ECMO did show some benefit, and there might be some select situations where it might be warranted but overall he says treatment protocols have changed considerably since 2020.

“If they're breathing at 40 times a minute for more than an hour, you're going to have to do it [ECMO],” Wilson. “But now we have modalities to treat those patients.”

One of the treatments that emerged was remdesivir for inpatients with severe COVID-19.

“I triage COVID between requiring oxygen and not requiring oxygen,” said Scott Roberts, MD, associate medical director of Infection Prevention, Yale School of Medicine. “And then once you become severe enough to require it, we really start remdesivir as soon as we can in the inpatient setting. And we know from many studies at this point there are reductions in mortality in those who do receive remdesivir. We use it for all really severe patients.”

This is episode 2 of our 4-part series. Check back for future episodes.

Reference
1.COVID Tracker. CDC. Accessed December 10, 2024.
https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalization-network

In this week's episode, the panel discusses therapies and care involving inpatients, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and remdesivir.

COVID-19 Therapy Roundtable: Addressing Inpatient Clinical Care 

Jason M Pogue, PharmD, BCPS, BCIDP discusses the findings, pharmacokinetics, why ceftolozane-tazobactam may be the preferred choice for resistant infections, and more.

A newly published study, the CACTUS Study, compares the effectiveness of ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) in treating multidrug-resistant (MDR) 

 infections. The findings show that CT and CZA have similar clinical outcomes: 62% of CT-treated patients achieved clinical success, compared to 55% of CZA-treated patients. The overall 30-day mortality rates were also similar: 20% for CT and 19% for CZA.

In this first part of our interview with Jason M Pogue, PharmD, BCPS, BCIDP, clinical professor at the University of Michigan and investigator of the CACTUS Study we discuss the background and purpose of the study. The study involved 420 patients, with 210 matched pairs, ensuring robust statistical power to compare the two drugs’ efficacy.

Pogue discussed how CT and CZA are cephalosporins that have shown superior efficacy over older, more toxic treatments such as polymyxins and aminoglycosides, which have been previously used to treat resistant Pseudomonas infections. “Both of these agents are recommended in guidelines for the treatment of drug-resistant Pseudomonas. The reason they're included in these guidelines is that they have been shown to be superior to older treatments that were used before the availability of these novel cephalosporins.”

Before the CACTUS Study, some smaller studies compared CT and CZA, but these studies had significant limitations. Many had small sample sizes, inconsistent susceptibility testing, and heterogeneous patient populations. “Some of the studies haven’t routinely tested susceptibility to these two drugs, so you don’t even know whether or not they’re active all the time in patients who got it,” Pogue said.

Also, disease state could play a role in how patients respond to therapy. “Some disease states are more or less likely to respond to nuanced differences in therapies,” Pogue explained. For instance, if patients with urinary tract infections were included, any differences between the two drugs might not be observed, as both drugs concentrate well in the urine.

The CACTUS Study was designed to address these issues by focusing specifically on pneumonia and bloodstream infections, conditions where treatment could have a significant impact on patient outcomes. In addition, pharmacokinetics (PK) and pharmacodynamics (PD) differences between CZA and ceftolozane-tazobactam could influence treatment success, making these infection types ideal for comparison.

“We wanted to limit it to disease states where we thought therapy might have a big impact on outcomes,” said Pogue, adding that pneumonia was chosen due to these potential PK/PD differences. To ensure high-quality data, the study included 28 US sites with leading researchers in resistant gram-negative infections. “The reason we did that is because we were going to get good data, and that allows you to get significantly more numbers,” Pogue said.

One challenge with observational studies like CACTUS is dealing with biases such as indication bias or residual confounding, which can affect the interpretation of results. To minimize bias, the study used a matched-pair design. “For every CZA patient, they had a matched ceftolozane-tazobactam patient, and they were matched on severity of illness, infection type, and time to treatment initiation,” Pogue explained.

Patients treated with CT were more likely to receive longer infusions of the drug (≥3 hours), with 36% of patients receiving the prolonged infusion compared to just 19% of those on CZA (P=0.005). However, no significant differences were found between the two drugs regarding microbiologic failures, recurrent infections, or resistance development.

“We hypothesized that ceftolozane-tazobactam would be superior because of some of these PK/PD advantages,” said Pogue. “We adequately powered the study to show if there was a difference.” Despite the similar outcomes, the study’s robust design helps provide a clearer understanding of these two treatments and their comparative effectiveness.

Stay tuned for the next parts of our interview with Pogue, where we dive deeper into clinical success, mortality rates, treatment-emergent resistance, and more.

Elizabeth Leung, PharmD, BCPS-AQ ID

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