Army suicide rate highest in 3 decades

Numbers rise despite increased awareness

By By Pauline Jelinek
Associated Press

Friday, January 30, 2009

WASHINGTON — Suicides among U.S. soldiers rose last year to the highest level in decades, the Army announced Thursday.

At least 128 soldiers killed themselves in 2008. But the final count is likely to be considerably higher because 15 more suspicious deaths are still being investigated and could turn out to be self-inflicted, the Army said.

A new training and prevention effort will start next week. And Col. Elspeth Ritchie, a psychiatric consultant to the Army surgeon general, made a plea for more U.S. mental health professionals to sign on to work for the military.

“We are hiring and we need your help,” she said.

The new suicide figure compares with 115 in 2007 and 102 in 2006 and is the highest since record keeping began in 1980. Officials calculate the deaths at a rate of roughly 20.2 per 100,000 soldiers — which is higher than the adjusted civilian rate for the first time since the Vietnam War, officials told a Pentagon news conference.

Officials have said that troops are under tremendous and unprecedented stress because of repeated and long tours of duty due to the simultaneous wars in Iraq and Afghanistan.

The stress has placed further burdens on an overwhelmed military health care system also trying to tend to huge numbers of troops suffering from post-traumatic stress, depression and other mental health problems as well as physical wounds and injuries of tens of thousands.

Yearly increases in suicides have been recorded since 2004, when there were 64 — only about half the number now. And they’ve occurred despite increased training, prevention programs and psychiatric staff.

When studying individual cases, officials said they found that the most common factors for suicides were soldiers suffering problems with their personal relationships, legal or financial issues and problems on the job.

The statistics released Thursday cover soldiers who killed themselves while they were on active duty — including National Guard and Reserve troops who had been activated.

The previous year’s rate of suicides — 18.8 per 100,000 soldiers — had also been the highest on record. But the new pace of 20.2 per 100,000 was the first time the rate surpassed the civilian number, when adjusted to reflect the Army’s younger and male-heavy demographics.

The Centers for Disease Control and Prevention said the suicide rate for U.S. society overall was about 11 per 100,000 in 2004, the latest year for which the agency has figures. But the Army says the civilian rate is more like 19.5 per 100,000 when adjusted.

The new estimated rate of 20.2 is more than double the 9.8 in 2002 — the first full year after the start of the war in Afghanistan

The true incidence of suicide among military veterans is not known, according to a report last year by the Congressional Research Service.

Based on numbers from the Centers for Disease Control and Prevention, the VA estimates that 18 veterans a day — or 6,500 a year — take their lives, but that number includes vets from all previous wars.

The huge commercial success of the fluoroquinolones can be traced to 1990 and the first Gulf War, when the U.S. military was concerned that Iraqi forces with whom they were soon to do battle were planning to use anthrax as a bacterial weapon. The armed forces ordered 30 million doses of the fluoroquinolone ciprofloxacin—Cipro—to be administered to troops as a preventative measure. That drug was chosen mainly because it was new, and the Iraqis would not have been expected to have selected an anthrax strain resistant to it.

Although no anthrax attack is known to have been launched in Kuwait or Iraq (and Desert Storm veterans have blamed the side effects of the antibiotic for some of the symptoms of Gulf War Syndrome), Cipro got the reputation as a kind of superdrug, and sales rose through the 90s. The actual anthrax attacks of October 2001 triggered a wave of panic-buying and pill-swallowing, and Cipro’s manufacturer Bayer responded by producing 200 million additional doses within two months.

At the time, a shocked David Flockhart, chief of clinical pharmacology at the Indiana University School of Medicine, told the Los Angeles Times, “Cipro is basically a big gun whose benefits outweigh its risks in certain circumstances, but the bigger gun you use, the more damage you can expect as collateral.” Of more than 3,000 postal employees who took Cipro following the anthrax attacks, 26 percent had problems with their digestive system, and 14 percent reported neurological problems.

Cipro and its newer fluoroquinolone cousins have since become the most frequently prescribed class of antibiotics in the United States, accounting for one prescriptions out of four. By 2003, more than a half-billion prescriptions had been written for Cipro and Levaquin alone. Under contracts then in effect, the Defense Department and Veterans Administration together were dispensing about 9 million doses of fluoroquinolones per year.

