History of Quinolones

Chloroquine

7- Chloroquinolone

Nalidixic Acid Belgium Patent Sterling Drugs1967 Oxolinic Acid (quinoleine) German Patent Warner/Lambert

History of Fluoroquinolones

1973 Flumequine (benzo quinolizine) German Patent Rikker Labs

1974 Pipemidic Acid (pyrido-2-3-pyrimidine) German Patent Roger Bellon

1978 Norfloxacin (6-fluoro-7-pyrididino-quinoleine) Belgium Patent Kyorin

1979 Pefloxacin German Patent Roger Bellon/Dainippon

1982 Ofloxacin European Patent Daiichi

1983 Ciprofloxacin German Patent Bayer AG

1985 Sparfloxacin Daiichippon

1987 Levofloxacin European Patent Daiichi

1987 Clinafloxacin Kyorin

1988 Temafloxacin Toyama

1988 Gatifloxacin Kyorin

1989 Grepafloxacin Otskuda

1993 Trovafloxacin Pfizer

1994 Moxifloxacin Bayer AG

1994 Gemifloxacin LG Chemicals LTD Korea

Overview

Most patients, who suffer from the adverse drug reactions (ADRS) of quinolones or fluoroquinolones, have never even heard the term "Quinolone" or "Fluoroquinolone" in their lives. Just what exactly is a Quinolone or Fluoroquinolone? In the simplest of terms it is a broad spectrum antibiotic. When you had a cold or the flu you no doubt have received a prescription from your doctor for penicillin or tetracycline or any number of the proven and safe antibiotics. However, the newest class of antibiotics the Fluoroquinolones, are man made (synthesize) in which the nucleus is the Quinoline Ring. They are neither proven effective nor safe in our opinion.

The Quinoline Ring is also the nucleus for several anti-malarials: quinine, mefloquine, the 4-aminoquinolines and the 8-aminoquinolines, which have had numerous severe and at times fatal adverse reactions associated with them. Unfortunately, this is also the nucleus for the broad-spectrum fluoroquinolones. Our research indicates clearly to us that there is an inherent "defect" within this nucleus by which the severe adverse reactions continue to manifest with each new drug of this class.

To fully comprehend the exact nature of such ADRS one must first have a complete understanding of the drugs in question. Quinine is a naturally occurring compound in nature and serves as the lead molecules for the development of many popular drugs such as Chloroquine and Lariam (anti-malarial drugs) and the class of antibiotics, the Fluoroquinolones (anti-bacterial), which we are discussing here. Boring, as the following may first appear, it is essential in understanding the adverse drug reactions of fluoroquinolones and the treatment of same, so please indulge us.

The Quinoline Ring is the Nucleus for several anti-malarials: quinine, mefloquine, the 4-aminoquinolines and the 8-aminoquinolines. It is also the nucleus for the broad-spectrum fluoroquinolones. The following text is paraphrased from an article by Joe Lenthall, Magdalen College School, Oxford, and entitled "Quinine":

"Quinine may be familiar to you if you drink gin and tonic or perhaps vodka and tonic. This is because quinine is in the tonic and gives it that bitter taste. It is a white powder that is obtained from the bark of the cinchona tree that is found in the Andes mountain range of Ecuador and Peru. They were probably discovered by Peruvian Jesuits, who introduced quinine into Europe around 1640. However the destruction of these trees to obtain quinine made them rare and so a way of making it synthetically was sought."

Unlike botanical quinine, Chloroquine (as well as 7-Chloroquine) is a synthetically manufactured product that belongs to a class of compounds known as 4-amino quinolines, first developed in 1934 by the German Pharmaceutical Company, Bayer, who continues to manufacture various products from this nucleus. The class of antibiotics commonly referred to as Fluoroquinolones, is one such product. The first 4-amino quinolone was called Resochin. A slight modification a few years later produced Sontochin. In 1943 its composition was again changed slightly and it was renamed Chloroquine. Modified again in 1958 with the results being the drug 7-Chloroquinolone.

