#441 More Clinical Pearls (New antibiotics, syphilis, heart disease, cirrhosis, lots more!) from ACP #IM2024 - The Curbsiders (2024)

Audio

Video

Transcript available via YouTube

More clinical pearls from ACP #IM2024, including emerging infectious diseases in the US (malaria, dengue, super gonorrhea, and a resurgence of syphilis), new C. diff treatments, coagulopathy and cirrhosis, fatty liver disease, HFpEF, peripheral arterial disease, Lp(a) and ApoB, CAR T-cells for autoimmune disease, SGLT2i for gout, and hematology updates. Paul and Watto are joined by Drs. Nora Taranto, Beth Garbitelli, and of course Chris “The Chiu Man” Chiu.

Claim CME for this episode at curbsiders.vcuhealth.org!

Patreon | Episodes | Subscribe | Spotify | YouTube | Newsletter | Contact | Swag! | CME

Show Segments

• 00:00 Tropical Diseases: Resurgence of Malaria and Dengue Fever
• 03:44 Infectious Diseases: Syphilis Rates and New Treatments for C. diff
• 08:28 Coagulopathy and Cirrhosis: Managing Hemostasis and Portal Vein Thrombosis
• 11:34 Fatty Liver Disease: Risk Stratification and Treatment
• 14:59 Cardiology Updates: Cardiovascular Kidney Metabolic Syndrome
• 31:03 New Medications for Hypertension
• 32:54 Renal Denervation and Hypertension
• 33:51 Lp(a) Drugs and Their Potential
• 36:01 Peripheral Arterial Disease and Claudication
• 38:10 SGLT2 Inhibitors and Gout
• 41:50 APO-B and LDL Cholesterol
• 42:45 Secondary Hypogonadism and Head and Neck Radiation
• 45:30 VEXAS: A Genetic Autoimmune Condition
• 49:08 Obesity-Induced Leukocytosis
• 52:49 CAR T-Cell Therapy in Rheumatologic Diseases

Infectious Diseases Pearls

(Re)emerging Pathogens: New Bugs on the Rise w/ Dr. Heather Yun MD and

Update in Infectious Disease w/ Dr. Victoria Burke MD, Dr. Fred Lopez MD

Concerning drug-resistant pathogens, such as candida auris and acinetobacter baumannii, are growing in prevalence across the United States (Forsberg 2019, Lyman 2023,Kyriakidis 2021, Cain 2023). Per Dr. Yun, you can consider candida auris infection when other cases have been identified in the unit or patients had overnight stays in hospitals abroad in the past year. She said that some automated methods will sometimes misidentify candida auris, so have higher suspicion if you’re seeing increased “unidentified” candida infections in your hospital. Some data indicate that there are common risk factors, such as living in a long term care facility, that raise a patient’s risk for carrying a carbapenem-resistant acinetobacter baumannii (known as CRAB) and/or candida auris (Harris 2023). A new drug for CRAB is sulbactam-durlobactam, recently studied in the ATTACK Phase 3 trial in combination with imipenem-cilastatin (Kaye 2023).

And unfortunately, old bugs are back. The USA was certified as malaria-free in 1970. Sadly in 2023, there were locally acquired cases of plasmodium vivax and plasmodium falciparum in Florida, Texas, and Arkansas. Mosquito populations are thriving in increasingly warm temperatures. Perhaps more concerningly, the United States is having locally acquired Dengue Fever. Per Dr. Yun, there were 176 local cases in Florida in 2023 and 1,025 in Puerto Rico (CDC ArboNET). Globally, cases are also increasing. In 2023, there was a record of 4.5 million cases, expanding areas of transmission. (PAHO/WHO 2024).

And vibrio vulnificus infectious have increased on the eastern seaboard 8x from 1988-2018. The geographic range is moving northward at 48 km/year, with severe and fatal infections reported from North Carolina, to New York and Connecticut (CDC 2023).

