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Drug-resistant strain of typhoid spreads in Pakistan

An antibiotic-defying strain of the bacterium that causes typhoid fever is gaining a foothold in Pakistan, leading some researchers to warn that it could turn the clock back 70 years, when surviving the disease was more a matter of luck than treatment. In the past 6 months, more than 2000 people in Pakistan have been infected with extensively drug-resistant (XDR) Salmonella typhi, according to the National Institute of Health in Islamabad. Only one oral antibiotic, azithromycin, works against the XDR strain, and the other options—expensive intravenous (IV) drugs—are impractical for widespread use in Pakistan and other low-income nations. S. typhi experts worry that the outbreak could soon spill into other countries.

“This is indeed a really alarming situation,” says pediatrician Zulfiqar Bhutta of The Aga Khan University in Karachi, Pakistan. “I’m not sure what can be done, as the horse has bolted. This will jump boundaries before long.”

Spread through contaminated water and food, S. typhi causes up to 22 million cases of typhoid fever a year. Early symptoms include high fever, headaches, and stomach pain. Left untreated, typhoid fever can lead to intestinal hemorrhage and perforation of the bowel, and kill up to 15% of infected people. Despite the availability of effective antibiotics, about 200,000 people die annually.

Early this year, researchers warned that Pakistan was experiencing the world’s first outbreak of  XDR S. typhi strain, reporting 339 cases that were mainly in Hyderabad, east of Karachi. The strain can’t be stopped by the three antibiotics most commonly used to treat typhoid fever, or two additional classes of drugs used to treat strains resistant to those antibiotics, they reported on 20 February in mBio. The XDR strain, which has now made significant headway in Karachi and other locales, is “really quite frightening,” says Myron Levine, an S. typhi vaccine developer at the University of Maryland School of Medicine in Baltimore who was not involved in the mBio study. It is only a matter of time, he notes, before S. typhi develops resistance to azithromycin, too. If that happens, the remaining effective drugs, carbapenems, require hospitalization and an IV drip; treatment can cost thousands of dollars per patient.

Pakistan began a vaccination campaign in February using a recently approved formulation that, for the first time, works in young children and triggers longer-lasting immunity than older versions. The Bill & Melinda Gates Foundation in Seattle, Washington, is funding the campaign, which aims to administer 200,000 doses of the new vaccine. And earlier this month, Gavi, the Vaccine Alliance, a nonprofit based in Geneva, Switzerland, agreed to purchase 10 million additional does for Pakistan.

Inappropriate use of antibiotics is probably only an indirect cause of S. typhi’s acquisition of extensive drug resistance, says Elizabeth Klemm, an infectious disease geneticist at the Wellcome Sanger Institute in Hinxton, U.K., and the first author of the mBio study. Rather, she says, it appears the XDR strain emerged because an existing S. typhi strain that was resistant to multiple drugs—probably because of antibiotic overuse—obtained an additional resistance gene from a plasmid (a circular piece of DNA) likely transferred from Escherichia coli, a bacterium common in human waste and polluted waterways.

Pediatrician Anita Zaidi, who heads the Gates Foundation vaccine program and is from Pakistan, says the country’s municipal and provincial governments have had difficulty working together to solve sanitation problems. She expects the situation to worsen because “we’re now getting into monsoon season, so there’s even more mixing of drinking water and sewage.”

Rumina Hasan, a microbiologist at The Aga Khan University who was the senior author of the mBiostudy, says her lab already finds the XDR strain in about one in three blood samples from typhoid fever patients it tests.

Travelers to Pakistan—including two from the United States—have already returned home with the XDR strain. This poses little threat of spread in developed countries such as the United States, says Eric Mintz, head of the Global Water, Sanitation, and Hygiene Epidemiology team at the U.S. Centers for Disease Control and Prevention in Atlanta. But in countries that have a weak water and sewage infrastructure, an imported case could trigger an outbreak. “This is a very serious problem,” Zaidi says. “If it can happen in one country, it can happen in others.”


Cellectar Sees Strong Trial Response For Rare Blood Cancer Drug

Cellectar Biosciences Inc CLRB 885.31% shares are pushing northward on over five times their average volume after the company reported positive results from an ongoing midstage trial.

Cellectar shares were advancing more than 20 percent to $9 at the time of publication Tuesday.

