Antimicrobial Stewardship

Ebola

HCV / Hepatitis

Blood-Borne Diseases

Climate Change

Coronavirus

Covid Vaccine Race

E. Coli

Food Safety

Listeria

Salmonella

Food Borne Infection / Food Safety

Fungal Infections

C. Difficile

H. Pylori

Norovirus

Gastrointestinal Infections

Healthcare Associated Infections (HAI)

Antibiotics

Immunizations

Vaccines

Prevention

Community-Acquired Pneumonia 

HAP / VAP

Influenza

Respiratory Infections

HIV / AIDS

PrEP

Sexually Transmitted Diseases

MRSA

Skin & Soft Tissue Diseases

Lyme Disease

ZIKA

Zoonotic & Vector-Borne Diseases

News

Media

Medical World News

Podcasts

Videos

Insights

Peer Exchange

News Network

Roundtables

Conference

Conference Coverage

Conference Listing

Publication

CME/CE

Partners

Resources

Interactive Tools

Special Projects

Contribute

Case Studies

Writers and Mentors

Subscribe

Contagion® is a fully integrated news resource for practitioners and specialists to assist with the identification, diagnosis, treatment, and prevention of infectious diseases.

About Us

Advertise

Editorial

Contact Us

Do Not Sell My Information

Privacy

Terms & Conditions

Contagion Live | Infectious Disease News & Expert Insights

Facebook

LinkedIn

Spotlight

Bench to Bedside With SIDP

C. difficile 

Clinical Corner

Hepatitis

RSV: A New Era in Prevention

Clinical

COVID-19

Food-Borne Infections

Healthcare-Associated Infections

Respiratory Diseases

Respiratory Syncytial Virus (RSV)

Video Series

Peers and Perspectives

1rem

Authors

Infectious Disease Physician at Cleveland Clinic.

Nabin K. Shrestha, MD, MPH, evaluates the Cleveland Clinic's Outpatient Parenteral Antimicrobial Therapy (OPAT) program, revealing its effectiveness in managing infections while highlighting challenges in monitoring and the impact of infectious disease pharmacists on patient outcomes.

Enhancing Outcomes in Outpatient Parenteral Antimicrobial Therapy

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

COVID-19 and Immunocompromised Individuals


On May 5, 2023, the World Health Organization declared an end to the global health emergency phase of COVID-19, the disease caused by the novel coronavirus SARS-CoV-2.

The virus is estimated to have infected more than 775 million individuals worldwide and is attributed to more than 7 million deaths.

 The landscape of COVID-19 has shifted throughout the years with the development and identification of pharmacologic agents used for prevention and treatment, as well as with the evolution of new SARS-CoV-2 variants.

The development of effective COVID-19 vaccines was paramount to the pandemic response, protecting against severe disease while helping to reduce new outbreaks of the virus.

 However, patients with compromised immune systems may be unable to receive adequate protection from the latest vaccinations and remain at risk of severe disease, owing to suboptimal antibody response and inadequate levels of SARS-CoV-2 neutralizing antibodies following vaccination.

This is best illustrated by results of an observational study to assess COVID-19 health outcomes of immunocompromised individuals compared with the general population in the United Kingdom using data from the National Health Service during 2022.

 Of nearly 12 million patients, only 3.9% were classified as immunocompromised, yet this cohort made up 22% of COVID-19 hospitalizations, 28% of COVID-19 intensive care unit admissions, and 24% of COVID-19 related deaths. Patients with more profound immunosuppressive conditions (eg, stem cell transplant within 2 years or solid organ transplant) were at the highest risk for adverse COVID-19 outcomes.

Seropositivity Following COVID-19 Vaccination in Immunocompromised Individuals


Several vaccine response studies have found decreased seropositivity in immunocompromised individuals compared with those without immune compromise. Haider et al conducted a prospective observational study to measure antibody responses and neutralization titers following COVID-19 vaccination in individuals with a range of immunocompromising conditions compared with immunocompetent health care workers (HCWs).