The quinolone family of antibiotics grew out of research on anti-malarial drugs, which also carry a heavy load of side effects. One member of that family, a malaria medication called mefloquine (Larium), has become notorious for causing problems that include, according to FDA, “psychiatric symptoms ranging from anxiety, paranoia and depression to hallucinations and psychotic behavior. On occasions, these symptoms have been reported to continue long after mefloquine has been stopped.”

I believe that Cipro and or Lariam is causing an increase in the rate of suicides in the US military. Some veterans that are suffering from gulf war syndrome may in fact be suffering from Cipro or Lariam toxicity. Click on the link below for information on what the US military is dealing with. http://www.takenasdirected.com/thebuzz98.html

Student pleads guilty to ‘05 family assault

Blames bizarre, bloody attack on antibiotic Cipro

By Lawrence Buser
Contact

Tuesday, June 19, 2007

On Monday, he pleaded guilty to five counts of aggravated assault and was sentenced to three years in prison on each, with the sentences to run concurrently. Brewer remains free on $50,000 and will return to Criminal Court on Aug. 20 to ask Judge James Lammey for diversion.

Diversion would allow Brewer’s five felony counts to be removed from his record after a period of good behavior.

Family members who were victims in the attack support his request for diversion and say the attack was out of character.

The attack occurred May 25, 2005, when Brewer left his campus at the University of Louisiana at Monroe, drove to his Whitehaven home on Clower and began attacking his parents, grandmother, aunt and brother with knives, lamps and ashtrays.

His brother was stabbed 15 times and his 75-year-old aunt still had a knife in her back when police arrived, said state prosecutor Greg Gilbert.

Brewer, who left the house but turned himself in about an hour later, had undergone toe surgery two weeks earlier and had been taking Cipro or Ciprofloxacin, an antibiotic than can have rare side effects such as seizures, uncontrollable shaking, fear of harm from others, hallucinations, depression and suicidal thoughts.

Please warn your family and friends about the long lasting severe physical and neurological effects of Levaquin, Cipro and other quinolone antibiotics. These reactions are not rare as you can see by reading the links below.

Concealing discoveries of contaminated imported honey is immoral, unethical and often illegal — and it happens far too often, U.S. honey producers say.

“It doesn’t take a wizard to determine whether there are bad things in the honey we handle, nor a hero to do what it takes to keep it from our food supply,” said Mark Brady, a Texas beekeeper who sits on the National Honey Board.

“If we buy Chinese honey, as we do far too often, we know it may contain chloramphenicol or some other antibiotic that is illegal in any food product,” said Brady, who produces about a million pounds of honey a year. “To find it and not report it is criminal.”

Two-thirds of the honey Americans consume is imported and almost half of that, regardless of what’s on the label, comes from China, the Seattle P-I reported last month.

The newspaper’s five-month investigation into honey laundering — the intentional mislabeling of the country of origin — found that tons of Chinese honey coming into the U.S. is tainted with banned antibiotics.

But when the contamination is discovered by the industry through internal testing, insiders say, federal health or customs officials are almost never notified, and the honey ends up being dumped back on the market.

That practice is wrong, said Kenneth Haff, the newly elected president of American Honey Producers.

“We don’t want to risk this tainted honey ever getting packed and distributed for human consumption,” said Haff, who believes the industry could solve the problem if companies simply alert the Food and Drug Administration each time they discover a tainted shipment.

Instead, some major packers simply return bad honey to the importer, naively trusting them to destroy the shipment and not seek another buyer.

Said Haff: “We run the risk of the importer trying to resell this same adulterated honey for a cheaper price somewhere else.”

That happens all too often. Court documents the P-I obtained after the arrests last year of two Chicago-based executives with Alfred L. Wolff, a German food distributor, reveal how rampant the sale and resale of bad honey is.

Testimony from federal investigators and informants offer a glimpse into a typical deal: Wolff sold Chinese honey to a U.S. honey producer. The packer tested the shipment and found traces of antibiotics. Wolff took the honey back and resold it to another packer who didn’t test for contaminants.

If convicted, the Wolff executives face up to five years in prison for conspiring to falsify country of origin on the Chinese shipments.

In its series, the P-I reported that it had received shipping papers showing that Chinese honey, falsely labeled as a product of India, was sold to several U.S. honey packers, including one of the nation’s largest — Sue Bee Honey Association.

Sue Bee Vice President Bill Huser said 315 different beekeepers supply 60 percent of the 40 million pounds of honey the Iowa-based company sells each year. The rest is imported.