Syphilis rates are rising globally and domestically (CDC 2023, CDC 2023) Per Dr. Yun: “Syphilis rates are as high as they have been since antibiotics were discovered.” Any sexually active person is at risk. Suspected underlying etiologies for worsening syphilis cases, includes closure of public health clinics, declining clinic visits, and diversion of public health resources towards pandemic mitigation. In a review of syphilis cases reported from 2022 about 36.8% had no/non-timely testing, 11.2% had no or undocumented treatment, 39.5% had inadequate treatment (CDC 2023, CDC 2023). Among those with timely testing, ⅔ had inadequate treatment and rates of inadequate treatment rose from 2015 to 2022 (CDC 2023). While penicillin still works excellently against syphilis (check out Dr. Tony’ Breu’s fantastic tweetorial on this phenomenon), there unfortunately is a shortage of benzathine penicillin G.

Drug-resistant STIs are of increasing concern, especially multi-drug resistant gonorrhea. The first US case of MDR/ceftriaxone-resistant gonorrhea was identified in southern Nevada in 2019 (CDC 2020). A new antibiotic in development for this is zoliflodacin, an oral antibiotic that halts DNA synthesis by inhibiting type II topoisomerase(Taylor 2019). A phase 3 study demonstrated a cure rate of 90% and minimal adverse events with this new agent (SEC Filing 2023). Zoliflodacin could be a promising treatment modality for urogenital gonorrhea, with full results coming within the next year and then, hopefully, FDA approval,A per Dr. Taylor.

Another new antibiotic on the horizon for complicated staph aureus bacteremia is ceftobiprole. A recent study found it was non-inferior to daptomycin (Holland 2023), and it was just approved in April 2024 and likely will hit the market soon.

Regarding c.diff treatment, new therapies are coming down the pipeline with microbiome reconstitution via live biotherapeutic products. Filtered liquid microbiota suspension prepared from human donor stool RBX2660 (Rebyota) was FDA approved in 2022. It is administered as retention enema given after antibiotic course, and in the PUNCH CD3 study led to decreases in c.diff recurrence compared to placebo (30 vs 43%, although notably use ofPCR testing might have led to higher reported c.diff cases ). Another medicine is SER-109 (Vowst) which was FDA approved 2023. It is a PO treatment made with ethanol cleansed spores! Use in one study was associated with decrease in c.diff recurrence rates compared to placebo (12 vs. 40%), using stricter diagnostic criteria (Feuerstadt 2022, Cohen 2022). Both medications are quite expensive per wholesale pricing that was quoted during the conference.

In Multiple Small Feedings of the Mind w/ Dr. Ali Rezaie (GI), Dr. Megan Kamath (Cardiology), and Dr. Daniel Hunt (Hospital Medicine)

Dr. Rezaie talked about C.Difficile infection and the high rates of recurrence (Song 2019) even after one episode, with recurrence rates of 20-30% after the first episode, 40-50% after a second episode, and >60% after a third episode. First line recommended therapy remains oral vancomycin or fidaxomicin, but Dr. Rezaie also spoke about new therapies coming down the pipeline for secondary prophylaxis, including Bezlotoxumab (Wilcox 2017), which is a monoclonal antibody against C.Diff Toxin B. Bezlotuxumab is given as a single intravenous infusion and decreases absolute recurrence by around 10% versus placebo. Bezlotoxumab is typically given as secondary prophylaxis in combination with oral antibiotic therapy for C.Diff, not by itself, but it is quite well tolerated.

Cardiology Pearls

Multiple Small Feedings of the Mind w/ Dr. Ali Rezaie (GI), Dr. Megan Kamath (Cardiology), and Dr. Daniel Hunt (Hospital Medicine)

–Cardiology Clinical Pearls w/ Dr. Megan Kamath

Dr. Kamath discussed SGLT2 inhibitors moving to first-line therapy in the HFpEF guidelines (Kittleson 2023) based on the DELIVER and EMPEROR-PRESERVED trials. Based on the STEP-HFpEF trial, look for future guidelines that will likely include semaglutide for heart failure.