 The study enrolled 1271 participants (1099 immunocompromised and 172 immunocompetent HWCs) from April to July 2021. Seropositivity was lower among those with solid organ transplants (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) compared with immunocompetent HCWs (92.4%) (

< .01 for all). Neutralization titers were also significantly lower in immunocompromised individuals compared with immunocompetent HCWs. Additionally, in a systematic review and meta-analysis, Lee et al compared rates of seroconversion in immunocompromised individuals with those without immune compromise following the first and second doses of the COVID-19 vaccine.

 Seroconversion rates following both COVID-19 vaccine doses were significantly lower in organ transplant recipients and those with solid cancers, hematological cancers, and immune-mediated inflammatory disorders than the immunocompetent controls. Based on decreased rates of seropositivity following COVID-19 vaccination, it has been theorized that certain immunocompromised individuals may benefit from passive immunity through preventive monoclonal antibody infusions.

Monoclonal antibodies are synthetic proteins that mimic the immune system’s ability to fight off pathogens such as the SARS-CoV-2 virus. Anti–SARS-CoV-2 monoclonal antibodies have been utilized as prophylactic agents for COVID-19 in individuals with moderate to severe immune compromise.

Tixagevimab/cilgavimab (Evusheld) was the first monoclonal antibody authorized by the US Food and Drug Administration (FDA) for pre-exposure prophylaxis (PrEP) against SARS-CoV-2. Unfortunately, new SARS-CoV-2 variants emerged with reduced neutralizing susceptibility to tixagevimab/ cilgavimab, which led to the withdrawal of the Emergency Use Authorization (EUA) for tixagevimab/cilgavimab.

In March 2024, the FDA issued an EUA for pemivibart (Pemgarda) for use as PrEP against SARS-CoV-2 in individuals 12 years or older with moderate to severe immune compromise (

Pemivibart is a recombinant human monoclonal antibody that targets the spike protein receptor binding domain of SARS-CoV-2, thus preventing the virus from attaching to host cells. The FDA’s authorization came after the release of data establishing immunobridging for pemivibart, a study end point often used in monoclonal antibody clinical trials. Immunobridging for pemivibart was established by comparing serum antibody titer response at day 28 for variant JN.1 (the predominant variant in circulation at the time) with historical antibody titer data of adintrevimab against the Delta variant. It was determined that serum-neutralizing titers of pemivibart for JN.1 were consistent with those of previously authorized monoclonal antibodies against COVID-19.

In clinical studies, pemivibart was administered as a single 4500-mg intravenous infusion over at least 60 minutes.

 Repeat dosing every 3 months may be performed to ensure serum antibody titers persist at adequate levels. For patients who have been recently vaccinated against COVID-19, pemivibart should be administered at least 2 weeks after vaccination. Like previously authorized monoclonal antibodies for COVID-19, the medication should be administered only in settings where health care providers are accessible and able to treat adverse reactions, including anaphylaxis. It is recommended to monitor patients during and for at least 2 hours following completion of the infusion. In clinical studies, the most commonly reported adverse reactions included upper respiratory tract infection (6%), local infusion site reactions (5%), and systemic infusion-related and hypersensitivity reactions (4%); there were rare reports of anaphylaxis (0.6%).

As mentioned previously, JN.1 was the pre-dominant sublineage at the time of pemivibart’s authorization for use as COVID-19 PrEP. Since then, there has been a continual change in predominant COVID-19 variants and sublineages. The most recent data from the Centers for Disease Control and Prevent-ion’s national SARS-CoV-2 genomic surveil-lance system for the 2 weeks ending August 31, 2024, show predominant circulating JN.1 sublineages to be KP.3.1.1 (42.2%), KP.2.3 (16.4%), KP.3 (14.2%), and LB.1 (13.5%).10 Of note, sublineage KP.3.1.1 continues to spread and is now the predominant SARS-CoV-2 variant circulating in the US.