To protect consumers, Huser said, the company does extensive and elaborate testing on the imported honey, finding shipments laced with chloramphenicol, an illegal antibiotic, about once a month.

When it’s found, he said, it’s sent back to the broker who imported it.

Won’t report it to FDA

That doesn’t sit well with some members of the cooperative. Several told the P-I that returning tainted honey to the marketplace is wrong. They said the issue has been raised in recent years, but the company has refused to change its policy.

Bill Allibone, Sue Bee’s president, said the company has no intention of telling government regulators about the bad honey it finds.

It’s not really Sue Bee’s honey, he said, “because technically, it’s still (the importer’s) property until we pay for it.

“We have not notified the FDA in the past because we don’t have title to that property,” Allibone said.

“We deal with a core group of suppliers that have long, established ties in the import business, and we’re assuming that when we reject a load of honey, they’ll return it to the people they purchased it from.”

Allibone said he has no idea whether the tainted honey is resold to other U.S. packers. Asked whether the company had an obligation to take action to protect the public health, the president repeated: “It’s just not our honey.”

Medical experts agree that the presence of contaminants in honey is a health concern. A small number of people can be sickened or killed by eating even trace amounts of the banned antibiotics, the FDA says in its import alerts on the Chinese honey.

One of them could be Heidi Witherspoon of Seattle, who suffers from a hypersensitivity to quinolones, a class of “flox” antibiotics found in some honey.

“Even the littlest amount sends me into horrible pain, insomnia and twitching,” she said in an e-mail.

John Fretti, a former pharmacy representative from Hummelstown, Pa., also has severe sensitivity to the drugs Chinese beekeepers were using.

“Allowing even the slightest chance that these antibiotics and other drugs can end up in honey on our store shelves is criminal,” Fratti said. “You can’t begin to imagine the pain and harm that can come to us sensitive to those drugs.”

‘We just gave up’

Does the National Honey Board serve as a watchdog for tainted honey? There is considerable debate within the industry on that question.

Bruce Boynton, the chief executive of the board, a trade group created by the U.S. Agriculture Department, said policing honey is the FDA’s job.

“It’s not something we do,” he said. “We have no knowledge about any bad honey out there. That’s not our job, and we never get reports of problems.”

But in 2006, he sent an e-mail to honey board members, warning that tainted honey had been found in stores. In his warning, Boynton wrote that the industry had tested samples taken from products on supermarket shelves and found illegal levels of antibiotics.

“Two samples tested positive for ciprofloxacin at the level of 14.07 (parts per billion) and 5.61 ppb,” Boynton wrote.

In a recent interview, Boynton initially denied any knowledge of the warning. He stressed that the board is “not a regulatory agency” and has no obligation to notify health agencies of potential hazards.

That’s wrong, argues Texas beekeeper Brady.

“If the honey board knows there’s honey in the commercial pipeline that’s contaminated, it has a clear responsibility to report it,” he said.

Sonia Jimenez, who monitors the actions of the honey board for USDA’s Agricultural Marketing Service, first told the P-I that the board “would have no way to know about contaminated honey,” but when told of the CEO’s e-mail, she said further comments would have to come from the agency’s press office, which did not respond.

“It is in the interest of the honey industry to assure that adulterated honey doesn’t get into the marketplace to compete with the legitimate products made by honest producers,” said Martin Stutsman, who heads most of FDA’s efforts at policing adulterated food.

“We encourage industry, upon discovering that a food is adulterated, to let the local FDA office know about the particulars,” he said. “That benefits the honest industry generally and also helps FDA in its enforcement activities to protect the public.”

But blowing the whistle on bad honey at the local level can be difficult.

Eric Olson is one of several Washington state beekeepers who say they’re concerned that slipshod practices by some of the state’s honey packers can endanger everyone’s ability to sell honey.

“There are worrisome things happening all the time,” said Olson, who runs an apiary in Yakima.

“Truck drivers tell us about bringing full semi loads of foreign honey across the border to packers in our state and Oregon. That honey didn’t come from Canadian bees, but it’s sold with a label saying ‘from U.S. and Canadian honey.’ ”

Some beekeepers have reported such practices to state and federal agencies, but “nothing is done,” Olson said.

“We’ve screamed our heads off for so long, so that’s kind of a dead subject. We just gave up.”

SEATTLEPI.COM

Read the P-I’s two-part series investigating fraud in the honey trade online at seattlepi.com/specials/honey.

