Evelyn Pringle March 17, 2006
The antibiotic, Tequin, manufactured by Bristol Myers Squibb, has been linked to both hypoglycemia and hyperglycemia by researchers who examined treatment outcomes associated with various antibiotics in approximately 1.4 million patients, 66 years of age and older, between April 2002 and March 2004.
A team of Canadian scientists from the Institute of Clinical Evaluative Sciences, recently reported the results of their study in the New England Journal of Medicine.
Worldwide, Tequin (gatifloxacin) is a commonly used drug. In 2004, over 30 companies were marketing the antibiotic under brand names like Gaticin, Gatilox, Gatiquin, Gatoxc and Microgat. The Canadian scientists reported that on an average, Tequin is prescribed about 500 times a day in Canada.
Tequin is a member of the class of antibiotics called fluoroquinolones. According to the Mayo Clinic web site, the drug is used to treat many different bacterial infections including pneumonia, bronchitis, sinus infections, respiratory tract infections, urinary tract infections and certain sexually transmitted diseases. Some of the other antibiotics in this class include Cipro (ciprofloxacin), Floxin (ofloxacin), and Levaquin (levofloxacin).
The Canadian findings were the result of two population-based, case-control studies. For each patient, the researchers identified up to 5 controls matched according to sex, age, the presence or absence of diabetes, and the timing of antibiotic treatment.
In the first study, 788 patients were identified who had been treated in the hospital for hypoglycemia (low blood sugar) within 30 days of receiving outpatient treatment with either a macrolide, a second-generation cephalosporin antibiotic, or a respiratory fluoroquinolone antibiotic (gatifloxacin, levofloxacin, moxifloxacin, or ciprofloxacin).
The use of Tequin was linked with a 4.3 times higher risk of hypoglycemia and a small increased risk of low blood sugar was also found with Levaquin. There was no increased risk shown with any of the other antibiotics examined.
In the second study, 470 patients were identified who received hospital care for hyperglycemia (high blood sugar) within 30 days after antibiotic therapy. When compared with macrolides, Tequin was associated with a 16.7 times higher risk of hyperglycemia, while no risk was noted with the other antibiotics.
Within the groups, there were 61 Tequin recipients with hypoglycemia and 86 with hyperglycemia. Overall, one of every 100 patients who took the drug was hospitalized.
The increased risks were similar in both groups of patients regardless of the previous presence or absence of diabetes.
"As compared with the use of other broad-spectrum oral antibiotics, including other fluoroquinolones," the study concluded, "the use of gatifloxacin among outpatients is associated with an increased risk of in-hospital treatment for both hypoglycemia and hyperglycemia."
The importance of these findings prompted the New England Journal of Medicine to make the study available online nearly a month in advance of its regular publication date of March 30, 2006. Changes in blood sugar levels can induce coma and other serious problems, including death.
The Mayo Clinic say patients taking Tequin need to be aware of the signs and symptoms of blood sugar fluctuations which include:
In February 2006, Health Canada and the FDA issued advisory statements that said Bristol-Myers had told doctors that Tequin should not be used with diabetics, and that patients with kidney problems were more likely to experience serious side effects from the drug. The public health agencies also announced label changes for Tequin to include stronger warnings about the drug's link to blood-sugar related problems.
The editorial, "Serious Adverse Drug Effects - Seeing the Trees through the Forest," by Dr Jerry Gurwitz from the Meyers Primary Care Institute in Worcester, MA appears with the NEJM online study and says the FDA should consider mandating a "black-box" warning for Tequin's label or package insert.
"For every approved indication for [Tequin], there are safer, equally effective and less costly alternatives," Dr Gurwitz wrote in the editorial.
However, Dr David Juurlink, one of the Canadian researchers involved in the study, does not believe stronger warning labels are enough. He urges doctors not to prescribe Tequin at all.
"There are multiple alternatives," he says, "that are just as good and do not have this set of side effects that is unpredictable and potentially life threatening," according to the March 2, 2006 Wall Street Journal.