In recent weeks, at least 2 non–peer-reviewed studies assessing pemivibart’s in vitro neutralizing activity against the current circulating JN.1 sublineages, including JN.1.1, LB.1, KP.2.3, KP.3, KP.3.3, and KP.3.1.1 have been posted online.

 The results of these studies have raised questions regarding the effectiveness of pemivibart against select sublineages, most notably KP3.1.1. However, in response to the newly circulating variants, on September 3, 2024, Invivyd, Inc, issued a news release announcing its reference laboratory had confirmed continued neutralizing activity of pemivibart against LB.1 and KP.3.1.1.13 Details on pemivibart’s neutralization activity and 50% effective concentration (EC50) against KP3.1.1, LB.1, and other variants of interest have not yet been released but are likely to appear in an upcoming update to the medication’s prescribing information.

The news release suggested that pemivibart has maintained the ability to produce sufficient virus-neutralizing antibody titers against current circulating variants and remains an option for PrEP for those with moderate to severe immune compromise.

In August 2024, the Infectious Diseases Society of America published a clinical practice guideline update on the use of pemivibart as PrEP for COVID-19.

 The focused update suggests using pemivibart for PrEP in patients with moderate or severe immune compromise when predominant regional variants are susceptible (conditional recommendation with low certainty of evidence). The current EUA authorizes use of pemivibart for PrEP for as long as the combined national frequency of COVID-19 variants with substantially reduced susceptibility is 90% or less. With the recent statement from Invivyd, which suggested pemivibart maintained antibody neutralization activity against the current US predominant variant KP3.1.1, use of pemivibart for patients with moderate to severe immune compromise appears to be a practical option for patients unlikely to achieve protection from COVID-19 vaccines. Ongoing evaluation of pemivibart and its ability to produce sufficient neutralizing antibody titers against future COVID-19 variants will be needed.

Although vaccination remains the first-line prevention against COVID-19, some individuals with profound immunosuppression may not mount an adequate response to vaccination. Anti–SARS-CoV-2 monoclonal antibodies have been developed as prophylactic agents for COVID-19 in individuals with moderate to severe immune compromise. Currently, pemivibart is the only monoclonal antibody agent authorized for PrEP of COVID-19. As new SARS-CoV-2 variants continue to emerge, it is essential to evaluate pemivibart’s effectiveness against new variants.

Sarker R, Roknuzzaman ASM, Nazmunnahar, Shahriar M, Hossain J, Islam R. The WHO has declared the end of pandemic phase of COVID-19: way to come back in the normal life. 

 World Health Organization. 2024. Accessed September 9, 2024 https://covid19.who.int/

Moghadas SM, Vilches TN, Zhang K, et al. The impact of vaccination on COVID-19 outbreaks in the United States. 

 2021;73(12):2257-2264. doi:10.1093/cid/ciab079

Cheung MW, Dayam RM, Shapiro JR, et al. Third and fourth vaccine doses broaden and prolong immunity to SARS-CoV-2 in adult patients with immune-mediated inflammatory diseases. 

2023;211(3):351-364. doi:10.4049/jimmunol.2300190

Evans RA, Dube S, Lu Y, et al. Impact of COVID-19 on immunocompromised populations during the Omicron era: insights from the observational population-based INFORM study. 

 2023;35:100747. doi:10.1016/j.lanepe.2023.100747

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

Lee ARYB, Wong SY, Chai LYA, et al. Efficacy of COVID-19 vaccines in immunocompromised patients: systematic review and meta-analysis. 

. 2022;376:e068632. doi:10.1136/bmj-2021-068632

Evusheld. Fact sheet for healthcare providers. AstraZeneca. 2023. Accessed September 9, 2024. https://www.fda.gov/media/154701/download

Pemgarda. Fact sheet for healthcare providers. Invivyd, Inc. 2024. Accessed September 1, 2024. https://www.fda.gov/media/177067/download

Variants & genomic surveillance. Centers for Disease Control and Prevention. Updated September 17, 2024. Accessed September 17. 2024. https://covid.cdc.gov/covid-data-tracker/#variants-genomic-surveillance

Planas D, Staropoli I, Planchais C et al. Escape of SARS-CoV-2 variants KP.1.1, LB.1 and KP3.3 from approved monoclonal antibodies. 

