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petri dish with antibiotic discs

PIVMECILLINAM (PIVYA®), A NEW ANTIBIOTIC FOR UTI

Pivmecillinam (Pivya®), a penicillin-class antibiotic, was recently approved to treat female UTIs caused by Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus. Its effects were evaluated in a trial where 259 women with an acute uncomplicated UTI were randomized to pivmecillinam 185 mg three times a day for 3 days or cephalexin 250 mg four times a day for 7 days. Treatment success, defined as symptom resolution with a negative urine culture on Day 10, occurred in 72% of pivmecillinam-treated patients and 76% of those treated with cephalexin. Side effects are generally mild and include nausea (4.3%), diarrhea (2.1%), and vaginal yeast infection (1.8%). One precaution worth noting is that pivmecillinam contains pivalate, an acid that improves absorption but also depletes carnitine, a compound involved in muscle fatty acid metabolism. It should not be given to patients with carnitine deficiency or those receiving other carnitine-depleting drugs, including valproic acid, valproate, carbamazepine, and phenytoin.

New antibiotics are always welcome; however, pivmecillinam doesn't appear to improve on available therapies. Its thrice-daily dosing and higher cost make it less attractive than other options. In the study above, it had a 72% cure rate, similar to nitrofurantoin but less than the 90% or greater rates seen with fluoroquinolones.


Prazosin + cyproheptadine for alcohol use disorder
shots of liquor
Animal studies have suggested that alcohol addiction may be caused in part by abnormal regulation of noradrenergic and serotonergic regions of the brain. The combination of prazosin, a noradrenergic alpha blocker used to treat hypertension, and cyproheptadine, an antihistamine with antiserotonergic activity, has been shown to reduce alcohol cravings in mice. To evaluate their effects in humans, researchers randomized 154 people with a baseline average alcohol consumption of 7.8 drinks/day to cyproheptadine + prazosin (2 different doses) or placebo. After 3 months, patients receiving cyproheptadine 12/prazosin 10 mg (high dose group) reduced their daily alcohol intake by 3.4 drinks compared to 2.4 in the placebo group.

tablets with ECG

STUDY EVALUATES BETA-BLOCKERS IN MI PATIENTS WITH PRESERVED EF

In the past, beta-blockers were routinely recommended for patients with myocardial infarction (MI), regardless of heart failure status. This guidance was based on studies primarily performed in the 1980s, which showed beta-blockers improved survival across a broad range of patients. Since then, mechanical (e.g., PCI) and pharmaceutical advances, along with earlier detection and treatment, have improved MI outcomes, and the effects of beta-blockers in contemporary care are unknown. Studies have shown they have an indisputable benefit in patients with reduced ejection fraction (EF), but their role in patients without heart failure is less clear. To answer these questions, researchers randomized 5020 patients with acute MI who had undergone coronary angiography and had an EF ≥ 50% to beta-blocker therapy (metoprolol or bisoprolol) or no beta blocker. After a median follow-up of 3.5 years, the primary outcome, a composite of death from any cause or new myocardial infarction, was not significantly different between groups (beta-blocker 7.9%, no beta-blocker 8.3%, p=0.64).

Medical advances have improved MI detection and treatment so that myocardial damage is often limited and heart failure is prevented. This study answers an important question, showing that beta-blockers are not routinely beneficial in CAD patients without heart failure. Recent AHA guidelines, which only recommend beta-blockers in CAD patients with an EF of less than 50%, are consistent with these findings.
FTC bans noncompete clauses
On April 23rd, the Federal Trade Commission (FTC) announced it plans to ban noncompete clauses, agreements many healthcare providers practice under. According to federal law, the ban will take effect 120 days after it is published in the Federal Register. However, the final say will not likely come for some time, as it's unclear whether the FTC has the authority to do this, and legal challenges have already been filed. I found myself under one in my last job, and foolishly, I didn't read it until I was unhappy and thinking of leaving. It was very restrictive, prohibiting me from working within a 25-mile radius for two years, essentially leaving me unemployed unless I was willing to drive hours every day. Fortunately, my employer had already broken other parts of the contract, so I was able to get out of it.