The actual number of blood-sugar risks are estimated to be much higher than listed in the study. Dr Juurlink was quoted by Reuters on March 1, 2006 as saying: "We can't identify everybody, only those who survived [a seizure from low blood sugar and made it] to the hospital or those sick enough to go to the hospital."
"If they died at home or in a pre-hospital setting, they would not have made it into the study," he said in the March 2, 2006 LA Times.
In the US, Tequin labeling has repeatedly changed over time based on other reports indicating that the antibiotic could dramatically alter blood sugar levels.
It came on the market in 1999, and by 2001, 3.3 million prescriptions per year were being written for the drug. Researchers began noticing problems that year, particularly alterations in glucose metabolism, according to the Times.
By 2003, 17 deaths had been linked to Tequin and prescriptions dropped to about 1.7 million per year.
One major contributor to that number, according to the Times, is the Department of Veterans Affairs, which added the drug to its formulary, designated an antibiotic of first choice, in part because Bristol-Myers offered the government a deal price of $1.35 per pill, verses the $8 to $10 per pill charged for Tequin and other fluoroquinolones at pharmacies, said Dr. Richard Frothingham of Duke University, according to the Times.
The government also chose Tequin because its risk of glucose abnormalities did not seem to be any higher than other antibiotics in the class, Dr Juurlink said. In light of the new findings, he told the Times, "the VA needs to very promptly revisit their policy."
Other adverse effects have also contributed to the withdrawal or restriction of several other drugs in this class of antibiotics including kidney failure and liver problems, according to the Mayo Clinic web site.
In addition, a wide range of neurological adverse effects linked to the fluoroquinolone antibiotics, reportedly found to occur in as many as 7% of patients, are described in a medical study conducted in 2001. These side effect symptoms include pins and needles, numbness, tingling, muscle and joint pain, palpitations, malaise, panic attacks, and anxiety, according to the study, "Peripheral Neuropathy Associated with Fluoroquinolones," by Jay S. Cohen, MD, in the December 2001, issue of The Annals of Pharmacotherapy, Volume 35.
Dr Cohen, President and Executive Director of the Center for the Prevention of Medication Side Effects, authored the study on long-term reactions to fluoroquinolones and the results were pre-released in October 2001, during the anthrax scare when Cipro was being widely prescribed without proper warnings to patients.
Within days of the publication, Dr Cohen says the CDC changed their guidelines and listed doxycycline and penicillin antibiotics as the preferred treatment for anthrax exposure before Cipro.
Doxycycline and penicillin were associated with much fewer serious side effects than fluoroquinolones, and were not linked to the disabling and long-term reactions identified in the study.
In most cases, he says side effects were multiple and involved many systems of the body.
The study found nervous system symptoms occurred in 91% of the patients, sensory system symptoms in 42%, musculoskeletal side effects in 73%, cardiovascular adverse effects in 36%, skin reactions in 29%, and gastrointestinal symptoms in 18% of the patients.
Dr Cohen found it especially alarming that severe reactions were occurring in patients who were young, healthy, and active, and most often were receiving antibiotic treatment for mild infections such as sinusitis, urinary or prostate infections. Most reactions occurred quickly, sometimes with just a few doses of the antibiotic.
For example, a male patient, age 36, previously in good health, ended up with chronic, debilitating multi-focal neuropathy, fibromyalgia, chronic fatigue, gastrointestinal problems, heart arrhythmia requiring pacemaker, carpal tunnel syndrome, chronic multiple joint pains, and chronic pain. Five years later at age 41, the patient was still disabled.
A previously healthy 32-year-old female patient was treated for a urinary infection and after 5 days, developed pain in wrists, neck, back, knees, hips, elbows, shoulders, and Achilles tendons.
A 34-year-old healthy male, was treated for a prostate infection and experienced side effects that included muscle spasms and twitching, numbness, impaired coordination, weakness, increased sensitivity to temperatures, fatigue, multiple joint, muscle pain, palpitations, and blurred vision for more than 1 year.