. Published online August 21, 2024. doi:10.1101/2024.08.20.608835

Wang Q, Guo Y, Ho J, Ho DD. Pemivibart is less active against recent SARS-CoV-2 JN.1 Sublineages. 

. Published online August 13, 2024. doi:10.1101/2024.08.12.607496

Invivyd announces antiviral activity of VYD222 (pemivibart) against SARS-COV-2 KP.1.1 FLIRT & KP.3 variants. News release. Invivyd. June 14, 2024. Accessed September 4, 2024. https://investors.adagiotx.com/news-releases/news-release-details/invivyd-announces-antiviral-activity-vyd222-pemivibart-against

Bhimraj A, Falck-Ytter, Y, Kim AY, et al. Infectious Diseases Society of America Guidelines on the treatment and management of patients with COVID-19. 

 Updated August 12, 2024. Accessed September 10, 2024. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

New therapeutics offer some hope in this emerging market.

STAY PrEPARED: Understanding COVID-19 Pre-Exposure Prophylaxis

Obesity is a worldwide epidemic and widespread in the US, affecting over one third of the population. According to the Centers for Disease Control and Prevention (CDC), all US states have an obesity prevalence that exceeds 20% and obesity disproportionately affects certain geographic, socioeconomic, ethnic, and racial groups.

 Obesity is an independent risk factor for various types of infections as well as poorer infection-associated clinical outcomes.

Obesity has significant effects on the pharmacokinetics (PK) of various anti-infective drugs, including antifungals, with two of the most important being volume of distribution (Vd) and clearance. Vd generally increases with obesity as a result of increased adipose and lean tissue mass, particularly for lipophilic and highly protein bound drugs. This increased Vd may necessitate higher individual doses and, in particular, loading doses. Additionally, wider variability may be seen in overall exposure in obese patients for drugs dosed by weight, increasing risk of both over- and underdosing. Clearance may be increased in obese patients due to increased renal mass and renal blood flow. However, clearance can also be affected by comorbid conditions associated with obesity like chronic kidney or liver disease. Variations in the clearance of obese patients may affect maintenance dosing requirements.

 species and exhibit free-drug 24-hour area under the curve relative to the organism mean inhibitory concentration (

AUC/MIC targets were originally established in murine models then subsequently validated in retrospective human studies. Species-specific targets for echinocandins are 

This review aims to provide echinocandin dosing considerations in obese patients from the available literature.

Anidulafungin demonstrates linear PK with typical doses and protein binding approximating 99%.

 Anidulafungin is generally given intravenously (IV) as a loading dose of 200 mg followed by a maintenance dose of 100 mg daily for most indications and 200 mg daily for endocarditis or cardiac device infections.

 Anidulafungin clearance is unique amongst the echinocandins in that it undergoes non-hepatic spontaneous biodegradation.

Liu et al studied pooled patients from phase 2 and 3 clinical trials to assess the impact of obesity on clinical outcomes and anidulafungin PK parameters. Included for analysis were 262 patients. Weight was found to be modestly negatively associated with decreased AUC but not to a clinically significant degree. When comparing patients at the extremes of weight (40 kg vs. 150 kg), similar clinical efficacy and safety outcomes were observed.

 Hutton et al, in a retrospective study of 173 critically ill patients with candidemia treated with anidulafungin, found no difference in mortality between obese and non-obese patients.

Other PK analyses have shown variable results. Wasmann et al, in a single-dose PK study of 20 healthy obese and non-obese volunteers found that obese patients had a lower AUC due to increased clearance and Vd, though these patients did not have clinical disease.