From Wikipedia, the free encyclopedia  

Fluoroquinolone toxicity syndrome or quinolone toxicity syndrome is the term employed to describe the numerous adverse reactions which can occur as a direct result of the administration of fluoroquinolone antibacterial drugs. Such adverse reactions manifest during, as well as long after fluoroquinolone therapy had been discontinued. These adverse drug reactions (ADRS) induced by the fluoroquinolones can be, for some patients, severe, prolonged and in some cases permanent, disabling and even fatal. The dose, length of time and number of exposures to fluoroquinolones as well as combination with corticosteroids or NSAIDs may increase the risk of the patient suffering specific ADRS. The concurrent use of corticosteroids increases the risk of multiskeletal injury, manifesting as spontaneous ruptures of tendons, muscles and cartilage or chronic tendonitis, and the concurrent use of NSAIDs may induce severe and prolonged seizures.^[1] Increased and repeated exposure to the Fluoroquinolone class appears to increase the risk of the patient suffering multiple ADRS.

The distinction between a quinolone drug and a fluoroquinolone drug is the addition of the fluorine atom to the pharmcore, resulting in a fluorinated drug. Hence the name fluroquinolone. The term quinolone and fluoroquinolone are often times used interchangeably, without regards to this distinction.

Whilst people of all ages may experience severe and prolonged ADRS to the fluoroquinolones, the elderly and especially the young are particularly more susceptible to the toxic effects of fluoroquinolones and their use in these populations is often times discouraged. Toxic reactions have been reported to occur after a single dose.^[2]

The adverse drug reactions (ADRS) to the fluoroquinolones have been associated with serious and detrimental effects upon the Multiskeletal System, Cardiovascular System, Central and Peripheral Nervous System, Circulatory System, Maxillofacial System, Endocrine System, Gastrointestinal System, Urological System, the Liver, the Brain, the Skin, all five senses; hearing, sight, taste, touch and smell, as well as the patient’s DNA, since the mid sixties (see Nalidixic Acid).^[3]

There are no known treatment protocols available for the majority of these reactions and the medical community often times fails to recognize such events as even being related to fluoroquinolone therapy.

[edit] CNS effects

Fluoroquinolones can induce a wide range of bizarre adverse psychiatric effects including hallucinations, psychosis and convulsions. Manifesting as extreme anxiety, panic attacks, depression, anhedonia, cognitive dysfunction (or brain fog), depersonalization, paranoia, hallucinations, toxic psychosis, seizures, tremors, photosensitivity, taste perversions, abnormal dreams, chronic insomnia, vertigo, delirium, and usually involves all five of the senses: Sight, Hearing, Taste, Touch, and Smell. Additionally the fluoroquinolones showed depressant activity on the CNS, as was indicated by the depressant syndrome, decreased spontaneous motor activity, and hypothermia found in animal studies. Concomitant use of NSAIDs may increase seizure risk.

Chronic insomonia has been reported as being one of the most difficult CNS reactions to treat, lasting for months or even years in some patients. Failing to respond to the drugs often times used to treat such a condition.

The fluoroquinolones cause CNS disturbances through the blocking of GABA receptor-binding, and this has been supported by excitatory changes observed on EEG. CNS excitation also occurs through the inhibition of ƒ|N-methyl-D-aspartate or adenosine receptors as well as GABA.

A positive correlation exists between the doses of fluoroquinolones and the prolongation (increases) in the caffeine elimination half-life. (In one case a six-fold increase).

If the fluoroquinolone CNS injury (resulting from inflammation) is severe enough, a cascade of events occurs that may include injury-induced neuroexcitation, transient blood-brain barrier breakdown, changes in cerebral vascular autoregulation, neuronal degeneration, axonal swelling and retraction, and hypertrophy and proliferation of glia. It is now known that the resident macrophages of the central nervous system (CNS), the microglia, when activated may secrete molecules that cause neuronal dysfunction or degeneration. The fluoroquinolones significantly reduced brain glucose uptake.

Electrolyte imbalances are common with previous reports of fluoroquinolone-induced seizures.

The fluoroquinolones inhibit the specific binding of the adenosine receptor ligands L-3H-N6-phenylisopropyladenosine (L-3H-PIA) and 3H-N-ethylcarboxamidoadenosine (3H-NECA). The CNS side effects of these antibiotics result, in part, from interaction with sites which mediate the inhibitory neurotransmission of adenosine.