As far as healthcare is concerned, I can see arguments on both sides. A medical group doesn't want to fund a practice startup just so the provider can leave and open a clinic across the street once he acquires a full slate of patients. Conversely, a business threatening an employee with a lawsuit if they try to work in the same city after quitting seems draconian and undemocratic.

Even though I was miffed by my clause (truthfully, at myself for not reading it), at the end of the day, this is America, and I believe an individual and a business should be allowed to enter into an agreement and be bound by its terms. Since my ordeal, I've quizzed other providers about their contracts and have yet to find one who could tell me what their noncompete says. I suspect this is probably a big reason employers are able to impose them, as many healthcare providers, including myself, are not good at reading their contracts and considering the long-term consequences.

paxlovid box

IF IT'S COVID, (you probably don't need) PAXLOVID

Paxlovid, an antiviral containing nirmatrelvir and ritonavir, received an emergency use authorization to treat COVID-19 in December 2021 based on results of the EPIC-HR trial, where it lowered the absolute risk of COVID-19-related hospitalization or death by 5.54% in unvaccinated patients with risk factors for severe COVD. Since then, a large portion of the population has been vaccinated, and the virus has evolved, raising questions about its effects on newer strains in vaccinated patients. To address these issues, the drug's manufacturer conducted the EPIC-SR study (N=1296) that compared Paxlovid to placebo in vaccinated subjects with risk factors for severe disease and unvaccinated subjects without risk factors (57% of participants had been vaccinated). At the study's conclusion, the primary outcome, median days to symptom resolution, was not significantly different between Paxlovid and placebo (12 vs 13 days, respectively, p=0.60). A secondary outcome that included COVID-19 hospitalizations and overall mortality was also nonsignificant.

The EPIC-SR study found that Paxlovid was not beneficial in a mostly vaccinated population. Notedly, vaccinated was defined as having received a complete primary series with or without boosters. Half of the subjects had one or more risk factors for severe COVID, although this designation is soft, considering BMI > 25 and hypertension were two of the top qualifying conditions. According to the Pfizer website, 75% of Americans have one or more "severe" risk factors. Obese patients (18%) and those older than 65 (5%) were underrepresented, so it was not possible to judge its effects in the most susceptible patients.

In summary, Paxlovid does not improve outcomes in vaccinated and unvaccinated subjects with mostly modest risk factors for severe disease. Providers can safely reserve its use for patients with significant comorbidities, including morbid obesity, elderly (> 70), marked respiratory disease, and immunosuppression.
Resmetirom (Rezdiffra™) - The first drug approved to treat NASH
rezdiffra label
Resmetirom, a thyroid hormone receptor-beta (THR-β) agonist, received accelerated FDA approval to treat nonalcoholic steatohepatitis (NASH) in patients with moderate to advanced liver fibrosis. In NASH, hepatic THRs are impaired, leading to fatty acid accumulation and fibrosis. Resmetirom stimulates THR receptors, promoting triglyceride metabolism and reducing hepatic adiposity. The effects of resmetirom on NASH-induced liver disease were evaluated in the ongoing MAESTRO-NASH trial (N=966), where 52-week interim results showed that it was superior to placebo for the two primary outcomes, NASH resolution (30% vs 9.7%) and fibrosis improvement (26% vs 14.2%). The full trial is planned for 54 months and will include the following endpoints: mortality, hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal bleeding), and liver transplant.

Resmetirom is given as a once-daily tablet with weight-based dosing. Common side effects are diarrhea (33%), nausea (15%), pruritus (10%), vomiting (8%), and constipation (8%). Notable drug interactions requiring dose adjustments include certain statins and CYP2C8 inhibitors.

In the past, I've been reluctant to pursue extensive NASH workups since the only real treatment was weight loss. Now, I have to give it more consideration. The main challenge is identifying patients who will benefit the most from resmetirom, as it is expensive, and the majority of NASH patients do not progress to cirrhosis. For primary care doctors, selecting appropriate candidates may follow the following sequence: (1) Calculate a FIB-4 score; (2) If FIB-4 is > 1.3, order an ELF test; (3) If ELF is > 7.7, order a liver biopsy; (4) if F2 or F3 fibrosis is present, start resmetirom. Given its projected cost of $47,400 per year, it's likely insurance companies will require prior authorization that includes proof of liver fibrosis.