In 1962 Sterling Drugs added naphthridone to 7-chloroquine resulting in Nalidixic Acid which had a very narrow antibacterial spectrum (enterobacteriacease only), a very short half life (1.5h), but a very high protein binding (90%). In 1967 in an attempt to reduce the protein binding Warner Lambert modifies naphthyridone into a quinoliene and cuts it in half. The new drug is called Oxolinic acid. In 1973 Rikker Labs patents Flumequine, which showed a weak but broad gram - activity. The new drug is called benzo-quinoizine. In 1974 Robert Bellon introduces Pipemidic acid which showed a longer ½ life. (pyrido-2-3-pyrimidine).

The combing of all three features brings us to the 1st generation fluoroquinolones. Norfloxacin in 1978. This conversion of Chloroquine had a broader gram - activity, less protein binding (50%) and a longer half-life (3-4h). Robert Bellon/Daimiippon in 1979 adds methyl to increase the ½ life even further resulting in a drug called Pefloxacin. In 1982 Daichi adds triyclic compound (as in Flumequine but morpholine ring) resulting in ofloxacin. In 1983 Bayer AG add cyclopropyl to increase the potency - Cipro results. The active form of ofloxacin is the (-) s isomer. Levofloxacin, introduced in 1987 is the pure (-) s isomer. Twice as active as ofloxacin.

The adding of nathridone to 7-chloroquine gives us nalidixic acid

Adding piperazine to nalidixic acid gives us Norfloxacin

Adding methyl give us Pefloxacin

Adding morpholine gives us ofloxacin

Adding cyclopropyl gives us Cipro

The pure (-) s isomer give us Levaquin.

You will see here nothing more than increasing the potency, half life, and reduction of the protein binding of the 1934 anti malaria drug Chloroquine, resulting in a broader gram-negative activity. No where do we see the REDUCTION of the ADRS first reported almost sixty years ago. They continue in the same fashion unabated since that day.

The following text is paraphrased from an article by Joe Lenthall, Magdalen College School, Oxford, and entitled "Quinine":

" It has been documented in medical research that excessive doses of quinine can lead to "cinchoism", which is characterized by ringing in the ears, temporary deafness, blurred vision, nausea and abdominal upset. In severe cases, it may even lead to circulatory collapse, kidney failure and coma. At that point of time, no one actually knew that the potent ingredient was the alkaloid quinine.

There are, however, conditions known as hypersensitivity to quinine, when small doses of Cinchona alkaloids cause toxic manifestations; the individual is usually hypersensitive to the drug. Cinchonism is the term given to a group or symptoms, which usually occur when quinine is given repeatedly in full doses. The most common adverse reaction to Cinchona alkaloids (quinine and quinidine) in Australia from November 1972 to March 1988 were thrombocytopenia, anorexia, nausea, vomiting, diarrhea, skin rash, fever, rigors, disturbed liver function, arrhythmia, hypertension, arthralgia, and deaths. The toxic effects of quinine are tinnitus, vertigo, visual impairment, rashes, nausea, vomiting, diarrhea, abdominal pain, fever, hypertension, convulsions, respiratory depression, cardiac irregularities, weakness, drop in blood pressure, and kidney failure with anuria."

The following text is from an article regarding the history of fluoroquinolones, author unknown:

" The original quinolone antibiotics included nalidixic acid (NegGram), Cinoxacin (Cinobac) and Oxolinic acid (no longer available in the United States). The addition of fluoride to the original quinolone antibiotic compounds yielded a new class of drugs, the fluoroquinolones, which have a broader antimicrobial spectrum and improved pharmacokinetic properties.

In June 1999, the U.S. Food and Drug Administration (FDA) issued a public health advisory warning about the risk of liver toxicity with Trovafloxacin after 14 cases of acute liver failure were associated with its use. The advisory recommended that Trovafloxacin therapy be reserved for infections judged to be life- or limb-threatening, with treatment initiated only in the inpatient setting and when the benefits of Trovafloxacin outweigh the risks.

Six new fluoroquinolones have been introduced in the United States during the past five years. Levofloxacin (Levaquin) and Sparfloxacin became available in 1996, and Grepafloxacin (Rexar) and Trovafloxacin were introduced in 1997. Gatifloxacin (Tequin) and Moxifloxacin (Avelox) became available in early 2000. In December 1999, Grepafloxacin was voluntarily withdrawn because of the possibility of torsades de pointes occurring with its use.