What Happened

Cellectar Biosciences announced a patient treated in the lymphoplasmacytic lymphoma, or LPL, arm, with advanced Waldenstrom macroglobulinema showed a 94-percent reduction in tumor burden and complete resolution in four of the five targeted tumor masses.

The results were from a Phase 2 trial for CLR 131, its pipeline candidate for hematologic cancer.

The patient in a question, a 67-year-old female, received two lines of multidrug therapy, prior to receiving two 25mCi/square meter doses of CLR 131 over a 30-minute infusion period, according to Cellectar.

Why It’s Important

In addition to the robust clinical response, CLR 131 also resolved symptoms shortly after the first dose that affected the quality of life, such as shortness of breath associated with moderately sized pleural effusion, the company said.

“CLR 131 has shown good clinical response in LPL as well as other hematologic indications and could provide an excellent addition to the treatment armamentarium,” treating physician Sikander Ailawadhi of the Mayo Clinic in Jacksonville, Florida said in a statement.

What’s Next

About 80 participants are expected to be enrolled in the open-lablel, multicenter midstage trial. The study is slated for completion in March 2019, according to data.

Major payers unlikely to see financial hit from risk-adjustment halt: Fitch

  • The Trump administration’s move to suspend Affordable Care Act risk-adjustment payments to insurance companies may cause ACA market instability, but Fitch Ratings predicted the issue won’t affect health insurers’ ratings.
  • Fitch said stopping payments is a credit negative for companies currently owed money. However, major publicly-traded insurers and Blues plans, which usually participate in the ACA marketplace, won’t see deterioration in capital strength.
  • Not everyone is as optimistic. A new Commonwealth Fund report said suspending the program adds more uncertainty and may lead to higher premiums and fewer payers in the marketplace.

The ACA’s risk adjustment program helps protect payers from potential losses related to enrolling more at-risk and high-cost members. It requires payers with fewer higher-risk members to pay into a pool, while companies with more higher-risk members get money from the fund to help offset the extra cost.

CMS stopped $10.4 billion worth of payments last week. The agency blamed two conflicting federal court cases on the use of statewide average premiums. CMS said it can’t collect or distribute funds for the payments until the matter is resolved.

Payers spoke out against the decision. The Blue Cross and Blue Shield Association predicted large premium increases and fewer choices in 2019. “CMS should use all legal avenues available to make the payments on schedule and should do so to protect consumers,” BCBSA president and CEO Scott Serota said in a statement.

Though many large payers expected to receive risk-adjustment payments, Fitch said not receiving the money won’t cause them major problems. Also, companies no longer required to make the risk-adjustment payments may see a one-time benefit to earnings and capital.

If the payment program ends permanently, Fitch expects higher premiums and more payers dropping out of the individual and small group markets.

The Commonwealth Fund said states and payers are concerned about how stopping risk-adjustment payments will affect the marketplace. This year could be a repeat of last year, with payers dropping out of the marketplace over the summer and state officials scrambling to fill counties with no payers in the individual market.

But despite Republican efforts to repeal the ACA, a recent Brookings reportconcluded the individual market is not in any worse shape than in the final days of Barack Obama’s presidency. Premiums are higher and fewer payers are in the market, but Brookings said “these conditions are not fundamentally worse.”

Instead, the ACA’s core market remains similar to 2016. That’s despite a number of actions to chip away at the law, including killing the individual mandate penalty, ending cost-sharing reduction payments, expanding association health plans and short-term health plans, cutting ACA marketing campaigns, reducing the open enrollment period and continuously bashing the law.

Another theory is that the ACA market may actually improve in 2019. A recent Robert Wood Johnson Foundation report suggested proposed rate hikes so far are more moderate than in 2018, and no payers have announced exits from the marketplace.

In fact, there are new payer entries. Oscar Health, Bright Health, Medica and Wellmark all expect to expand their ACA plan footprint next year.

The report found payers in the ACA market are seeing “favorable financial results.” That’s partly connected to silver loading, which is when an insurer puts all the losses associated with the end of cost-sharing reduction payments on silver plans alone. The Robert Wood Johnson Foundation said silver loading has helped stabilize part of the market.

“It’s possible that, at least in some markets, the marketplace population has become less costly to serve over time. It may be that the market is reaching the end of a multi-year ‘Goldilocks Process,’ characterized by initially too many market participants, then too few, now perhaps closer to an amount that is ‘just right,’ although this remains to be seen,” according to the report.