Each LDL particle has an associated Apolipoprotein B (ApoB) particle attached, with levels above 130-140 considered high, and some thought that ApoB levels may be more reliable than LDL levels, which can vary in size and density. Extremely high Lp(a) (lipoprotein(a)) levels are associated with increased cardiovascular disease risk. Multiple drugs that lower Lp(a) now exist (see Curbsiders #361), but we don’t yet know if they prevent major adverse cardiac events. Dr. Kamath points out that the 2019 European (Table in section 5) and Canadian guidelines already advocate checking ApoB and Lp(a) and this is likely to become common practice in the US, eventually. Dr. Williams (#america’s pcp) is skeptical about this practice and what to do with the information. *Note: both sets of guidelines recommend checking Lp(a) at least once, and this is consistent with advice from Dr. Michos in Episode #361.

Update in Cardiology w/ Dr. Clyde Yancy

A new entity has been described in the literature and it is Cardiovascular-Kidney-Metabolic (CKM) Syndrome–a systemic disorder characterized by pathophysiologic interactions across the kidneys, the cardiovascular system, and metabolic risk factors which lead to multi-organ dysfunction and high cardiovascular event rates. A recent synopsis of the evidence and management of CKM Syndrome from the AHA was published in Circulation in late 2023 (Ndumele 2023). In addition, the AHA’s CKM Scientific Advisory Group developed the PREVENT (Predicting Risk of CKD Events) equations to better assess the risk of CVD. The PREVENT equations are not only sex-specific but also race-free and incorporate traditional risk factors like smoking, blood pressure, lipid levels and diabetes (with Hba1c), as well as renal specific factors like eGFR and urine albumin-to-creatinine ratio. Most interestingly, you can input a Zip Code if you have it to estimate social deprivation index (SDI).

What are some newer antihypertensives on the horizon? The KARDIA-1 Trial was a phase 2 trial looking at zilebesiran which is a novel RNA interference therapeutic that targets hepatic angiotensinogen synthesis. Administered subcutaneously at various doses and intervals, zilebesiran significantly reduced systolic blood pressure at 3 and 6 months compared to placebo. Notable adverse events included injection site reactions and mild hyperkalemia, affecting 16.9% of zilebesiran-treated patients. These results suggest that zilebesiran could be an effective antihypertensive option with up to 15 mmHg improvement in blood pressure with the convenience of quarterly or biannual dosing. This medication could potentially overcome lack of adherence to treatment (Schiffrin 2024) and might be used in combination with standard of care agents.

Renal Denervation may also show promise as an additional tool in the physician toolbox in management of hypertension. Dr. Yancy pointed out that several different Renal Denervation (RDN) Systems did receive FDA approval in November 2023. Early last year, RADIANCE II (Azizi 2023) looked at ultrasonography Renal Denervation’s (uRDN) effectiveness in hypertension management compared to sham. This study showed a significant reduction in daytime ambulatory systolic blood pressure by 6.3 mmHg. Dr. Yancy quoted his own Editor’s Note saying: “[t]he magnitude of blood pressure reduction attributable to uRDN approximates that of the addition of a single other drug class and is likely less than the addition of mineralocorticoid receptor antagonist therapy. Similarly, the individual and aggregate benefit of lifestyle modification equates and likely exceeds the reduction of blood pressure reduction attributable to uRDN. Nevertheless, many patients do not respond adequately to these combined efforts, and new pathways to blood pressure control are welcomed, provided efficacy and safety have been established”(Yancy 2023).

During Curbsider’s Episode #361 Advanced Lipidology with Erin Michos, we had talked about antisense oligonucleotides like Pelacarsen and siRNAs like Olpasiran to decrease Lp(a) levels. Dr. Yancy presented a study from November 2023 from JAMA on Lepodisiran which is another type of siRNA (Nissen 2023). Although it was a small trial of 48 participants, the study found that lepodisiran was well-tolerated and significantly reduced Lp(a) concentrations with the highest dose achieving up to a 94% reduction at day 337.

Chronic Peripheral Artery Disease for the Internal Medicine Physician w/ Dr. Anuj Gupta

Dr. Gupta notes that approximately 2 million Americans have reduced quality of life from claudication, and 10 times that number have asymptomatic disease. Men Are more likely to complain about symptoms of claudication, but prevalence of peripheral artery disease (PAD) is similar between genders (Pabon 2022). Major risk factors include tobacco use, diabetes, hypertension, and hyperlipidemia.