Because the fluoroquinolones have a large volume of distribution, they concentrate in tissues at levels that often exceed serum drug concentrations. Penetration is particularly high in renal, lung, prostate, bronchial, nasal, gall bladder, bile and genital tract tissues. Urine drug concentrations of some fluoroquinolones, such as Ciprofloxacin and ofloxacin (Floxin), may be as much as 25 times higher than serum drug concentrations. Consequently, these agents are especially useful in treating urinary tract infections.

FIRST GENERATION

The first-generation agents include Cinoxacin and nalidixic acid, which are the oldest and least often used quinolones. Because minimal serum levels are achieved, use of these drugs has been restricted to the treatment of uncomplicated urinary tract infections.

Cinoxacin and nalidixic acid require more frequent dosing than the newer quinolones, and they are more susceptible to the development of bacterial resistance. These agents are not recommended for use in patients with poor renal function because of significantly decreased urine concentrations.

SECOND GENERATION

The second-generation quinolones have increased gram-negative activity, as well as some gram-positive and atypical pathogen coverage. Compared with first-generation drugs and considered as a group, these agents have broader clinical applications in the treatment of complicated urinary tract infections and pyelonephritis, sexually transmitted diseases, selected pneumonias and skin infections.

Second-generation agents include Ciprofloxacin, Enoxacin, Lomefloxacin, Norfloxacin and ofloxacin. Ciprofloxacin is the most potent fluoroquinolone against P. aeruginosa. Because of its good penetration into bone, orally administered Ciprofloxacin is a useful alternative to parenterally administered antibiotics for the treatment of osteomyelitis caused by susceptible organisms.

Although the FDA has labeled some second-generation quinolones for the treatment of lower respiratory tract infections and acute sinusitis, it should be stressed that S. pneumoniae is frequently resistant to agents in this class. Consequently, second-generation quinolones are not the drugs of first choice for lower respiratory tract infections and acute sinusitis.

Of the second-generation agents, ofloxacin has the greatest activity against Chlamydia trachomatis.

Ciprofloxacin and ofloxacin are the most widely used second-generation quinolones because of their availability in oral and intravenous formulations and their broad set of FDA-labeled indications.

THIRD GENERATION

The third-generation quinolones currently include Levofloxacin, Gatifloxacin, Moxifloxacin and Sparfloxacin. These agents are separated into a third class because of their expanded activity against gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant S. pneumoniae, and atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae. Although the third-generation quinolones retain broad gram-negative coverage, they are less active than Ciprofloxacin against Pseudomonas species.

Because of their expanded antimicrobial spectrum, third-generation quinolones are useful in the treatment of community-acquired pneumonia, acute sinusitis and acute exacerbations of chronic bronchitis, which are their primary FDA-labeled indications. Gatifloxacin also has FDA-labeled indications for urinary tract infections and gonorrhea. Levofloxacin (the more active component of the ofloxacin racemic mixture and Gatifloxacin are available in oral and intravenous formulations.

Sparfloxacin carries a significant risk of phototoxicity. Grepafloxacin, Sparfloxacin and Moxifloxacin have been reported to cause prolongation of the QT interval; Gatifloxacin has not. However, the FDA recommends that all of these drugs should be avoided in patients who are taking drugs that are known to prolong the QT interval, such as tricyclic antidepressants, phenothiazines and class I antiarrhythmics.24 In contrast, Levofloxacin does not affect the QT interval.

FOURTH GENERATION

Trovafloxacin, currently the only member of the fourth-generation class, adds significant antimicrobial activity against anaerobes while maintaining the gram-positive and gram-negative activity of the third-generation quinolones. It also retains activity against Pseudomonas species comparable to that of Ciprofloxacin.

Trovafloxacin is available in an oral tablet and as the prodrug alatrofloxacin (Trovan IV) in an intravenous formulation. Although the findings of few clinical trials on Trovafloxacin have been published, the drug was originally labeled by the FDA for the treatment of a wide spectrum of infectious diseases. Because of concern about hepatotoxicity, Trovafloxacin therapy should be reserved for life- or limb-threatening infections requiring inpatient treatment (hospital or long-term care facility), and the drug should be taken for no longer than 14 days.