NEWS IN BRIEF

Does d-mannose prevent UTIs?

woman with uti
D-mannose, a sugar found in many fruits that theoretically blocks bacteria from adhering to the urinary epithelium, has been found to prevent recurrent UTIs in unblinded studies. To get a definite answer, researchers randomized 598 women with recurrent UTIs (2 in the previous six months or 3 in twelve) to d-mannose 2 grams daily or placebo. After 6 months, there was no significant difference in the incidence of UTIs between the d-mannose group and placebo (51% and 55.7%, respectively, p=0.26)

AASLD proposes new name for fatty liver disease

fatty liver
If you find the terms "fatty" or "nonalcoholic" offensive, you will be relieved to know the American Association For the Study of Liver Diseases (AASLD) has taken up the cause to protect us all from these divisive labels. In a recent publication, they recommend abolishing the terms "nonalcoholic fatty liver disease" and "nonalcoholic steatohepatitis" because they are "stigmatizing" and replacing them with "metabolic dysfunction–associated steatotic liver disease," or MASLD for short. They claim, "The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification." A recent study in the JAMA already adopted the new name (see link below).

Over-the-counter birth control now available

Opill box
Opill®, a progestin-only birth control pill containing norgestrel, is now available, making it the first oral contraceptive sold over-the-counter in the U.S. A one-month pack retails for $19.99, and a three-month pack costs $49.99. It can also be purchased directly from the manufacturer, Perrigo, on their website. The pill should be taken at the same time every day, and the box instructs patients to use a barrier method for 48 hours if they are more than 3 hours late in taking it. Another company is currently in talks with the FDA about marketing an over-the-counter combined oral contraceptive.

Combination inhaler with albuterol and budesonide available

asthma inhaler
Inhaled corticosteroids (ICS), short-acting beta agonists (SABA), and long-acting beta agonists (LABA) are the most commonly prescribed asthma treatments. Recent studies have found that as-needed ICS/LABA therapy is equal or superior to a daily ICS and as-needed SABA, contradicting traditional views that an ICS must be used daily to be effective. Recent GINA guidelines also recommend as-needed ICS/LABA therapy for most asthmatics. Keeping with the trend, Airsupra, the first inhaler to combine a SABA with an ICS, has been approved. It contains albuterol and budesonide and comes in a canister with 120 inhalations. Dosing is two puffs as needed with a max of 12 in 24 hours. It was superior to albuterol as a rescue inhaler in a double-blind study (N=3132) where participants were receiving maintenance ICS therapy.

"Wellbutrin DM" hits the market

bottle of tablets
A new antidepressant called Auvelity combines bupropion, a widely prescribed dopamine-norepinephrine reuptake inhibitor, with dextromethorphan, a cough suppressant that inhibits NMDA receptors. One caveat of the combination is that bupropion inhibits dextromethorphan's metabolism, increasing its exposure. Auvelity comes in one strength (dextromethorphan 45 mg/bupropion 105 mg), and maintenance dosing is one tablet twice daily. A very small 6-week study (N=87) found that it was superior to bupropion monotherapy for treating depression in adults. For those who are interested, GoodRx shows Auvelity costs more than $1000 for 60 tablets, while a one-month bupropion prescription and a bottle of dextromethorphan will set you back about $30.

NEW DRUGS

POPULAR BUT UNPROVEN

  • Meniscal surgery - It's one of the most common orthopedic procedures performed, but does it do anything?
  • CPAP for sleep apnea - Sleep doctors are on every corner it seems, but what are the benefits of diagnosing and treating sleep apnea?
  • Knee injections - these treatments are popular among orthopedists and primary care doctors, but are they effective?
  • Pneumonia vaccines in adults - vaccine manufacturers, the CDC, and Medicare want everyone to get a pneumonia vaccine, so they must be highly effective, right?