While managing symptoms is obviously important, it’s also important to remember that PAD is often accompanied by other atherosclerotic cardiovascular disease. 40-60% of patients with intermittent claudication have concomitant coronary artery disease and 25-50% also have cerebrovascular disease. This should prompt very aggressive risk factor modification. Even patients with mild PAD are three times as likely to die from a heart attack or stroke compared to patients without PAD. Critical limb ischemia carries a particularly dire prognosis, with about a 20% mortality rate by one year after initial intervention (Teraa 2016).

Tobacco use has a dose-dependent association with development of PAD. Conversely, tobacco cessation can reduce the risk of progression of PAD to critical limb ischemia. Cessation also reduces severity of claudication and reduces chest discomfort. Also, you live longer (Behrooz 2023). So yes, help your patients to quit smoking.

GI/Hepatology Pearls

Coagulopathy of Cirrhosis w/ Dr. Christin DeStefano

Dr. DeStefano covered a wide swath of content around cirrhosis and coagulopathy, describing that hemostasis in cirrhosis is rebalanced, with changes occurring in both procoagulant and anticoagulant factors. It can therefore be hard to tell where on the pro-bleeding to pro-clotting spectrum these patients are. Labs such as PT/INR, PTT, Platelet count, and fibrinogen are not reliable in determining the risk of bleeding or clotting in these patients and should not be targets for repletion in clinically stable patients (“Don’t treat a number” is the general recommendation, here). Administration of blood products on the basis of labs can alter normal homeostasis in these patients and also cause volume shifts, worsening of portal hypertension, and lead to cirrhosis decompensation. Thromboelastography (TEG scans) can be more helpful in determining the balance of clotting factors and bleeding risk in these patients prior to high-risk surgeries, and can help with decisions about blood product supplementation in surgery.

Regarding thrombocytopenia of cirrhosis and procedural risk, Dr. DeStefano discussed that thrombopoietin-receptor agonists can be used when platelets are below 50,000 to increase platelet counts prior to planned procedures (Rose 2021). Two drugs are approved in this setting – lusutrombopag, avatrombopag–and should be started around 10-14 days before procedures, but can raise platelet counts substantially in this setting (Roberts 2023).

What about Portal Vein Thrombosis in patients with cirrhosis? Dr. DeStefano talked about acute versus chronic PVT, focusing mostly on acute PVT and emphasizing that if liver transplant for a patient is on the table, then the acute PVT should be treated aggressively if possible as the portal vein is important to maintain from a procedural perspective. This means treating with anticoagulation. Treating PVT also improves outcomes, decreasing the risk of variceal bleed (from decreases in portal hypertension and recanalization of the portal vein) and decreasing all-cause mortality in these patients (Loffredo 2017). Chronic PVT should be approached on a case-by-case basis, with balance of the risks and benefits of anticoagulation.

How to treat PVT? Well, as in many other disease entities requiring anticoagulation, the pendulum is moving towards DOACs in PVT in select patients. In a 2021 network meta-analysis, DOACs were noted to be superior to LMWH, VKA, and no-treatment for complete recanalization, without any bleeding or mortality differences noted (Ng 2021). Remember that in cirrhosis, it can be difficult to use INR to guide vitamin K antagonist dosing, so DOACs can be easier to use from this perspective.

Dr. DeStefano’s approach to DOACs, supported by the society guidelines (both the EASL 2022 and AASLD 2020 guidelines): Individualizing to the patient, you can generally use any DOAC if Child Pugh Class A, can use some DOACs with caution if Child Pugh Class B (considering dose-reductions and avoiding rivaroxaban), and should avoid them if Child Pugh C.

The duration of anticoagulation for PVT is typically 3-6 months of full-dose anticoagulation (Riva 2023), with imaging to evaluate the patency of the portal vein afterwards and with consideration of indefinite anticoagulation if patients are tolerating anticoagulation and have had no bleeding complications. Long-term treatment can decrease variceal bleeding risk going forward and help to manage the ongoing increased risk of VTE from cirrhosis. Dr. DeStefano stated that using lower dose anticoagulation can be appropriate after initial treatment for secondary prophylaxis.