4-aminoquinoline compounds.

Derivatives of nalidixic acid, fluoroquinolones were discovered accidentally in the early 1960s during the synthesis of the anti-malarial agent, Chloroquine. To date, more than 10,000 analogues of Nalidixic Acid have undergone initial screening, and the first fluoroquinolone antibiotic was approved for clinical use in the late 1980s. These highly effective antimicrobials act on bacterial topoisomerases, a class of enzymes that is essential for maintaining the physicochemical stability and biological activity of bacterial DNA.39 In general, the newer quinolones have longer serum half-lives with proven post-antibiotic effects from one to six hours, allowing patient-friendly single- or twice-daily dosing and higher peak levels for maximum bactericidal activity.

More than 300 cases of fluoroquinolone-induced tendinitis, arthralgias, and tendon rupture in adult patients have been documented in the literature. Those identified to be at risk included patients over the age of 60 and patients on long-term steroid therapy. The pathophysiology of fluoroquinolone-induced tendon disorders is unclear, and the onset of symptoms can occur within one or two days after starting therapy. Patients affected typically develop joint pain and swelling (arthralgia), followed by difficulty with movement, some progress to tendon rupture, with accompanying nodules and ecchymoses. Diagnosis is usually made clinically, although ultrasound is helpful as an adjunct evaluation. Tendon rupture may require surgical intervention and has caused prolonged disability. In response to these reports, the FDA has asked clinicians to alert their patients to this potential side effect and has requested that manufacturers revise the package inserts to include similar warnings. "

As one can tell by reading this brief report by Joe Lenthall, that Quinine is far from being a benign drug. Every ADR listed in this report has also been associated with the Fluoroquinolone class of antibiotics. A quick search regarding the adverse drug reactions associated with Chloroquine (circa 1939 used as anti malaria drug) indicates the following. Keep in mind this is the drug considered to be the first quinolone. (not fluoroquinolone which is a quinolone with the fluoride molecule added):

Adrs:

VISION:

Corneal verticillata & whorls, mechanisms of production of corneal & lens changes are drug deposition causing cycloplegia  (mechanism unknown)

Ptosis (Chloroquine) First visible evidence = pigmentary mottling of macular area classic pattern develops granular hyperpigmentation surrounding zone of hypopigmentation hypopigmented zone, in turn, surrounded by pigmented annulus.  May resemble RP.  FFA shows dramatic hyperfluorescence of macular area

Other changes: attenuated retinal arterioles, optic atrophy, peripheral VF loss, altered ERG, progressive VA impairment can occur following cessation of Rx, risk of retinopathy with hydroxychloroquine appears considerably less that that associated with Chloroquine

Mechanism

Pigmented tissue of the eye bind drug for a long period of time following cessation of Rx this can cause degeneration of the RPE

Chloroquine also accumulates in neurosensory retina there is also breakdown of the BRB

GASTROINTESTINAL:

Gastrointestinal toxicity is the main problem with therapy, although headache and skin rashes are also relatively common. Rarely, blood disorders (such as thrombocytopenia, agranulocytosis and aplastic anemia) may occur

DELAYED DRUG EFFECTS:

Some reactions e.g. cancers, Chloroquine retinopathy and retroperitoneal fibrosis, may become manifest months or years after exposure.

Reported to cause prolongation of the QT interval or torsades de pointes (Chloroquine.)

Lancet 1993; 341:1299-1303 Steffen R et al., adr rate considered to be 19%. This is the frequency for Chloroquine but less than that for the combination of Chloroquine and proguanil.

Some of the observed neuropsychiatric reactions are depression and suicidal ideation, anxiety, panic, confusion, hallucinations, paranoid delusions and convulsions." sic)

I may not be the brightest bulb on the tree but does this not sound a lot like the adrs we are all experiencing with these drugs? And this has been documented, in medical journals, since 1934. Since 1939 this drug has been associated with retina problems, aplastic anemia, prolongation of the QT intervals, neuropsychiatric disorders (suicide and depression) anxiety, panic attacks, hallucinations, and for more than SIXTY THREE YEARS patient's lives have been destroyed by these drugs and nobody seems to know anything about it.