 Similarly, Luque et al in 23 critically ill patients with invasive fungal infections and Dowell et al in 225 patients with serious fungal infections found weight was positively associated with clearance.

 Conversely, Liu et al in a population PK study of 454 patients with invasive aspergillosis and Bruggemann et al in a PK study of 36 critically ill patients with invasive fungal infections found no effect between weight on anidulafungin PK.

In summary, multiple clinical studies have found no difference in clinical outcomes between obese and non-obese patients treated with anidulafungin. Additionally, PK studies have had mixed findings and even those with detectable signals have acknowledged unclear clinical significance. Thus, the data does not appear to support dose adjustments of anidulafungin for obese patients.

Caspofungin generally displays linear PK with conventional doses and protein binding is high, exceeding 90%.

 Caspofungin is traditionally given as a loading dose of 70 mg IV once followed by a 50 mg IV daily maintenance dose thereafter. A higher dosing regimen of 150 mg daily is used for endocarditis or cardiac device infections.

 Caspofungin, similar to other echinocandins, is generally well tolerated even at higher doses (ie, 150 mg daily).

Ryan et al performed a post hoc pooled analysis of patients from phase 3 and 3 clinical trials of caspofungin to assess comparative efficacy and safety between obese and non-obese patients. In total, 1,134 patients across nine trials were evaluated, 163 (14%) were obese and 312 (28%) were overweight. The authors found no difference in clinical success and adverse drug reactions between obese and non-obese patients. This effect held true for studies of esophageal candidiasis, invasive candidiasis, and empirical therapy. There was a signal towards poorer outcomes in studies of invasive aspergillosis, though this is not a condition for which echinocandins are generally used as monotherapy.

Findings from PK studies of caspofungin in obese patients have been inconsistent. Two dose ranging studies conducted by Wurthwein et al and Muilwjik et al demonstrated either no impact or a detectable but clinically insignificant impact of weight on caspofungin clearance for doses between 50 to 200 mg daily. Of note, Wurthwein et al did find a 20% lower caspofungin AUC in patients weighing 80 kg vs those weighing 60 kg but this was not assessed to be sufficiently clinically meaningful given pharmacodynamic targets were still met. Both studies concluded that standard caspofungin dosing may be adequate for obese patients.

However, 2 subsequently published PK studies had opposing findings. van der Elst et al in an analysis of 20 critically ill patients found a positive association between weight (defined overweight as ≥80 kg) and caspofungin clearance as well as Vd. Based on these findings, the authors recommended a weight-based dosing regimen of 1 mg/kg/day.

 Martson et al in a study of 15 critically ill patients found a similar association (defined overweight as ≥120 kg) and recommended a loading dose of 2 mg/kg followed by a maintenance dose of 1.25 mg/kg/day to optimize AUC.

Taken together, there does not appear to be strong clinical evidence to support universally increasing dosing of caspofungin in obese patients. Obesity does not appear to impact clinical outcomes for patients with invasive and non-invasive candidiasis treated with caspofungin. That said, findings from PK analyses suggest risk of inadequate exposure, particularly in critically ill obese patients. Given the reliable safety profile of caspofungin and lack of dose-dependent toxicity in doses up to 150 mg daily, clinicians may consider a modest dose increase (eg, 70 mg daily) on a case-by-case basis in critically ill patients with severe candida infections receiving 50 mg daily dosing. A referenceable weight cutoff is used by the European Medicines Agency, which recommends using a maintenance dose of 70 mg daily (instead of 50 mg daily) in patients weighing 80 kg or greater.

Micafungin, the most commonly used echinocandin in clinical practice, exhibits linear PK and has high protein binding at >99%.

 PK/pharmacodynamic (PD) targets have been defined in patients with invasive candidiasis or candidemia based on AUC/MIC ratio.19 Micafungin is generally dosed at 100 – 150 mg IV every 24 hours with 150 mg designated for esophageal candidiasis. Data from two randomized, controlled phase 3 clinical trials found an AUC/MIC ratio breakpoint between 5,000 and 12,000 to have a 98% success rate for all 

Only one study has assessed the impact of obesity on micafungin clinical effectiveness.