A 47-year-old female patient who was previously in good health, sought treatment for sinusitis and within 2 days of taking the antibiotic, developed severe joint pain in her hands, insomnia, severe agitation, weakness, dizziness, severe fatigue, mental infusion, abnormal dreams, and gastrointestinal symptoms, with many of the adverse effects listed as still severe after 7 months.
Another woman aged 49, with previous good health, received antibiotics for a pelvic infection that resulted in burning pain, memory loss, joint pains, palpitations, nerve pain, insomnia, abnormal sense of smell, tinnitis, and panic attacks for a duration of more than 3 years.
Another 35-year-old male, in good health, received treatment for a prostate infection and after one dose of medication he experienced ringing in the ears and peripheral nerve symptoms that lasted 2 weeks. He then developed tendonitis in his shoulders, elbows, wrists, hands, and Achilles tendons, with burning pain and tightness in his calves. This man was still unable to walk more than a short distance 2 months later.
"Prior to taking the medication I asked about side effects and was told there were none for adults except an upset stomach," this patient told Dr Cohen. "Afterwards I was told that what I was experiencing could not be related to the drug," he said.
Denying the link between the adverse events and the fluoroquinolones is apparently common. "In most cases," Dr Cohen says, "their doctors have dismissed their complaints or outright deny that the reactions could occur with fluoroquinolones."
"Yet extensive medical workups do not find any other cause," he reports.
"Worse, there are no known effective treatments," he says. "Thus, these people suffer pain and disability for weeks, months, years."
"Overall, my sense is that these reactions are not rare," Dr Cohen advises.
"Patients have a right of informed consent, and this includes warnings of potential serious, disabling reactions," he notes.
"Most of all," he warns, "we must educate doctors to avoid prescribing fluoroquinolones for minor infections, instead saving them for serious infections, just as we do with other groups of antibiotics with serious toxicities."
In the January 8, 2002 article titled, "Side Effects of Quinolone Antibiotics Like Tequin (Gatifloxacin) Can Be Serious," Mary Shomen gives a first-hand account of how varied and frightening some of the Tequin side effects can be.
Ms Shomen was prescribed Tequin for a sinus infection at an urgent care clinic and within one day experienced dizziness, tingling in her hands and knees, pain in her legs, and weakness in her arms and legs. A day later she says shortness of breath set in.
"I thought my symptoms might be related to my sinus infection," she wrote, "until I realized that they went away at night, and would start up again about an hour after taking my morning Tequin pill."
After four days Ms Shomen said, "I started having worsening shortening of breath, and difficulty swallowing, so I took two Beneadryl and called the doctor."
The call to the doctor resulted in a trip to the emergency room to see whether she was having a life-threatening allergic reaction to Tequin. At the hospital they discovered her airways were swollen so she was instructed to stay on Benadryl for 2 days.
"In the meantime," Ms Shomen recounts, "the tingling, numbness, difficulty swallowing and other neurological symptoms continued."
Four days later she says her memory was shot and she was still experiencing the tingling, numbness and dizziness. "After a night-time emergency call to my regular physician," she notes, "she suggested that I take some clonazepam (Klonopin), a mild tranquilizer, to see if that could calm down the overreactive nervous system."
The Klonopin calmed the symptoms and the doctor recommended that she remain on the drug until the side effects fully subsided.
"What I had was a dangerous - and even potentially life-threatening - drug reaction," Ms Shomen explains. "Who knows what might have happened had I not taken the Benadryl - an antihistimine - when the shortness of breath and airway constriction began?"
On March 1, 2006, Reuters reported that Bristol-Myers spokesman, Eric Miller said the company had decided to stop actively marketing Tequin, although his comments seemed to imply that the decision was based on economics rather than safety concerns.
Mr Miller noted that although Tequin was introduced onto the market in 1999, it only generated $150 million in sales for Bristol-Myers in 2005.
However, Bristol-Meyers choices related to the sale of Tequin may be limited. According to the editorial accompanying the study in the online NEJM. "It seems clear that the drug's place among broad-spectrum antibiotics available for outpatient use is tenuous at best."