Numerous drugs within this class have been either denied approval by the FDA, due to severe and toxic adverse reactions (i.e.: Factive/ Pfizer), or removed from clinical use (i.e.: Trovafloxacin/ Pfizer) for killing too many people. Despite the fact that tendon rupture and damage was documented in 1982 (Bailey et al and Casperian et al) physicians today still have no knowledge of this side effect and continue to hand out these drugs like they were Halloween candy. It was not until 1996, a full fourteen years later that even a warning of this was added to the drug inserts. This was not done as a result of the benevolence of the manufacturers, but was a direct result of a petition demanding that the FDA do so, which was filed by a private foundation (Public Citizen).

What you have read to this point is a bit technical in nature but the point being made is that severe adverse reactions have been documented since around 1640 (for quinine), the early 1930’s for 4-amino quinolines, the 1940’s for Chloroquine, the 1950’s for 7-Chloroquinolone, the 1060’s for Nalidixic Acid and Oxolinic Acid, the 1970’s for Norfloxacin, Flumequine, Pipemidic Acid, and Pefloxacin, the 1980’s for Ofloxacin, Ciprofloxacin, Sparfloxacin, Levofloxacin, Clinafloxacin, Temafloxacin, Gatifloxacin and Grepafloxacin, the 1990’s for Trovafloxacin, Moxifloxacin and Gemifloxacin. Even now, in the 2000’s these drugs are marketed as being "safe with minimal side effects". In a recent article written by Dr. Peter Ball he states:

"New fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance. The main elements of their adverse reaction profile were predictable from human experience with precursor naphthyridines and quinolones, and from toxicological studies in animals. Thus gastrointestinal reactions (1 to 5%), skin disturbances (less than 2.5%) and central nervous system (CNS) effects (usually around 1 to 2%) were anticipated. Individual group members exhibit particular properties in relation to their chemical structures, for example the phototoxicity associated with 8-halogenation of the nucleus and found to be a particular problem with Lomefloxacin and Sparfloxacin. Other members, for example ofloxacin, are linked to a higher than usual incidence of CNS reactions and psychological disturbance. However, despite increasing usage, none of the present group have been implicated in joint damage in children, which had been a major concern following reports of this effect in juvenile animals in chronic toxicity studies. Furthermore, intravenous formulations appear to have no associated increase in toxicity. Crystalluria with associated renal damage, originally thought likely to limit intravenous dosage, has not proved to be a problem in humans. Clinically significant interactions may occur but, as with those involving various NSAIDs and potentially leading to convulsions, they have been defined and are thus avoidable. Post marketing surveillance studies and prescription event monitoring have largely confirmed the limited adverse reaction profile defined during clinical trials. However, some unexpected reactions have appeared after launch, most notably the episodes of haemolysis, renal failure and hypoglycemia which led to the withdrawal of Temafloxacin. These effects have not been observed with other fluoroquinolones. However, severe tendinitis appears to be a group effect, albeit rare, and anaphylactoid reactions have been reported with several of the fluoroquinolone group, often in AIDS patients. The new fluoroquinolones are essentially a well tolerated group of antibacterials, the benefits of which clearly outweigh their disadvantages in a wide range of indications. Clinical efficacy has been a larger determinant of which members have succeeded in the marketplace than potential toxicity. However, the lesser potential for adverse effects of some of the class, e.g. Norfloxacin, ofloxacin and Ciprofloxacin, has undoubtedly led to their more widespread use. For others, e.g. Enoxacin, limited clinical utility and a perception of increased toxicity have resulted in sidelining. There remains the potential for development of safer and yet more active fluoroquinolones via chemical manipulation both of the nucleus and the side chain substituents."(sic)

When one takes a moment and reviews the following list of Adverse Drug Reactions associated with Fluoroquinolones, one cannot help but to respond to Mr. Ball’s statement that "...New fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance, with the rather vulgar British _expression "Bullocks!"