 In this retrospective cohort study of 132 adult patients, no significant difference in clinical improvement or all-cause mortality was observed between obese and non-obese patients who received micafungin or caspofungin. The authors concluded further research in prospective, multicenter, larger study populations is needed.

While only one study assessed clinical outcomes, six PK studies have been completed that will be briefly summarized.

 Of these studies, four recommend micafungin dose increases with variations on the use criteria. Gumbo et al evaluated 62 hematopoietic cell transplant patients and concluded that patients with weight > 66.3 kg had increased clearance and decreased AUC, thus recommending 150 mg/day if above this weight cutoff.

Interestingly, while providing a cutoff based on weight, the findings were lower than obesity definitions. This could be augmented renal clearance due to the population or other factors that impact PK discussed later in the review. Hall et al utilized PK data from 36 healthy volunteers and recommend, similarly to Gumbo et al, dose increases in patients with weight 

 66 kg. Interestingly, they found a poor correlation between BMI and clearance of micafungin.

 Maseda et al performed a PK/PD study to evaluate probability of micafungin AUC/MIC target attainment in obese and morbidly obese ICU patients. BMI for all patients was > 45 kg/m2. Upon Monte Carlo simulation, the authors showed that the standard 100 mg micafungin dosing provided inadequate coverage for 

species. They recommend specific dosing based on 

, they recommend 150 mg/day for obese patients up to 115 kg and 200 mg/day in patients over 115 kg. For 

, the recommendation is 200 mg/day for obese patients up to 115 kg, but no recommendation for patients > 115 kg.

 Lastly, Wasmann et al investigated 24 healthy volunteers with BMI > 40 kg/m2 and found increased clearance, Vd, and low AUC. The following recommendations were provided in order to reach micafungin’s PD target: for patients > 125 kg and infected 

species with a micafungin MIC of 0.016 µg/mL provide a dose of 200 mg/day; while if the MIC is 0.032 µg/mL, increase the micafungin dose to 300 mg/day.

Controversially, Tabata et al and Lempers et al both performed PK studies and concluded micafungin dose increases were not necessary.

 Tabata et al evaluated 179 patients and healthy volunteers and found that increasing weight was not associated with a reduction in micafungin exposure.

 Similarly, Lempers et al conducted a small PK study of 20 ICU patients and found micafungin PK values including clearance, Vd, and AUC, were not impacted by weight or BMI. 

In summary, the majority of the studies have shown lower exposures of micafungin in obese patients, but the one available clinical study found no impact on clinical outcomes reported. Clinicians can utilize these studies to tailor micafungin dosing to their patients' characteristics such as weight and infecting 

species, however, further research on patient outcomes is needed.

Rezafungin is a novel echinocandin with a prolonged half-life of ~133 hours allowing for extended-interval dosing; the approved dosing scheme includes a 400 mg loading dose IV followed by 200 mg IV weekly infusions. Few studies are currently available, however a poster abstract presented at IDWeek 2020 by Vazquez et al utilized STRIVE Phase 2 study data to evaluate outcomes stratified by BMI (< 30 or 

 Overall response, mycological response, and investigator assessment of clinical cure was similar between the two groups with no concerning safety trends observed. However, following one dose of rezafungin 400 mg, the ranges of AUCs by BMI category observed a minor mean difference of ~20%, lower for those with BMI 

Obesity significantly impacts the pharmacokinetics (PK) of antifungal drugs like echinocandins, including volume of distribution (Vd) and clearance. However, despite these PK differences, current clinical evidence generally does not support the need for universal dose adjustments in obese patients. Clinicians should consider personalized dosing based on patient characteristics, infection severity, and specific drug properties due to echinocandins' favorable safety profiles.

Nabin K. Shrestha, MD, MPH

Articles

Latest Updated Articles