Shorts


Jule Klotter

Fluoroquinolone Warnings

On July 26, 2016, the US Food and Drug Administration issued a recommendation to limit the use of fluoroquinolones, a group of powerful antibiotics. In the past three decades, FDA has approved levofloxacin (Levaquin), ciprofloxacin (Cipro), moxifloxacin (Avelox), norfloxacin (Noroxin), ofloxacin (Floxin), and gemifloxacin (Factive) to treat urinary tract infections (UTIs), acute bacterial sinusitis, and acute bacterial infection in people with COPD.1 In addition, these drugs have been used off-label to treat and prevent infections in cancer patients with low neutrophil counts, according to K. Kaur et al. The agency now says that the risk of serious, potentially permanent, adverse effects is greater than benefit for people with UTIs, sinusitis, and acute infections who have other treatment options. FDA recommends fluoroquinolone use only for serious infections such as anthrax, plague, and bacterial pneumonia.

Over the years, FDA has made several labeling changes as more information about fluoroquinolones’ adverse effects has come to agency attention. The first Boxed Warning was added in July 2008, to highlight an increased risk of tendonitis and tendon rupture among fluoroquinolone users. The Boxed Warning was expanded to include “risk of worsening symptoms for those with myasthenia gravis” in February 2011. The possibility of irreversible peripheral neuropathy was added to the label in August 2013. “These side effects can occur hours to weeks after exposure to fluoroquinolones and may potentially be permanent,” according to the July 26, 2016, FDA news release.

After the 2013 labeling change, more serious adverse effects came to light. J. Pyne Danielson reports that the FDA Office of Safety and Epidemiology has linked fluoroquinolone use to Parkinson’s, Alzheimer’s, ALS, and other neurodegenerative conditions. Moreover, researchers at the University of South Carolina have published evidence of fluoroquinolone-related neuropsychiatric and mitochondrial toxicities.2,3

Charles Bennett, MD, PhD, of the University of South Carolina leads the Southern Network on Adverse Reactions (SONAR), a pharmaceutical watchdog group. SONAR has collected hundreds of patient reports that link Levaquin and other fluoroquinolones to muscle weakness, chronic fatigue, cardiomyopathy, hearing loss, developmental disorders, nerve damage, and severe depression. In 2013 and 2014, SONAR filed citizen petitions requesting that neuropsychiatric toxicity and mitochondrial toxicity be added to the fluoroquinolone Boxed Warning.

Bennett is senior author of a study on fluoroquinolone-related neuropsychiatric and mitochondrial toxicities. As part of the study, the authors conducted a web-based survey of people who experienced adverse effects after one or more doses of a fluoroquinolone (FQ).2 Ninety-three of 94 respondents reported neuropsychiatric adverse effects within days of taking a FQ antibiotic “or days to months of FQ discontinuation.”  Symptoms included anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory. The psychiatric effects occurred more frequently in patients taking levofloxacin (Levaquin) compare to those taking ciprofloxacin (10% vs. 2%).

The South Carolina researchers also conducted a lab experiment with five groups of mice that received between 10 mg/kg and 50 mg/kg of ciprofloxacin and a group of control mice. “Mice treated with ciprofloxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls,” they report. The researchers note that fluoroquinolones are known to “affect mammalian topoisomerase II, especially in mitochondria,” producing DNA damage.

Why did it take so long for FDA to restrict use of fluoroquinolones? A 2016 lawsuit, filed by former Levaquin users, alleges that former FDA commissioner Margaret Hamburg, MD, who headed the agency from May 2009 to April 2015, suppressed the drugs’ harmful effects. The lawsuit charges Hamburg, Levaquin manufacturer Johnson & Johnson, Hamburg’s husband Peter Brown, and Renaissance Technologies with collusion “to mislabel and misbrand Levaquin.”4 Peter Brown is co-CEO of the hedge fund Renaissance Technologies, which heavily invests in pharmaceutical companies including Johnson & Johnson. Restricting fluoroquinolone use would deeply cut into Johnson & Johnson and hedge fund profits. “The suit falls under the federal Racketeer Influenced and Corrupt Organizations (RICO) act, the law used to prosecute organized crime,” reports Michelle Llamas.