Most payers will focus on subsidized members. The unsubsidized portion will get more complicated with the end of the individual mandate penalty in 2019 and expansion of short-term and association health plans. All of this points to potentially tighter margins next year, according to the report.

Hospital groups lose drug pricing suit in federal appeals court

  • The U.S. Court of Appeals for the D.C. Circuit has denied the American Hospital Association’s lawsuit against HHS for $1.6 billion in cuts made to the 340B drug pricing program beginning this year. The lawsuit had previously been denied because the cuts hadn’t yet taken effect.
  • In the ruling, Circuit Judge Gregory Katsas writes that AHA failed to present a reimbursement claim to HHS Secretary Alex Azar before filing its lawsuit, a requirement AHA argued was fulfilled by submitting comment during the rulemaking process.
  • AHA, the Association of American Medical Colleges and America’s Essential Hospitals said in a joint statement that they plan to “refile promptly in district court,” but after this ruling, they will first have to properly meet the requirements laid out by the court.

The decision is definitely a setback for the hospital industry, which has been fighting tooth-and-nail to prevent cuts to the much-contested 340B program, which requires drugmakers to provide outpatient drugs to certain providers at a reduced cost. AHA, AEH, AAMC and three hospitals originally filed the lawsuit in November after the CMS’ final rule that lowered payments for 340B.

The groups argue the cuts will hurt hospitals’ ability to provide community care and argue that the reimbursement change exceeds HHS authority.

U.S. District Judge Rudolph Contreras dismissed the lawsuit late last year, saying changes to the federal drug discount program had not taken effect before the suit was filed.  Contreras said his decision was based upon the “plaintiffs’ failure to present any concrete claim for reimbursement to the (HHS) secretary for a final decision.” Contreras also refused to comment on the merits of the case.

Katsas did the same in this ruling, saying the three-judge panel that presided over the appeal has “no authority to consider the merits” of the case due to a lack of subject-matter jurisdiction.

In their joint statement, the hospital associations said they are “deeply disappointed that the courts have once again failed to rule on the merits of our case,” but plan to refile. In order to do so, they will first have to properly present a reimbursement claim to HHS.

CytoDyn touts new data in drug-resistant HIV patients

  • Weekly injections of CytoDyn’s experimental antibody PRO140 cut down the viral load of HIV-1 patients who are resistant to antiretroviral drugs reducing plasma RNA levels below 50 copies/mL in 81% of patients given CytoDyn’s drug together with antiretroviral therapy.
  • A viral-entry inhibitor that blocks a cellular receptor called CCR5, PRO140 aims to protect healthy T cells from viral infection. Several patients who continued to receive PRO140 in an extension stage of the study have maintained viral load suppression for over two years.
  • The Food and Drug Administration has granted a Fast Track Designation to PRO140 and CytoDyn plans to file an application to the regulator for approval of the drug as a combination therapy. A rolling submission is expected to begin as soon as year end.

CytoDyn has had a busy July. Last Thursday, it announced a non-binding letter of intent to acquire CCR5-focused cancer startup ProstaGene, in order to expand its clinical focus to include cancers and immunological indications.

ProstaGene brings drug discovery and screening expertise, along with know-how in prostate cancer diagnostics and therapeutics aimed at blocking cancer metastasis by blocking CCR5, which also plays a role in inflammation.

As it expands into cancer, CytoDyn will continue to advance its clinical programs in HIV and graft-versus-host disease. That said, CytoDyn plans to pursue “partnership opportunities to support all of our development programs,” according to company chair Anthony Caracciolo.

Drug resistant HIV patients are, by definition, hard to treat, and targeting that population could serve as a differentiator for the company. CytoDyn reported in February that its combination study with PRO 140 met its primary endpoint in reducing RNA viral load. The data announced Monday are from a subsequent four months of follow-up study.

According to the World Health Organization, levels of HIV drug resistance were around 7% in developing countries until 2010. “Recently, some countries have reported levels at or above 10% amongst those starting HIV treatment, and up to 40% among people re-starting treatment,” the WHO said in a 2016 statement.

The cutoff of 50 HIV-1 RNA copies/ml is one of the definitions of undetectable viral load, and this level is associated with durable clinical and immunological benefits, as well as a reduced risk of transmission.

Are Doctors Reluctant to Prescribe Weight Loss Drugs?