Xolair approved to prevent ige-mediated food allergies
peanuts with allergy sign
IgE antibodies have a propensity to attach themselves to mast cells and basophils, where they react with environmental antigens and stimulate the release of inflammatory mediators (e.g., histamine, leukotrienes). Reactions, which are marked by vasodilation, capillary permeability, and smooth muscle contraction, occur within seconds to minutes of exposure and are the cause of many difficult-to-treat conditions, including urticaria (hives), allergic asthma, allergic rhinitis, and anaphylaxis. Omalizumab (Xolair), a monoclonal antibody that binds IgE and blocks it from attaching to cells, was recently approved to prevent food allergies in adults and pediatric patients one year and older; it has been available since 2003 and carries indications for asthma, rhinosinusitis with nasal polyps, and urticaria. Its use in food allergies is based on a study that enrolled 180 patients (median age 7 years) with an allergy to peanuts and two or more of the following: cashew, milk, egg, walnut, wheat, or hazelnut. Patients received omalizumab every 2 to 4 weeks for 16 to 20 weeks, with dosing based on body weight and total IgE levels. The primary outcome was tolerance (i.e., no dose-limiting effects) of a ≥ 600 mg peanut protein oral challenge at the end of the treatment period. At the study's conclusion, 67% of omalizumab-treated patients met the primary endpoint compared to 7% in the placebo group. Results were similar for the six other food allergies in the inclusion criteria. Of note, patients with a history of food-induced severe anaphylaxis were excluded from the study.

Severe food allergies are frightening conditions, as affected individuals are often inadvertently exposed to their offending agent. Although the study was small and very high-risk patients were excluded, Xolair appears to offer some hope to patients and parents who live in daily fear of a life-threatening event.
Dual SGLT2/1 inhibitor approved for heart failure
pills for heart failure
Sodium-glucose cotransporter (SGLT) 1 and 2 are transport proteins in the apical membrane of the nephron that reabsorb filtered glucose and sodium in the proximal tubule. SGLT1 is also present in the small intestine, where it facilitates the absorption of glucose and sodium from the lumen. SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) block renal SGLT2 and are approved to treat diabetes, kidney disease, and heart failure. Sotagliflozin (Inpefa®), a dual SGLT2/SGLT1 inhibitor that blocks renal SGLT2 and intestinal SGLT1, was recently approved to prevent CVD events in patients with heart failure or diabetes and CKD. Approval was based on the two trials summarized below.
  • In the SOLOIST-WHF trial, 1222 diabetics recently hospitalized for heart failure were randomized to sotagliflozin or placebo. Over a median of 9 months, a composite of CVD deaths and heart failure exacerbations was significantly lower in the sotagliflozin group (245 vs 355 events, p<0.001). [PubMed abstract]
  • The SCORED trial randomized 10,584 diabetics with chronic kidney disease (GFR 25 - 60 ml/min) to sotagliflozin or placebo. Over a median of 16 months, a composite of CVD deaths and heart failure exacerbations was significantly lower in the sotagliflozin group (400 vs 530 events, p<0.001). [PubMed abstract]

In both trials, sotagliflozin's effect was primarily driven by reduced heart failure exacerbations, as CVD death did not differ between groups. SGLT2 inhibition, which has a pronounced diuretic effect, is the likely mechanism behind the heart failure benefit. It's unclear if SGLT1 inhibition plays a role; a study comparing sotagliflozin to an SGTL2 inhibitor would be informative but is unlikely.

Sotagliflozin's side effects are similar to those of SGLT2 inhibitors (e.g., UTI, dehydration, yeast infections), except for diarrhea, which occurred in up to 9% of sotagliflozin-treated patients and may be secondary to intestinal SGLT1 inhibition. Maintenance dosing is 400 mg once daily, and the tablet should be taken within an hour of the first meal.

CLINICAL CHALLENGE

A 45-year-old female comes to see you for her annual physical. She reports having gastric bypass surgery three years ago and says she followed up with her surgeon once and never went back. She asks you to order her routine lab work.

Given her history of gastric bypass, what lab work is recommended? Are any other studies indicated? Find out at the link below.