Fatty Liver Disease for the Internal Medicine Physician w/ Dr. Elliot Tapper

Dr. Tapper framed this entire discussion around the concept that you should let your patient’s phenotype guide your work-up of their liver disease. The presence of serum antinuclear antibodies is common in nonalcoholic fatty liver disease, and their presence does not impact long-term outcomes (Younes 2020). Dr. Tapper’s initial work-up is to check hepatitis C serologies because we can treat it, hepatitis B serologies because we can prevent it, and alcohol history because it is far more common than we appreciate. One in four patients with presumed metabolic dysfunction-associated fatty liver disease was found to have excessive alcohol consumption by assessment with ethylglucuronide (Staufer 2022).

A good test to familiarize yourself with is the phosphatidylethanol test, a blood test that is able to detect chronic heavy alcohol use. It is worth knowing that retrospective analyses have shown that patients often differ between self-reported use and PEth levels, particularly in patients with moderate to heavy use (Al-Salmay 2024), and so it is important to take an accurate history and use this test in a non-stigmatizing way to forward patient care.

Dr. Tapper also reviewed a noninvasive algorithm for determining whether a patient is likely to have cirrhosis (citing his own paper, like a boss). This is done by assessing the Fibrosis-4 Index (FIB-4) score and liver stiffness (by elastography). If the patient has a high FIB-4 and high liver stiffness, they are likely to have cirrhosis and should be treated as such. If they have a high FIB-4 but low liver stiffness, this is unlikely to be cirrhosis, and underlying risk factors (e.g., alcohol and obesity) should be addressed. If their FIB-4 score is low, but they have high liver thickness, they require further testing and should proceed to biopsy to determine degree of fibrosis (Tapper 2023).

Clinical Pearls: Gastroenterology and Benign Hematology with Dr. Iris Wang (GI) and Dr. Rahma Warsame (Hematology)

Dr. Wang provided excellent guidance regarding counseling patients on GLP-1 agonist side effects, which include nausea, vomiting, bloating, diarrhea, and constipation. She described the tachyphylaxis phenomenon which occurs with use and counsels patients that symptoms tend to improve after prolonged use of GLP-1 agonists (Nauck 2011, Maselli 2021). Management for severe side effects including reduced dose, smaller more frequent meals, and blenderized meals. Dr. Watto’s practice is to institute a strong bowel regimen at the beginning of GLP-1 agonist treatment and counsel patients to expect constipation as a side effect.

Prior to procedures, the American Society of Anesthesiologists (ASA) recommends holding GLP-1 agonists 1 week prior to procedure if the patient is on weekly dosing. While data indicates there are likely reduced side effects with longer use, some may have prolonged delays in gastric emptying (Friedrichsen 2021, Hjerpsted 2018). Some suggest more caution around procedures if the GLP-1 is a new medication (Raven 2023) and raise concern about the need for modified fasting recommendations for certain procedures (Fujino 2023) or longer dose holds (Jones 2023).

Among the many Hematology Pearls presented, Dr. Warsame discussed nuances of iron deficiency anemia (IDA) diagnosis, noting that for individuals who have chronic or acute inflammation, the ferritin threshold should be higher than the 30 that is diagnostic of IDA otherwise. Dr. Warsame’s rule: if the Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) are elevated, then a ferritin < 100 can be diagnostic of Iron Deficiency Anemia (also supported in the 2019 ASH How To Guide for the Management of Iron Deficiency, Ning 2019).

She reminded us that a specific formulation of IV iron, Ferumoxytol, can transiently affect the diagnostic efficacy of MRIs (Schieda 2013), and may last for up to 3 months after administration.