Adverse effects related to fluoroquinolones

Asthenia

Edema

Fever

Malaise

Rigors

Substernal Chest Pain

Syncope

Cardiovascular Disorders

Cardiac Failure

Circulatory Failure

Hypertension

Central and Peripheral Nervous System Disorders

Abnormal Coordination

Coma

Convulsions

Seizures

Hyperkinesia

Hypertonia

Hypoaesthesia

Involuntary Muscle Contractions

Paresthesia

Paralysis

Speech Disorders

Stupor

Tremor

Vertigo

Gastrointestinal System Disorders

Dry Mouth

Dysphagia

Gastroenteritis

G.I.Hemorrhage

Pancreatitis

Pseudomembranous Colitis

Tongue Edema

Hearing and Vestibular Disorders

Ear Disorders

Tinnitus

Heart Rate and Rhythm Disorders

Arrhythmia

Atrial Fibrillation

Bradycardia

Cardiac Arrest

Heart Block

Palpitation

Supraventricular Tachycardia

Tachycardia

Ventricular Fibrillation

Hematology

Decreased Lymphocytes

Liver and Biliary System Disorders

Abnormal Hepatic Function

Cholelithiasis

Hepatic Coma

Jaundice

Metabolic and Nutritional Disorders

Aggravated Diabetes

Mellitus

Decreased Glucose

Decreased Magnesium

Increased Calcium

Dehydration

Hyperglycemia

Hyperkalemia

Hypoglycemia

Hypokalemia

Increased LDH

Weight Loss

Musculo-Skeletal System Disorders

Arthralgia

Arthritis

Arthrosis

Muscle Weakness

Myalgia

Osteromyelitis

Rhabdomyolysis

Synovitis

Tendinitis

Myo, Endo, Pericardial and Valve Disorders

Angina

Pectoris

Coronary Thrombosis

Myocardial Infarction

Neoplasms

Carcinoma

Parosmia

Platelet, Bleeding and Clotting Disorders

Abnormal Platelets

Embolism

Epistaxis

Purpura

Thrombocytopenia

Psychiatric Disorders

Abnormal Dreaming

Aggressive Reaction

Agitation

Anorexia

Anxiety

Confusion

Delirium

Depression

Emotional Liability

Hallucination

Impaired Concentration

Impotence

Manic Reaction

Mental Deficiency

Nervousness

Paranoia

Sleep Disorders

Somnolence

Withdrawal Syndrome

Suicide

Red Blood Cell Disorders

Anemia

Reproductive Disorders

Ejaculation Failure

Resistance Mechanism Disorders

Fungal Infections

Genital Moniliasis

Respiratory System Disorders

ARDS

Asthma

Coughing

Dyspnea

Haemoptysis

Hypoxia

Pleural Effusion

Respiratory Insufficiency

Respiratory Failure

Skin and Appendages Disorders

Erythema Nodosum

Genital Pruritus

Increased Sweating

Skin Disorders

Skin Exfoliation

Skin Ulceration

Urticaria

Urinary System Disorders

Abnormal Renal Function

Acute Renal Failure

Face Edema

Crystalluria

Cylindruria

Hematuria

Vascular (Extracardiac) Disorders

Cerebrovascular Disorder

Phlebitis

Vision Disorders

Abnormal Vision

Conjunctivitis

Diplopia

Retina Damage

Cornea Damage

Ophthalmologic Abnormalities

Cataracts

Multiple Punctate Lenticular Opacities

White Cell and RES Disorders

Granulocytopenia

Leukocytosis

Leukopenia

Lymphadenopathy

WBC Abnormal Count

Allergic Pneumonitis

Anaphylactic Shock

Anaphylactoid Reaction

Dysphonia

Abnormal EEG

Encephalopathy

Eosinophilia

Erythema Multiforme

Hemolytic Anemia

Multi System Organ Failure (Death)

Increased International Normalized Ratio (INR) Prothrombin Time

Stevens-Johnson Syndrome

Tendon Rupture

Torsades de Pointes

Vasodilation

This is but a small sampling of various adverse reactions associated with such therapy.

This list goes on and on and on and on and on. As stated before the physician has no clue as to what these drugs can and will do to a patient. There is no known treatment for a majority of the severe reactions. Such reactions DO NOT abate once therapy is discontinued and the current research indicates that such events are to be considered permanent in nature. A recent report published in the Annals of Pharmacotherapy, by Dr. Cohen emphasizes this.