Hello. I’m Dr Charles Vega, and I am a clinical professor of family medicine at the University of California at Irvine. Welcome to Medscape Morning Report, our 1-minute news story for primary care.

Medscape surveyed almost 1300 healthcare professionals, including primary care physicians, endocrinologists, and obstetricians/gynecologists, about the management of obese and overweight patients and found major differences in prescribing patterns across specialties.

The survey also found that despite seeing a relatively high number of obese patients, the use of weight loss medications is not common. Only 58% of healthcare professionals prescribe weight loss medications to obese or overweight patients. Endocrinologists are the most likely to use these agents, at 85%. However, older agents tend to be preferred even though newer agents may be more effective. The most commonly prescribed weight loss drug is generic phentermine, even though it is only approved for short-term use.

Half of those who do prescribe obesity drugs typically do so only if lifestyle modifications fail. Less than 15% of providers recommend bariatric surgery to patients who actually qualify according to guidelines.

Obesity remains a crisis, yet weight loss medications are being underutilized.

Considering Using Fluoroquinolone? Think Again

Since this commentary was prepared, the US Food and Drug Administration (FDA) has strengthened its black box warning for fluoroquinolones to require a separate warning about the drug’s potential mental side effects (disturbances in attention, disorientation, agitation, nervousness, memory impairment, and delirium), and to add a warning about the risk for coma with hypoglycemia. They reiterate their position that because the risk for serious side effects generally outweighs the benefits for patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections, fluoroquinolones should be reserved for use in patients with these conditions who have no alternative treatment options.

Hello. I am Sarah Kabbani, a medical officer with the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention. Over the next few minutes, I will provide you with important information on fluoroquinolone prescribing and use data, and why appropriate fluoroquinolone prescribing is an important patient safety issue.

Fluoroquinolones are the third most commonly prescribed outpatient antibiotic class in the United States in adults, with an estimated 115 prescriptions per 1000 persons annually.[1] In 2016, the FDA issued a black box warning (its strongest warning) to stress serious and disabling adverse events associated with systemic fluoroquinolone use, including damage to tendons, muscles, joints, nerves, and the central nervous system.[2]

A new study published in Clinical Infectious Diseases[3] reports that fluoroquinolones are commonly prescribed for conditions when antibiotics are not needed at all, or when fluoroquinolones are not the recommended first-line therapy. In medical offices and emergency departments, about 5% of all fluoroquinolones prescribed for adults are completely unnecessary, and about 20% of all fluoroquinolone prescriptions do not adhere to recommendations about the use of fluoroquinolones as a first-line therapy.

Fluoroquinolones are not recommended for such conditions as uncomplicated urinary tract infections and respiratory conditions, including viral upper respiratory tract infections, acute sinusitis, and acute bronchitis. According to another study, published in JAMA Internal Medicine,[4] only 52% of patients received the recommended first-line antibiotic therapy for three common infections—otitis media, sinusitis, and pharyngitis.

CDC recognizes that the majority of healthcare providers are familiar with antibiotic prescribing guidelines, but many providers admit that they or their colleagues often choose an antibiotic that is not the recommended first-line therapy.[5] Specifically, fluoroquinolones, with their well-documented efficacy, a broad spectrum of activity covering many common pathogens, and favorable pharmacokinetics, are perceived to be safer than other antibiotics, despite the serious adverse events associated with systemic fluoroquinolone use. These characteristics of fluoroquinolones may have led to overprescribing.[6]Additionally, healthcare providers often cite patient satisfaction as a reason for prescribing an antibiotic when no antibiotic is recommended.

Improving antibiotic prescribing is important for preventing serious adverse events and potentially life-threatening Clostridium difficile infections. Based on the FDA’s warning, fluoroquinolones should be used only in patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, or uncomplicated urinary tract infections when no other treatment options are available.[2] It’s important to follow clinical guidelines when prescribing any antibiotic due to the serious potential adverse events.

Prescribing the right antibiotic, at the right dose, for the right duration, and at the right time helps optimize patient care and fight antibiotic resistance. CDC encourages healthcare providers, health systems, and regulators to view appropriate antibiotic prescribing as an important patient safety issue. For more information on antibiotic prescribing and use, please visit CDC’s Antibiotic Prescribing and Use.

Web Resources

CDC – Antibiotic Prescribing and Use in Doctor’s Offices