As such the CNS adrs are a combination of the interference with neurotransmissions, inhibiting of the clearance of other drugs (such as caffeine), reduction of brain glucose uptake, electrolyte imbalances, neuronal dysfunction or degeneration and inflammation, which if severe enough results in transient blood-brain barrier breakdown.

Whilst for some people the symptoms resolve relatively soon after discontinuing the fluoroquinolone antibiotic for others in the case of a neurotoxic effect symptomatology may persist for months or even years after discontinuation of fluoroquinolones.^{[2][4][5][6][7][8][9][10][11][12][13][14][15]}

[edit] PNS effects

The clinical manifestations of fluoroquinolone neuropathy depend on the type and distribution of the nerve populations that are affected, the degree to which they are damaged, and the course of the disease. When the motor nerves are damaged, the neuropathy manifests as weakness and muscle atrophy. Damage to sensory nerves can cause loss of sensation, paresthesias and dysesthesias, pain, and sensory ataxia. Autonomic dysfunction can result in postural hypotension, impotence, gastrointestinal and genitourinary dysfunction, abnormal sweating, and hair loss. Involvement of small unmyelinated fibers in sensory neuropathy typically results in loss of pinprick and temperature sensations, numbness, and painful burning, cold, stinging, or tingling paresthesias. Large fiber sensory involvement can manifest as loss of vibration and position sensations, sensory ataxia, and numbness or tingling paresthesias. Demyelinating neuropathies primarily affect the myelin sheaths, whereas axonal neuropathies target the peripheral nerve axons. Deep tendon reflexes are frequently diminished or absent, particularly in the demyelinating neuropathies. Since most nerve trunks are mixed, damage to the peripheral nerves often affects more than one of these functions.

Fluoroquinolones have also been shown since 1998 ^[16] to cause irreversible peripheral neuropathy. Typical symptoms involve fasciculations, parasthesia, tinnitus, and other sensorimotor problems. Symptoms usually occur after a delayed onset, and may even worsen. Quinolone induced peripheral neuropathy usually presents as burning pain and numbness, and in some cases this becomes an irreversible condition that cripples the patient for life. Most often this is the result of quinolone-induced damage to the peripheral nervous system (as noted above) manifesting as painful burning, cold, stinging, tingling paresthesias or numbness. This may also result from muscle and tendon damage as well if the pain is of a burning or stabbing nature upon use of the limb affected.

The exact manner in which the fluoroquinolones cause such PNS damage remains elusive. Several theories point to direct toxicity or vascular involvement. Peripheral neuropathy has been associated with the fluoroquinolone class since 1988 and has been reported in the leading medical journals for over two decades. However, this particular adverse reaction is rarely recognized as being associated with fluoroquinolone therapy by the treating physician. In 2004 the FDA added warnings to the package inserts concerning the possibility of the fluoroquinolone induced peripheral neuropathy becoming irreversible.^{[17][18][19][20][21][22][23][24]}

[edit] Blood Disorders

The fluoroquinolones have been associated with fatal hepatitis, thrombocytopenia, autoimmune hemolytic anemia, bone marrow depression, pancytopenia, coagulation abnormalities, hypersensitivity vasculitis, and abnormal lab results (such as dramatically increased white cell counts). Such reactions have been reported since the introduction of this class back in the mid sixties. (see Nalidixic Acid)

The exact mechanism of action regarding these adverse events remains unknown and unstudied.^{[25][26][27][28][29][30][31][32]}

[edit] DNA Damage

The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al). Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei. As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells. There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non abating adverse reactions experienced by some patients following fluoroquinolone therapy.^{[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]}

[edit] Gastrointestinal Damage

Damage to the digestive system is one of the leading adverse events associated with the Fluoroquinolone class. Nausea, vomiting and severe diarrhea are often times reported. Hepatotoxicity, acute pancreatitis, intestinal bacterial overgrowth, pseudomembranous colitis, and liver failure (either fatal or requiring transplantation) are all known adverse reactions to fluoroquinolone therapy. Fluoroquinolones induce hypersensitivity to common food additives which may also contributes to these digestive problems.

Additional Fluoroquinolone digestive disorders include acid reflux, erosion of the esophagus, severe bloating, loose bowels, trench mouth, yeast infections of the throat and tongue, gallbladder attacks, fatal hypo and hyperglycemia, fatal liver and kidney diseases, as well as severe nausea.