Electronic Health Records & Physician Burnout

Are electronic health records (EHRs) and computerized physician order entry (CPOE) contributing to physician burnout? Many hospitals and clinics have converted to computerized systems in order to coordinate and improve the quality of care. So far, studies have not consistently shown that these programs reduce errors and improve patient safety. Moreover, evidence suggests that EHRs and CPOEs contribute to physician dissatisfaction. “Electronic health records have increased the clerical burden on physicians, altered the patient-physician interaction, and can distract from the more meaningful aspects of medical practice,” write Tait D. Shanafelt, MD, and colleagues.5    

Shanafelt et al conducted a recent study that found a correlation between EHR/CPOE use and risk of physician burnout. From August 1, 2014, through October 31, 2014, the researchers asked 35,922 US physicians to take part in a national survey about the use of electronic health records, physician order entry, and electronic patient portals; 6880 (19.2%) responded, 6375 of whom were still in active practice. Of those in active practice, 84.5% (n=5389) used EHRs; and 82.5% in CPOE-relevant specialties (4858 of 5892 doctors) used CPOE. The survey consisted of questionnaires, including the validated Maslach Burnout Inventory.

After adjusting for age, gender, specialty, practice setting, and hours worked per week, the researchers found a direct correlation between EHR/CPOE use and decreased satisfaction with clerical tasks. Thirty-six percent of EHR users were satisfied or very satisfied with the system, 43.7% were dissatisfied or very dissatisfied, and the remainder was neutral. Pathologists were most likely to be satisfied. (The authors did not gather data that would indicate if specific EHR systems were more user-friendly than others.) Satisfaction with CPOE use was similar: 38.1% were satisfied or very satisfied, 41.9% were dissatisfied or very dissatisfied, and 20% were neutral. However, satisfaction or dissatisfaction had no bearing on physician burnout. Doctors who used EHRs or CPOE had a higher risk of experiencing burnout “regardless of whether they were or were not satisfied with their EHRs or CPOE.”

EHR/CPOE systems do not decrease the time that practitioners spend on clerical work. Logging into a computer and working within the confines of a regimented program with its check boxes and pop-up warnings takes more time than jotting down notes on paper. Christine Sinsky, MD, and colleagues observed 57 US doctors in family medicine, internal medicine, cardiology, and orthopedics. They report, “For every hour physicians provide direct clinical face time to patients, nearly 2 additional hours is spent on EHR and desk work within the clinic day. Outside office hours, physicians spend another 1 to 2 hours of personal time each night doing additional computer and other clerical work.”6

“How do we harness the value of these tools and simultaneously mitigate their negative effects on physicians?” ask Shanafelt and colleagues.5 One suggestion is to use medical scribes, who chart the physician’s observations during the patient visit. This method lets doctors turn their full attention to their patients and provides a real time record of their observations and recommendations. Clinically trained personnel (e.g., nurse, medical assistant) can further lighten a practitioner’s clerical burden by making non-physician orders, responding to patient emails, and providing health coaching and care coordination. Using scribes—clinically trained or not—can increase physician satisfaction and efficiency.

Justina Pelletier, Child Protection, and a Difference of Medical Opinion

Back in 2003, Townsend Letter carried the story of Alan Yurko, a Florida father who was falsely convicted of killing his infant son. Medical experts claimed that the child was the victim of Shaken Baby Syndrome. Yurko’s conviction was overturned in 2004, and he was released after serving over six years in prison. A British Medical Journal rapid response reported that the infant’s death was the result of multiple vaccinations and an overdose of heparin during hospitalization. Yurko’s case shows the importance of ruling out medical causes before calling in child protective services.

Some parents whose children have rare, poorly understood chronic diseases are also dealing with child abuse accusations. One of the most publicized cases is that of Justina Pelletier. Justina, who lives with her family in Connecticut, was diagnosed with mitochondrial disease by her doctors at Tufts Medical Center in Boston. When the then 14-year-old developed severe gastrointestinal problems in 2013, her doctors recommended that her parents take her to Boston’s Children’s Hospital. Doctors at Children’s Hospital, one of whom was a child abuse expert, decided that Justina’s problems were psychological and that her parents were abusing her by demanding unnecessary medical treatment. As a result, a juvenile court judge put Justina into state custody. The girl spent several months in the hospital’s psychiatric ward and, of course, no longer received treatment for mitochondrial disease. Her physical health continued to deteriorate. Her case gained national attention.

Sixteen months after placing Justina in state care, the judge restored custody to her parents, saying that the Pelletiers “‘have been cooperative and engaged in services,’” which included family therapy. The struggle to free their daughter involved countless trips from their home in Connecticut to Boston, work disruptions, and medical costs that destroyed the family’s finances. The Pelletiers filed for bankruptcy in 2015.

In February 2016, Justina’s parents filed a lawsuit accusing Boston Children’s Hospital and four doctors with gross negligence and civil rights violations.7 The lawsuit alleges that the defendants “misdiagnosed Justina Pelletier, cut her off from all communication with her long-time treating doctors, and falsely accused her parents of abusing her…ultimately resulting in her wrongful imprisonment in a locked psychiatric ward and other facilities for over one year,” according to KJC Law Firm, LLC (Facebook post, August 29, 2016).