She discussed leukopenia as well, and the relatively new entity of Duffy Absolute Neutrophil Count or Duffy-Null Associated Neutrophil Count (DANC). CBC reference ranges were developed for those of White European ancestry, and do not account for the Duffy Null phenotype, which is present in many of Sub-Saharan African descent, as well as many Black American and Middle Eastern individuals (as an evolutionary protective mechanism against malaria, as the Duffy receptor is the site of entry for P. Vivax). Duffy Null is associated with a lower neutrophil count, without a higher risk of infection, and therefore should be considered a normal variant, not a pathologic entity (Merz 2023). Testing for Duffy status can be done at any blood bank, in a similar way to ABO blood typing, and comes back in 1-3 days.

Individuals with low and stable absolute neutrophil counts should have Duffy Null testing sent to confirm status and do not need referrals to hematology, bone marrow evaluation, or treatment for their low neutrophil count as this is a normal variant. These individuals have historically undergone invasive testing, monitoring, and even treatment–and have also been excluded from clinical trials on the basis of their neutrophil count–a form of structural racism that is important to address by increasing awareness of DANC and testing for Duffy Null status.

And what about patients with chronic, persistent leukocytosis? It is possible to have a low grade, neutrophil predominant leukocytosis that is due to obesity (Herishanu 2006). The thought here is that the IL-6 present in adipose tissues induces white blood cell proliferation. It may also lead to insulin resistance, so if you see this chronic unexplained leukocytosis in a patient with obesity, you should be mindful of their increased risk of developing type 2 diabetes (Gu 2018).

Endocrine Pearls

Testosterone Therapy w/ Dr. Bradley Anawalt

Dr. Anawalt notes that weight loss can be helpful to increase testosterone in those with overweight/obesity. Even a 10% weight loss can increase serum testosterone levels by almost 60 ng/dL (Grossman 2017), and these data do not include patients who have started GLP-1a agents for weight loss. Conversely, obesity and aging synergistically decrease testosterone levels. So your takeaway here is to counsel your patients with a BMI > 25 to increase exercise, focus on a healthy diet, and try to achieve a 5-10% weight loss–and they may be able to increase their testosterone without additional medications.

Another pearl: head and neck radiation, despite being targeted, still has scatter effects. There is some data that this can cause secondary hypogonadism (Verdonck-de Leeuw 2021, Greenfield 2010).

Rheumatology Pearls

Updates in Rheumatology with Dr. Marcy Bolster

High serum urate levels predicted the recurrence of gout flares in a UK database of over 3600 patients with a mean 8.3 years follow-up. 95% of flares occurred in people with a baseline serum urate greater than or equal to 6 mg/dL (McCormick 2024). Dr. Bolster recommends a treat-to-target approach aiming for a serum urate level below 6, which is consistent with the ACR guidelines (Fitzgerald 2020).

SGLT2 inhibitors (SGLT2i) can lower urate and decrease the risk of developing gout in those without gout (Yokose 2024). McCormick et al. performed a comparative effectiveness trial of SGLT2i vs DPP4 inhibitors (DPP4i) in over 15,000 patients with prevalent gout and T2DM. Compared to DPP4i, SGLT2i lowered gout recurrence by 34% and reduced ED visits/hospitalizations by nearly 50% (McCormick 2023).

CAR-T cell therapy is an evolving treatment for rheumatologic and autoimmune disease and might even prove to be curative according to several small case series (Muller 2024).

VEXAS syndrome (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) is a hot topic in heme-onc and rheumatology. It is a syndrome caused by somatic (not germ-line) mutations in UBA1 in hematopoietic progenitor cells, with typical onset in later adulthood. Clinical manifestations include fever, chondritis (ears and nose), alveolitis, macrocytic anemia, venous thrombosis, neutrophilic dermatosis, vasculitis, and more (Grayson 2021).

Links

Included in the text above.

Goal

Listeners will recap even more top pearls from ACP #IM2024.

Learning objectives

After listening to this episode listeners will…

1. Feel generally warm and happy inside.
2. Feel like they attended ACP #IM2024.
3. Fall even deeper in love with Dr. Paul Nelson Williams, #AmericasPCP

Disclosures

The Curbsiders report no relevant financial disclosures.

Citation

Taranto N, Chiu C, Garbitelli B, Williams PN, Watto MF. “#441 More Clinical Pearls from ACP #IM2024”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast May 27, 2024.