The predominant mechanisms of action identified so far for this ADR is the reduction of the “good” bacteria found in the human gut as well as dangerous increases of the Candida species and yeast. Additionally damage to other organs that play a significant role in the digestive process such as the intestinal lining as well as damage to the liver and pancreas, have all been cited as being a probable mechanism of action in some cases.

A Clostridium difficile infection is the principal cause of nosocomial, fluoroquinolone-associated diarrhea and pseudomembranous colitis. C difficile can be fatal if left untreated. The spectrum of this disease ranges from asymptomatic carrier state to life-threatening pseudomembranous colitis and toxic megacolon. Pathogenesis of pseudomembranous colitis results from the fluoroquinolones suppression of the natural microflora of the colon, which creates an environment favorable for C difficile proliferation.

Severe constipation rather than diarrhea may result if the nerves controlling the colon are impaired. (see PNS heading above) This would result in a “lazy colon” in which fecal matter remains stagnant rather than moving along the colon to be expelled. Often times these adverse reactions are misdiagnosis as irritable bowel syndrome as the patient may alternate between severe constipation as a result of impaired nerve signals to the colon and the severe diarrhea resulting from the change in the natural flora of the gut. Painful gas attacks are also quite common as a result of decreases in the rate of ethanol elimination due to the fluoroquinolones.

The fluoroquinolones may also induce transient abnormalities in serum aminotransferase levels. Severe hepatotoxicity and acute pancreatitis are both associated with the use of the fluoroquinolones as noted above. Such injury to the pancreas and liver are to be considered a contributory factor in some the gastrointestinal adverse reactions. Trovafloxacin had been removed from clinical use due to fatal liver reactions and recently the manufacturers of Tequin ceased production due to reports of fatal hypo-hyperglycemia being associated with their product.

All of the gastrointestinal issues discussed above are to be considered a class effect independent of any structural modifications of the quinolone ring, with some fluoroquinolones having a more pronounced effect as compared to others in this class. Such events have been reported in the leading medical journals since 1990. With the main manifestation of this adverse reaction being the reduction of the “good” bacteria found in the human gut, the developing of Clostridium difficile, together with dangerous increases of the Candida species and yeast. There have also been numerous reports of fatal hepatotoxicity, fatal hypo-hyperglycemia and acute pancreatitis involving all of the drugs found within this class.^{[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]}

[edit] Pregnancy

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason the Fluroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The Flouroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.^[73][74]

[edit] Children

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the multiskeletal system, with two exceptions. Ciprofloxacin is being licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure) and Levofloxacin was recently licensed for the treatment of Inhalational Anthrax (post-exposure). However, the Fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious multiskeletal adverse event.^[75] Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9.3%.^[76]

Two recent pediatric studies involving the use of levofloxacin indicates that the pediatric patient has a greater than 50% chance of experiencing one or more adverse reactions. Which would be consistant with the studies found within the NDA (new drug application) for Levofloxacin^[77] which showed and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study ^[78]it is stated that “Of the 712 subjects evaluable for safety, 275 (52%) levofloxacin-treated subjects experienced one or more adverse event… Serious adverse events were reported in 33 (6%) levofloxacin-treated subjects…Two serious adverse events in levofloxacin-treated subjects resulted in fatal outcomes.” Within the second study^[79] it is stated that “Of the 204 subjects evaluable for safety, 122 experienced one or more adverse events…Twelve subjects (6%) discontinued study drug due to an adverse event…Seven subjects (3%) experienced 8 serious adverse events.” (circa 2007)

[edit] Fibromyalgia / Chronic Fatigue

As with any number of other drugs, drug induced fibromyalgia/chronic fatigue syndrome is also found with the fluoroquinolones. Whether this is truly fibromyalgia or a misdiagnosis by the treating physician remains a subject of considerable debate. The multiskeletal adverse reactions to the fluoroquinolones are often times misdiagnosis as numerous other rheumatological disease states, particularly fibromyalgia/chronic fatigue, hypothyroidism or rheumatoid arthritis. There have been numerous reports of fluoroquinolone-induced fibromyalgia, as well as severe chronic fatigue.^[80] Fluoroquinolone induced fibromyalgia may be conceptualized as impaired sensory information processing in a neural network, resulting in dysfunctional responses resulting from the CNS and PNS damage outlined above.^[81]

The fluoroquinolone induced fibromyalgia-like symptoms such as muscle pain and tenderness, exhaustion, reduced exercise capacity, and cold intolerance resemble symptoms associated with endocrine dysfunctions such as hypothyroidism and adrenal or growth hormone insufficiency.^[82] However extensive lab work most often times fails to disclose any such endocrine dysfunction. Blood tests for rheumatoid factor is usually found to be within the normal range as well as thyroid testing in such patients, even though the symptoms often times mimic such disorders.

Again the mechanism of action that results in this ADR remains poorly understood and nothing has been cited within the research that would implicate hypothyroidism as being fluoroquinolone induced. (However the fluoroquinolones do interfere with the absorption of thyroid medications^[83])

The symptoms presented by the patients such as muscle pain and tenderness, exhaustion, reduced exercise capacity, and cold intolerance may have more to do with the cascading adverse reactions involving tendon, cartilage and muscle damage, CNS and PNS events, as well as fluoroquinolone induced chronic insomnia, rather than a true presentation of fibromyalgia or the chronic fatigue syndrome.

[edit] Brain Damage

Hypoglycemia-induced anoxic brain injury has been associated with this class.^[84] The brain requires a constant flow of oxygen to function normally. A hypoxic-anoxic injury, also known as HAI, occurs when that flow is disrupted, essentially starving the brain and preventing it from performing vital biochemical processes. Hypoxic refers to a partial lack of oxygen; anoxic means a total lack. In general, the more complete the deprivation, the more severe the harm to the brain and the greater the consequences. The diminished oxygen supply can cause serious impairments in cognitive skills, as well as in physical, psychological and other functions. Recovery may occur in some cases, but it depends largely on the parts of the brain affected, and its pace and extent are unpredictable. As a result, fluoroquinolone induced HAI can have a catastrophic impact on the lives not only of those injured but their families, friends and caregivers as well.

Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), also referred to as increased intracranial pressure, is a well-known ADR to fluoroquinolone therapy.^[85] The primary problem is the presentation of chronically elevated intracranial pressure (ICP), and the most important neurological manifestation is the optic disc swelling (Papilledema) that is secondary to elevated intracranial pressure. This may lead to progressive optic atrophy and blindness. Such optic atrophy and blindness has been associated with fluoroquinolone therapy.^[86]Chronic papilledema may cause progressive visual loss and, for this reason, BIH is not to be considered a benign condition; fundal changes and visual function should be carefully monitored both during and after fluoroquinolone therapy. Symptoms of pseudotumor cerebri, which include headache, nausea, vomiting, vision disturbances and pulsating sounds within the head, closely mimic symptoms of large brain tumors.

The fluoroquinolones are known as gaba inhibitors and as such have the ability to bind to neurorecptor sites within the brain manifesting as severe CNS events. In recent years extensive in vivo and in vitro experiments have been performed and several mechanisms are thought to be responsible for this brain injury. The involvement of gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission as well as the kinetics of fluoroquinolones distribution in brain tissue are thought to be responsible. This particular aspect of the fluoroquinolone-induced damage to the patient’s brain is commented upon under the CNS heading of this article.

The fluoroquinolones have also been implicated in manifestation of strokes.^[87] Numerous studies have shown that the patient faces a greater risk of experiencing a stroke while undergoing fluoroquinolone therapy as opposed to other antibiotics. Within the study: Antibiotic use and risk of ischemic stroke in the elderly. (circa 2002). It was stated that the rates of stroke (per 1,000 person-years) were 9.27 for the fluoroquinolones as compared to 8.58 for trimethoprim-sulfamethoxazole, 7.97 for cephalosporins, 7.49 for tetracyclines, 6.88 for penicillins, 6.64 for macrolides, and 7.29 for subjects with no antibiotic claims.

[edit] Regulatory history

[edit] United States

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid.^[88] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.^[89] In a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would “update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture.”^[90]

By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA prompting the agency to act.^[91] Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.^[92]

In 2005, the Illinois Attorney General filed a petition with the FDA seeking black box warnings and “Dear Doctor” letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter.^[93] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a black box warning.^[94][93] In January 2008, Public Citizen filed suit to compel the FDA to respond to their 2006 petition.^[95][96] On July 7, the FDA ordered the makers of systemic-use fluoroquinolones to add a boxed warning regarding tendon rupture, and to develop a Medication Guide for patients.^[97] The package inserts for Cipro (ciprofloxacin), Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings.^[98] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.^[99] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.^[100] through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

[edit] References