Child abuse does occur. In Justina’s case, however, a medical malpractice tribunal confirmed in August 2016, that the Pelletiers have “a viable claim of medical malpractice.” “’This is not about revenge,’” Justina’s father, Lou, said in a Boston Globe article. “‘This is about making people accountable and making the medical community think twice before they take actions that can do damage to a child and a family that can be irreversible.’”8 He also expressed concern for other parents who fear losing custody when seeking emergency care for children with complex medical issues.

CRISPR Genome Editing

The legal struggle for intellectual property rights to CRISPR, a revolutionary genetic engineering tool, is in full swing. The technique uses Cas9, an enzyme found in bacteria, to make cuts in DNA.  In bacteria, the enzyme is part of a defense system against invading viruses. Instead of laboriously inserting genes from one species into another to create new characteristics, genetic engineers can use CRISPR-Cas9 to cut and modify the genome—a far simpler and less costly process. “It enables rank-and-file scientists—just about anyone with a modern laboratory and the right skills—to alter specific genes within plants and animals and make those changes heritable,” journalist Joel Achenbach explains.9  Proponents are hailing CRISPR as a potential solution to inherited disease. At this point, however, the technique is not precise enough to use on humans; and we don’t know enough about the genome to foresee possible adverse effects.

Because of CRISPR’s commercial potential, early developers of the technique are fighting for patent rights.10 Researchers at University of California-Berkeley and co-petitioners are challenging 13 CRISPR patents held by the Broad Institute (Cambridge, Massachusetts). The California researchers claim that Feng Zhang at the Broad Institute built upon their initial discovery of gene-editing components found in Streptococcus pyogenes andpublished on June 28, 2012. In April 2015, Zhang and colleagues reported using a Cas9 enzyme taken from Staphylococcus aureus. This enzyme, known as saCas9, can be transported by an adeno-associated virus into cells and used to modify a genome in vivo.  A French biopharmaceutical company, Cellectis, also claims rights to CRISPR-Cas9.

CRISPR technology changes the discussion about genetically-engineered food, as Rachel Feltman points out.11 At this point, the US government has no guidelines for regulating CRISPR-derived crops. As an example, Feltman refers to the work of Yinong Yang, a plant pathologist at Pennsylvania State University. Yang used CRISPR to create a white mushroom that does not bruise during harvest or turn brown with age. Since CRISPR gene editing does not involve the insertion of genetic material from foreign species, the US Department of Agriculture (USDA) has no authority to regulate the mushroom or other CRISPR crops. EPA is only concerned with pesticide use. FDA views all genetically-modified foods as being the same as non-engineered foods—an assumption that some independent researchers have questioned. Hence, the CRISPR-derived mushroom can be marketed.

Non-browning mushrooms may be a boon for mushroom producers and sellers, but I wonder if anyone has looked for other possible consequences of the genetic changes? Are these mushrooms as easy to grow as the natural ones? Do they have the same nutritional value? Are they digestible? What effect do they have on the gut microbiome? The attempt to delete one characteristic may have several unforeseen effects. We do not yet fully understand the interplay between environment, epigenetics, and the genome.

Climate Change, Carbon, and Soil

Reducing fossil fuel carbon emissions is just one part of the solution to address climate change; returning carbon to the soil is another. Soil and plants contain far more carbon than the atmosphere, as science journalist Nancy Averett explains in “Healthy Ground, Healthy Atmosphere: Recarbonizing the Earth’s Soils.”12 Conventional agricultural practices and land use that strips away trees and plants release carbon into the atmosphere instead of keeping it stored in biomass and soil.

Agriculture and land use practices that draw carbon back into the soil reduce atmospheric carbon and increase soil health. Soil’s ability to store water improves because of the increased carbon, benefiting plants and increasing crop production. Soil scientist Rattan Lal, director of the Carbon Management and Sequestration Center (C-MASC) at Ohio State University, told Averett that “increasing organic carbon in the soil surrounding plant roots by 1 ton per hectare per year can increase grain production by 32 million tons per year.”

One way to increase soil carbon is to use no-till agricultural techniques and cover crops. Whenever farmers till leftover plant material into the soil, they increase its decomposition, releasing carbon into the atmosphere instead of into the soil. Moreover, tilling disrupts soil microbial colonies, as soil researcher Elaine Ingram explained in a Sustainable World Radio interview.13 Conventional farming practices destroy soil organisms that help plants gain access to soil minerals and nutrients. Cover crops such as Austrian winter peas, crimson clover, and pearl millet prevent erosion, add nutrients to the soil, and provide habitat for microorganisms. When these annual plants die and decay slowly, they return carbon to the soil. Leaving organic matter on the soil may look messy to our eyes, but Nature loves it. “Every time we increase the organisms in the soil, we have an increase in productivity. We have not reached the top so we don’t know what that maximum production is,” says Ingram.

Ohio farmer David Brandt has been using cover crops and no-till practices on his farm since 1972. Over time, the amount of organic carbon in his soil has gradually increased and the costs of farming have decreased. He uses about 75% less fertilizer and herbicide with these practices and less fuel. “‘We operate this farm on 2.5 gallons of diesel fuel an acre, compared to 35 gallons an acre for conventional farms,’ he says.” Moreover, his crops can survive weather extremes better than conventionally-farmed crops.

Recently, world organizations have officially recognized the connection between soil health, agriculture, and climate change. The 4/1000 Initiative, promoted by French agriculture minister Stéphane Le Foll, encourages the use of farming practices that maintain or improve soil carbon and the preservation of carbon-rich soils, such as the Amazon. Twenty-five nations have signed on to this voluntary action plan to reduce greenhouse gas: “If we increase by 4‰ (0.4%) a year the quantity of carbon contained in soils, we can halt the annual increase in CO2 in the atmosphere, which is a major contributor to the greenhouse effect and climate change.” (http://4p1000.org/understand)

Detecting Nanoparticles

Increased commercial use of nanotechnology means more nanoparticles in our environment and in our bodies. Studying the interaction between these minute particles, often occurring at low concentrations (e.g., ppm), and biological tissue has been difficult. Dark field transmission electron microscopy accurately differentiates between nanoparticles, which are primarily crystalline, and biological systems, according to Nathan D. Klein and colleagues.14 “Dark field mode reduces visual noise but allows bright crystalline contrast for easy identification of nanoparticles in low-concentration samples,” the authors explain.

Their 2015 article compares bright and dark field images of gold nanoparticles incubated with Bacillus subtilis. In dark field mode, the nanoparticles are easily identified as bright individual spots. The researchers found that the nanoparticles clustered on the peptidoglycan layer of bacterial membranes. The particles did not appear inside cells with intact membranes.

Klein et al  believe that dark field microscopy offers a quick and accurate technique for studying the interaction of crystalline nanoparticles and biological tissue.   

This article was originally published in Townsend Letter, January 2017.

References

  1. FDA updates warnings for fluoroquinolone antibiotics (news release) July 26, 2016. www.fda.gov.
  2. Kaur K, Fayad R, Saxena A, et al. Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network (abstract). J Community Support Oncol. February 2016:14(2):54-65.
  3. Danielson JR. Rx warning: possible mitochondrial toxicity. The Catalyst. April 12, 2015. http://academicdepartments.musc.edu.
  4. Llamas M. Levaquin Users Sue J&J for $800M for Hiding Side Effects. January 26, 2016. www.drugwatch.com
  5. Shanafelt TD, Dyrbye LN, Sinsky C, et al. Relationship Between Clerical Burden and Characteristics of the Electronic Environment With Physician Burnout and Professional Satisfaction. Mayo Clin Proc. July 2016;91(7):836-848.
  6. Sinsky C, Colligan L, Li L, et al. Allocation of Physician Time in Ambulatory Practice: A Time and Motion Study in 4 Specialties. Ann Intern Med. September 6, 2016 (online).
  7. Barnett B. Pelletier family announces lawsuit against Boston Children’s Hospital. February 25, 2016. http://whdh.com
  8. Levenson M. Parents of Justina Pelletier Sue Boston Children’s Hospital (online). Boston Globe. February 25, 2016.
  9. Achenbach J. Scientists debate the ethics of an unnerving gene-editing technique. Washington Post. December 1, 2015.
  10. Cohen J. Dramatic twists could upend patent battle over CRISPR genome-editing method. Science Mag. October 5, 2016.
  11. Feltman R. Why this genetically modified mushroom gets to skip USDA oversight. Washington Post. April 18, 2016.
  12. Averett N. Healthy Ground, Healthy Atmosphere: Recarbonizing the Earth’s Soils. Environ Health Perspect. February 2016; 124(2):A30-A35.
  13. Cloutier J. Episode 128: Interview with Dr. Elaine Ingram (audio). April 8, 2016. www.sustainableworldradio.com.
  14. Klein ND, Hurley KR, Feng ZV, Haynes CL. Dark Field Transmission Electron Microscopy as a Tool for Identifying Inorganic Nanoparticles in Biological Matrices. Anal. Chem. 2015;87:4356-4362.

Published December 2, 2023

About the Author

Jule Klotter has a master’s in professional writing from the University of Southern California. She joined Townsend Letter’s staff in 1990. Over the years, she has written abstract articles for “Shorts” and many book reviews that provide information for busy practitioners. She became Townsend Letter’s editor near the end of 2016.