The following text is from the article Peripheral Neuropathy Associated with Fluoroquinolones, Dr. Jay S Cohen:

" Fluoroquinolones are important members of medicine’s arsenal of antibiotics. Serious ADEs involving the CNS and musculoskeletal systems have been reported but are considered infrequent. Mild ADEs involving the PNS have also been reported. This article, which presents a survey of a different population (with mainly serious, long-term symptoms) from a different source (the Internet), offers a new and different perspective on fluoroquinolone-related events involving the PNS. Further, better controlled investigation is warranted. The FDA should also review and re-port on its cases relating to fluoroquinolone antibiotics. If the occurrence of fluoroquinolone-associated ADEs of this severity and duration is confirmed, physicians need to be informed and warnings might be considered for these drugs’ product information. In the meantime, healthcare providers may need to be vigilant regarding ADEs associated with fluoroquinolones, and even mild events involving the nervous or musculoskeletal systems should prompt immediate discontinuation." sic)

One cannot possibly agree with the statements being made by Mr. Ball that "...New fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance…" after reviewing the material presented so far.

In addition to what we have outlined above we have the following that has been compiled by T R Ramanujam:

"Adverse Drug Effects

Gastro Intestinal Tract

All quinolones have varying degrees of GIT irritation ranging from mild nausea to severe gastritis which can be limited by administering ½ hr after food. Antacids / Divalent cations /H2 antagonists reduce GIT absorption and hence should not be used for treating GIT adverse effects.

Central Nervous System

The mechanism is not known but it is probably interfering with GABA activity. A direct pharmacological effect.

The Pharmacodynamic Drug interactions with NSAIDs manifest sometimes as convulsions (Enoxacin X fenbufen)

The Pharmacokinetic drug- drug interaction with Theophylline.

Sparfloxacin is devoid of proconvulsant activity

Proconvulsant activity with

Pefloxacin > Enoxacin > Ofloxacin > Norfloxacin > Cinoxacin >

Ciprofloxacin > Nalidixic acid etc., 3. Cardio Vascular System Toxicity

Both Sparfloxacin and Grepafloxacin are implicated in producing QT prolongation syndrome often mild but assumes significance when administered together with other agents like antiarrythmics, Macrolides, Cisapride, Azole antifungals, H1 antagonists like astemizole, cetrizine, terfinadine etc.,

Phototoxicity

Skin reactions like erythema, pruritus, urticaria and rashes with phototoxicity are often associated. Sunburns occur when exposed to UV rays of UVA 320-400nm especially transmitted by the clouds & windowpanes. Sparfloxacin, Lomefloxacin and Fleroxacin, show increased incidence of phototoxicity while Trovafloxacin, Grepafloxacin, and Moxifloxacin have reduced potential for Phototoxicity. Quinolones exhibit Photomutagenic & even photocarcinogenic effect in animals. The underlying mechanism appears to be due to the formation of photodegradation products and leading to the generation of reactive oxygen species. In this context newer quinolones are synthesized with chiral modification. It is not definite whether Tocopherols have any protective effect on phototoxicity.

Arthropathy

Interest has been focused on proteoglycan synthesis and mitochondrial function. Occurrence of this adverse effect precludes the use of very good antibacterials in pediatrics. Human data from the experience with 3 compound have revealed that Nalidixic acid has poor tissue penetrability and hence did not manifest chodrotoxicity and in the case of Ciprofloxacin and Norfloxacin there was reduced AUC and therefore low systemic exposure. In case of Pefloxacin with 5-10 times higher systemic exposure ( Higher AUC) is well known to be associated with high incidence of arthropathy in humans because the drug affects articular cartilage & epiphyseal growth plate. The importance of this toxicity is that it is irreversible and manifest later after the drug is discontinued. The use of Nalidixic acid in UTI and Ciprofloxacin in cystic fibrosis (pseudomonal) are officially permitted to be used in pediatrics. Similarly the use of Norfloxacin, Trovafloxacin, and Ciprofloxacin in shigellosis, