Fluoroquinolone toxicity

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Fluoroquinolone toxicity or quinolone toxicity is the term employed to describe the syndrome of 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][2][3] 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 fluoroquinolone. The term quinolone and fluoroquinolone are oftentimes used interchangeably, without regards to this distinction.

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).[4]

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

Epidemiology

Whilst many people take fluoroquinolones without experiencing serious or prolonged adverse reactions a number of patients do experience moderate to very severe adverse reactions. These adverse reactions can for some resolve over a period of weeks or months after discontinuation of fluoroquinolones but for a number of patients symptoms can persist for many months, years and for some individuals symptoms may never completely abate and may become permanent in nature. Some of the symptoms can be disabling and very distressing. 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 oftentimes discouraged. Toxic reactions have been reported to occur after a single dose.[5]

Delayed and permanent injury

The drugs found within fluoroquinolone class are insidious in that a majority of the reactions that make up the fluoroquinolone toxicity syndrome are delayed reactions. They manifest not only during therapy, but long after therapy has been discontinued and persist for years in some cases. There have also been numerous reports of the CNS, PNS and Multiskeletal injuries becoming permanent and disabling within the literature. Such reactions are typically resistant to medical care interventions and there have been no known treatment options available to the patient or a reasonable explanation found to explain the etiology of such injuries.[5]

The lack of knowledge within the medical community regarding these adverse reactions including delayed adverse reactions is universally underappreciated. Few, if any treating physicians have been exposed to the true safety profile of this class. Since such adverse reactions are far from intuitive, they fail to associate such reactions with the fluoroquinolones.[6] Often times denying that such an association even exists in the first place and attempting to treat the patient with drugs such as NSAIDS and steroids, which only makes the patient's condition worse. The use of such drugs are contraindicated due to the fact that they are believed to increase the severity of such reactions, rather than treat them. It is not unusual for a treating physician to instruct the patient to continue to take a fluoroquinolone drug while failing to recognize that numerous severe adverse reactions are taking place, thereby significantly increasing the patient's risk of suffering a permanent and non-abating adverse reaction. As recently illustrated within the article "A 76-Year-Old Man With Recurrent Clostridium difficile Diarrhea".[7]

Associated fatalities

A significant number of fatalities have been associated with this syndrome. Trovan (Trovafloxacin), Raxar (Grepafloxacin), Omniflox (Temafloxacin), and most recently Tequin (Gatifloxacin) have all been removed from clinical use due to such fatalities. Within the latest adverse drug reaction summaries for Levaquin, Floxin, Cipro, Avelox and Factive obtained under the freedom of information act from the FDA there are 2,298 total death outcomes by case, 806 attributed to Levofloxacin (Levaquin), 311 to Floxin (Ofloxacin), 837 to Ciprofloxacin (Cipro), 337 to Moxifloxacin (Avelox), and 7 to Gemifloxacin (Factive).[8]

Multiple skeletal injuries

One of the leading adverse events associated with this class involves spontaneous tendon ruptures and other such multiple skeletal events. Such injury to the patient include ruptures of various tendons (other than just the Achilles), muscles, as well as damage to the cartilage and ligaments.[9][10][11][12][13][14]

One of the most crippling adverse reactions is spontaneous rupture of multiple tendons, which may occur during, as well as years after therapy had been discontinued. Such multiple skeletal events have been reported since 1972.[15] Tendinitis, arthralgia, myalgia as well as severe joint, muscle and tendon pain are one of the most common adverse reactions. They are found to be the top three adverse reactions reported to the FDA via the Adverse Event Reporting System (AERS)[16] for all the drugs within this class. For example:

  • November 1997 – November 2001-- Ciprofloxacin 1,558 events

Bone, Tendon, Muscle and Ligament Damage 1. Pain in the Extremity (153) 2. Myalgia (148) 3. Tendonitis (122)

  • November 1997 – November 2001-- Levofloxacin 2,898 events

Bone, Tendon, Muscle and Ligament Damage 1. Arthralgia (368) 2. Tendon Disorders (318) 3. Tendonitis (232)

Since 1999, cases of rhabdomyolysis (muscle death), some with fatal outcomes, had also been associated with this class.[17][18][19][20][21][22] There has not been one year since 1983[23] that such multiple skeletal events have not been reported. Reports of tendonopathy occurring hours after a single dose further suggest direct cytotoxicity.[24][25] Although the onset of symptoms typically occurs within 12 weeks, injury was also described within hours to as long as months after the initiation of treatment, and even after discontinuation. Tendon injury was reported to occur as early as two hours after receipt of the first dose of a fluoroquinolone (ciprofloxacin)[26] to as late as 6 months after treatment had been terminated[27][28]. There have also been reports of such ruptures taking place in excess of one year after termination of therapy.

The odds ratios (ORs) of suffering a spontaneous rupture of the achilles tendon are 4.3%, for current exposure 2.4%, recent exposure and 1.4% for past exposure to a fluoroquinolone drug, respectively, compared with non-exposure.[29] Within the Netherlands[30], a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996 following the introduction of the fluoroquinolones. The authors of that study stated that the relative risk of suffering a spontaneous tendon rupture subsequent to fluoroquinolone therapy would be between 1.5% to 10.0%. The incidence of spontaneous tendon rupture within the kidney recipient population is even more common.[31] In the renal transplant population, an incidence of 12.2% - 15.6% is reported, compared with 0.6% - 3.6% for transplant recipients not receiving fluoroquinolones.[32][33] In one study of 149 heart transplant patients[34], fourteen (9.5%) patients developed Achilles tendinopathy, which in three patients (2.25%) progressed to tendon rupture.

However, the FDA, ignoring this significant amount of peer reviewed research that places odds ratios (ORs) to be anywhere between 1.5% to 10.0%, states that they believe the odds ratios (ORs) to be between 3-4 patients per every 100,000 treated; “Fluoroquinolone drugs can increase tendonitis and tendon rupture risk – which is about 1 in 100,000 – by three to four times”, according to Dr. Renata Albrecht, MD, of the FDA[35] when commenting on the recent addition of the Black Boxed Warnings.

Within an article published January 2009 [36] the authors stated that "This is the first reported case of MRI-confirmed, bilateral complete Achilles tendon rupture in a patient on levofloxacin with no exposure to corticosteroids." Even though between 2002 and 2004 there were dozens of reported cases of levaquin induced spontaneous rupture of the Achilles tendon and three of those patients had no previous exposure to corticosteroids.[37][38] Five years ago, in 2004, Kowatari et al [39] reported a case of spontaneous bilateral Achilles tendon rupture induced by levofloxacin in a 76-year-old man who was diagnosed with acute appendicitis and was commenced on oral levofloxacin 300 mg/day for 2 weeks. The authors stated that "Both Achilles tendons ruptured completely at the mid-portion. There was no obvious underlying disease or pathophysiological factor causing fragility of his achilles tendons."

CNS effects

Fluoroquinolones can induce a wide range of bizarre adverse psychiatric effects including hallucinations, psychosis and convulsions.[5][40][41][42][43][44][45][46] Some fluoroquinolones do not have psychosis listed on the US FDA approved package insert and have not had any reports of psychosis. [47]

These reactions may manifest as extreme anxiety, panic attacks, depression, anhedonia, cognitive dysfunction (or brain fog), depersonalization, paranoia, hallucinations, toxic psychosis, seizures, tremors, taste perversions, abnormal dreams, chronic insomnia, vertigo, delirium, suicidal thoughts and usually involves all five of the senses: Sight, hearing, taste, touch, and smell.[48][49]

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.[50] This class is associated with a significant number of serious psychiatric events.[51] 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, and failing to respond to the drugs oftentimes used to treat such a condition.

A positive correlation exists between the doses of fluoroquinolones and the prolongation (increases) in the caffeine elimination half-life. (In one case a sixfold increase).[52][53]

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 reduce brain glucose uptake.[54]

Electrolyte imbalances are common with previous reports of fluoroquinolone-induced seizures. [55]

The CNS ADRS are a combination of the interference with neurotransmissions (GABA), inhibiting of the clearance of other drugs (such as caffeine)[56], reduction of brain glucose uptake[57], electrolyte imbalances[58], neuronal dysfunction[59] or degeneration and inflammation, which if severe enough results in transient blood-brain barrier breakdown as noted above.

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.

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[60] to cause irreversible peripheral neuropathy. Typical symptoms involve fasciculations, parasthesia, tinnitus, hyperacusis, and other sensorimotor problems. Symptoms usually occur after a delayed onset, and continue to 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.[60][61][62][63][64][65][66]

In 2004 the FDA added warnings to the package inserts concerning the possibility of the fluoroquinolone induced peripheral neuropathy becoming irreversible.

Blood disorders

The fluoroquinolones have been associated with fatal hepatitis,[67] thrombocytopenia,[68] autoimmune hemolytic anemia,[69][70] bone marrow depression,[71] pancytopenia,[72] coagulation abnormalities,[73] hypersensitivity vasculitis,[74] 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.

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.[75][76][77][78][79][80][81][82][83][84][85][86][87][88]

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 oftentimes reported. Hepatotoxicity[89], acute pancreatitis[90], intestinal bacterial overgrowth[91][92][93][94][95][96], pseudomembranous colitis[97][98][99][100][101][102] , and liver failure[103][104][105][106] (either fatal or requiring transplantation) are all known adverse reactions to fluoroquinolone therapy. Fluoroquinolones induce hypersensitivity to common food additives which may also contribute to these digestive problems. Though digestive problems are quite common with antibiotic therapy, the severe and serious problems found with the fluoroquinolone class are far more dangerous, and have been associated with resultant fatalities.

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 hypoglycemia and hyperglycemia, fatal liver and kidney diseases, as well as severe nausea. On February 14, 2008 Bayer A.G. sent letters warning doctors in Europe of fatal or severe liver and skin adverse reactions in patients taking moxifloxacin (Avelox). However such letters were never issued in the United States.[107] At its July 2008 meeting, the agency's Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of oral moxifloxacin medicines continued to outweigh its risks. Due to serious safety concerns, mainly related to an increased risk of adverse hepatic reactions, it recommended restricting their use.[108]

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. Again, a common occurrence with antibiotic therapy, but with the fluoroquinolone class this overgrowth has shown to reach potentially fatal levels. 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.[109]

A Clostridium difficile infection is the principal cause of nosocomial, fluoroquinolone-associated diarrhea and pseudomembranous colitis. C difficile can be fatal if left untreated.[110][111][112][113] 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. Oftentimes these adverse reactions are misdiagnosed 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.[114]

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, while other drugs within this class (also associated with fatal liver reactions) have been allowed to continue being used in clinical practice; in spite of this proven risk.[115][116][117][118][119] Recently the manufacturers of Tequin ceased production due to reports of fatal hypo-hyperglycemia being associated with their product.[120][121][122]

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.[123][124][125] [126][127][128] There have also been numerous reports of fatal hepatotoxicity, fatal hypo-hyperglycemia and acute pancreatitis involving all of the drugs found within this class.[129][130][131][132][133][134][135][136]

Fibromyalgia and 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 debate. The multiskeletal adverse reactions to the fluoroquinolones are oftentimes misdiagnosed 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.[137][138] 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.[139]

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.[140] However extensive lab work most oftentimes fails to disclose any such endocrine dysfunction. Blood tests for rheumatoid factor are usually found to be within the normal range as well as thyroid testing in such patients, even though the symptoms oftentimes 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).[141]

Brain damage

Hypoglycemia-induced anoxic brain injury has been associated with this class.[142] 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.[143]

Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), also referred to as increased intracranial pressure, is a well-known ADR to fluoroquinolone therapy.[144] 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.[145][146][147][148] 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 neuroreceptor 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.[149]

The fluoroquinolones have also been implicated in manifestation of strokes.[150][151] 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.

Maxillofacial system

There have been persistent reports of unexplained paresthesia following the use of articaine (burning, tingling, and sometimes sharp shooting pains in tissues previously anesthetized with this anesthetic) during dental procedures involving patients who have had adverse reactions to the fluoroquinolones. As well as reports of persistent numbness in the area that was treated, that appears to be permanent in nature. It should be noted that prolonged paresthesia and numbness from articaine are very uncommon occurrences, and the chances of experiencing this type of reaction from articaine alone are to be considered quite slim.[152]

The fluoroquinolones have also been associated with the formation painful ulcers of the mucous membrane that covers all structures inside the oral cavity except the teeth, as well as the manifestation of severe and persistent oral yeast infections.

Hearing damage

The fluoroquinolones are associated with tinnitus (ringing in the ears) as well as total and partial hearing loss. Loss of balance due to damage to the inner ear has also been reported together with increased intracranial pressure (feeling of pressure in ears). Seizures have been reported to be triggered by ciprofloxacin eardrops.[153] In spite of the risk of seizures triggered by fluoroquinolone eardrops, as well as total or partial deafness, the FDA has approved clinical trials for the pediatric use of levofloxacin to treat common childhood ear infections. The results of several of these trials have shown an unacceptable adverse drug reaction rate.[citation needed]

High-pitched ringing in the ears (tinnitus), hearing loss in higher frequencies, deafness (both transient and permanent), have been commonly reported by the patients following fluoroquinolone therapy. Nausea, vomiting and dizziness (vertigo) had been reported by the manufacturers as being the number one adverse reaction to the fluoroquinolones. Some fluoroquinolones also appear to cause toxicity in the vestibular organ where our sense of balance, position, motion and orientation in space is controlled. The nausea, vomiting and dizziness being reported by the manufacturers may be signs of this kind of damage. No structural changes to the quinolone ring have been identified as being associated with this particular adverse reaction.[154]

The fluoroquinolones as a class are associated with deafness and reduced hearing. Health Canada has received 4 serious case reports of deafness or decreased hearing associated with ciprofloxacin. They involved men aged 35, 47, 65 and 67 years old. Three were receiving 1000 mg/d orally and one was receiving 800 mg intravenously. In all cases, the reactions began within 1 week after initiation of therapy. Three patients recovered, and the fourth experienced partial permanent deafness. The fluoroquinolones moxifloxacin and ciprofloxacin may cause such hearing loss as a result of cochlear toxicity.[155] The fluoroquinolones floxin, ciloxan and cipro HC have also been shown to be ototoxic, with the greatest toxicity to be found with floxin.[156]

The first symptom of ototoxicity from the fluoroquinolones, reported by patients, is typically a high-pitched ringing in the ears or hearing loss in higher frequencies. And in one case, a permanent and total loss of hearing had occurred resulting from Ciproflex I.V.[157]

Within the package inserts we find tinnitus being listed as an adverse reaction related to the peripheral nervous system. Tinnitus resulting from fluoroquinolone therapy must therefore be classified into two groups: Peripheral Tinnitus and Central Tinnitus. There is a noticeable difference in the perception of these two types of Tinnitus. Peripheral Tinnitus is assumed to originate from the peripheral nervous system and cochlea, while Central Tinnitus is assumed to originate in segments of the auditory neural pathways beyond the cochlea.[158]

Dear Doctor Letters and Advisories

United States

  • Within a FDA Medical Bulletin issued June 5, 1992 regarding Omnifloc (temafloxacin)the US Department of Health and Human Services gave notice to practicing physicians within the United States that temafloxacin had been removed from clinical use due to severe toxicity (ie: hemolytic hepatic reactions). Temafloxacin, a quinolone antimicrobial, was introduced in 1991. Shortly afterwards, its use became associated with severe adverse effects, including hypoglycemia, hemolytic anemia, renal failure, hepatitis and anaphylactic reactions. This led to its worldwide withdrawal by the manufacturer.[159]
  • Within a FDA Medical Bulletin issued October 1996, the FDA gave notice to practicing physicians within the United States regarding spontaneous tendon ruptures and chronic tendonitis being associated with the fluoroquinolones.[160]
  • Within a public health advisory (June 9, 1999) the FDA gave notice of the risks of fatal liver toxicity associated with the use of Trovan. [161]The European medical authorities suspended the European licenses of Trovan in June 1999. [162] The FDA decided to restricted its use, rather than suspending its licenses as the European medical authorities had. In 2007 Nigeria filed charges against Pfizer seeking $6.95 billion in damages for the drugmaker's alleged role in the deaths of children who received Trovan during a meningitis epidemic in the northern Muslim state of Kano back in 1996.[163]
  • Within a Dear Doctor Letter issued July 6, 2000 by Bayer Agriculture Division Animal Health, Bayer A.G., gave notice to practicing veterinarians within the United States that Baytril (enrofloxacin) is associated with permanent loss of vision.[164] Baytril was later banned by the FDA, after a five year legal battle with Bayer, regarding its use in poultry.[165]
  • Within a Dear Doctor Letter issued February 15, 2006 by the Bristol-Myers Squibb Company notice was given to practicing physicians within the United States that Tequin (gatifloxacin) is associated with serious and fatal hypoglycemia and hyperglycemia. Production of Tequin was terminated shortly after the issuance of this Dear Doctor Letter by the manufacturer.[166]
  • Within a Dear Doctor Letter issued November 2008 by Johnson and Johnson / Ortho McNeil notice was given to practicing physicians within the United States that Levaquin (levofloxacin)is associated with spontaneous tendon ruptures and chronic tendonitis.[167]
  • Within a Dear Doctor Letter issued October 2008, by Bayer A.G., notice was given to practicing physicians within the United States that Cipro (ciprofloxacin), Avelox (moxifloxacin)is associated with spontaneous tendon ruptures and chronic tendonitis. [168] NOTE: Notice regarding Proquin XR (Ciprofloxacin Hcl), was not included in this warning letter.

Canada

Within a number of Canadian Adverse Drug Reaction Newsletters Health Canada provided notice to practicing physicians within Canada regarding a number of serious adverse drug reactions to the fluoroquinolone class. August 1991, Health Canada gave notice to practicing physicians within Canada that Cipro (ciprofloxacin) is associated with severe adverse drug reactions in the elderly.[169] April 1995, that the fluoroquinolones are associated with spontaneous tendon ruptures and chronic tendonitis.[170] January 1998, that Cipro (ciprofloxacin) is associated with seizures, and certain drug interactions[171] October 2002, that Avelox (moxifloxacin) is associated with permanent vision loss.[172]

January 2004, that Cipro (ciprofloxacin) is associated with hearing loss and deafness.[173]

Within a Dear Doctor Letter issued December 19, 2005 by the Bristol-Myers Squibb Company notice was given to practicing physicians within Canada that Tequin (gatifloxacin) is associated with serious and fatal hypoglycemia and hyperglycemia. Production of Tequin was terminated shortly after the issuance of this Dear Doctor Letter by the manufacturer.

Europe and Asia

Dear Doctor Letters and Advisory notices were also issued by the regulator agencies in the following European and Asian countries:

Japan Oct 1994, the Pharmaceutical Affairs Bureau gave notice to practicing physicians that it had amended the product information to state that rhabdomyolysis may occur with the use of Enoxacin, Fleroxacin, Norfloxacin, Sparfloxacin and Tosufloxacin Tosilate.[174]

Denmark June 1995 Zagam (sparfloxacin) Subject: Rapid Alert. Phototoxicity

France. September 2000 Tavanic (levofloxacine aka levofloxacin) Subject: Dear Doctor Letter. Spontaneous tendon ruptures and chronic tendonitis.

Ireland January 2002. Fluoroquinolone antibiotics Subject: Advisory. QTc interval prolongation and of cardiac arrhythmias[175]

Belgium April 2002. Tavanic (levofloxacine aka levofloxacin) Subject: Dear Doctor Letter. Spontaneous tendon ruptures and chronic tendonitis.

New Zealand March 2003 Avelox (moxifloxacin) Subject: Signal. Respiratory insufficiency[176]

March 2003 Tequin (gatifloxacin) Subject: Signal. Rhabdomyolysis[176]

Italy (circa 2004) Tavanic (levofloxacine aka levofloxacin) Subject: Dear Doctor Letter. Spontaneous tendon ruptures and chronic tendonitis.

References

  1. ^ JM Kushner, HJ Peckman, and CR Snyder (2001). "Seizures associated with fluoroquinolones". The Annals of Pharmacotherapy. 35 (10): 1194–1198. doi:10.1345/aph.10359. PMID 11675843. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  2. ^ De Sarro A, De Sarro G (2001). "Adverse reactions to fluoroquinolones. an overview on mechanistic aspects" (PDF). Curr. Med. Chem. 8 (4): 371–84. PMID 11172695. {{cite journal}}: Unknown parameter |month= ignored (help)
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  4. ^ Package Inserts: Levofloxacin 2008, Moxifloxacin 2008, Ciprofloxacin 2008, Gemifloxacin 2008, Floxacin 2008, Gatifloxacin 2008, Lomefloxacin 2008, Nalidixic Acid 2008, Norfloxacin 2008, Proquin XR 2008
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  104. ^ Emergency Radiology Publisher: Springer-Verlag GmbH ISSN: 1070-3004 (Paper) 1438-1435 (Online) Issue: Volume 8, Number 2 Date: April 2001 Pages: 108 - 110 Acute liver failure due to trovafloxacin: CT findings H. K. Pannu A1, L. Gottlieb A2, E. K. Fishman A1 A1 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA Tel.: + 1-4 10-9 55 65 00 Fax: + 1-4 10-6 14 38 96 A2 Department of Surgery, Greater Baltimore Medical Center, Baltimore, MD 21287, USA
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  117. ^ Emergency Radiology Publisher: Springer-Verlag GmbH ISSN: 1070-3004 (Paper) 1438-1435 (Online) Issue: Volume 8, Number 2 Date: April 2001 Pages: 108 - 110 Acute liver failure due to trovafloxacin: CT findings H. K. Pannu A1, L. Gottlieb A2, E. K. Fishman A1 A1 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA Tel.: + 1-4 10-9 55 65 00 Fax: + 1-4 10-6 14 38 96 A2 Department of Surgery, Greater Baltimore Medical Center, Baltimore, MD 21287, USA
  118. ^ Ann Pharmacother. 2002 Jul-Aug;36(7-8):1162-7. Comment in: Ann Pharmacother. 2002 Nov;36(11):1810; author reply 1810. Possible gatifloxacin-induced fulminant hepatic failure. Coleman CI, Spencer JV, Chung JO, Reddy P. Hartford Hospital, Hartford, CT, USA
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  120. ^ Bristol-Myers To Stop Selling Antibiotic With Safety Risk Dow Jones - Apr. 27, 2006 By Peter Loftus Of DOW JONES NEWSWIRES
  121. ^ Bristol-Myers Squibb Hangs No Sale Sign on Tequin By Peggy Peck, Managing Editor, MedPage Today May 02, 2006 Also covered by: ABC News, CBS News, Forbes, Washington Post NEW YORK, May 2 — Bristol-Myers Squibb will no longer manufacture or sell Tequin (gatafloxacin), an antibiotic that has been linked to both hyperglycemia and hypoglycemia in diabetics and elderly patients.
  122. ^ AP Washington Drug Company Taking Tequin Off Market FROM NEWSDAY By RANDOLPH E. SCHMID Associated Press Writer May 1, 2006, 10:54 PM EDT
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  134. ^ Ann Pharmacother. 2002 Jul-Aug;36(7-8):1162-7. Comment in: Ann Pharmacother. 2002 Nov;36(11):1810; author reply 1810. Possible gatifloxacin-induced fulminant hepatic failure. Coleman CI, Spencer JV, Chung JO, Reddy P. Hartford Hospital, Hartford, CT, USA
  135. ^ Emergency Radiology Publisher: Springer-Verlag GmbH ISSN: 1070-3004 (Paper) 1438-1435 (Online) Issue: Volume 8, Number 2 Date: April 2001 Pages: 108 - 110 Acute liver failure due to trovafloxacin: CT findings H. K. Pannu A1, L. Gottlieb A2, E. K. Fishman A1 A1 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA Tel.: + 1-4 10-9 55 65 00 Fax: + 1-4 10-6 14 38 96 A2 Department of Surgery, Greater Baltimore Medical Center, Baltimore, MD 21287, USA
  136. ^ Publisher: Springer-Verlag GmbH ISSN: 0945-6317 (Paper) 1432-2307 (Online) DOI: 10.1007/s00428-003-0917-9 Issue: Volume 444, Number 1 Date: January 2004 Pages: 87 - 89 Case Report Ciprofloxacin-induced acute liver injury: case report and review of literature Annette Zimpfer1, Albert Propst2, Gregor Mikuz3, Wolfgang Vogel2, Luigi Terracciano1 and Sylvia Stadlmann3 (1) Institute of Pathology, University of Basel, Schoenbeinstrasse 40, 4003 Basel, Switzerland (2) Department of Gastroenterology and Hepatology, University Hospital Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria (3) Institute of Pathology, University of Innsbruck, Muellerstrasse 44, 6020 Innsbruck, Austria Received: 18 July 2003 Accepted: 19 September 2003 Published online: 8 November 2003
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  148. ^ Canadian Adverse Reaction Newsletter Volume 12 · Issue 4 · October 2002 http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adrv12n4_e.html#moxifloxacin Case Presentation - moxifloxacin (Avelox) Optic neuritis developed in a 22-year-old woman with sinusitis while she was receiving moxifloxacin (Avelox) therapy. After 1 dose she experienced fainting and somnolence, which resolved 2 days after initiation of therapy. After 4 days of treatment she lost vision in her left eye. She consulted an ophthalmologist and continued therapy for 6 days. An MRI scan ruled out multiple sclerosis. The patient was taking birth control pills concomitantly. It was reported that her vision would not likely return.
  149. ^ Pharmacol Toxicol. 1989 May;64(5):404-11. Neurochemical studies on quinolone antibiotics: effects on glutamate, GABA and adenosine systems in mammalian CNS. Dodd PR, Davies LP, Watson WE, Nielsen B, Dyer JA, Wong LS, Johnston GA. Department of Pharmacology, University of Sydney, N.S.W., Australia.
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  154. ^ Safety of the Fluoroquinolone Antibiotics: Focus on Molecular Structure CME Stacy J. Childs, MD, University of Colorado Health Sciences Center, Denver [Infect Urol 13(1):3-10, 2000. © 2000 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.]
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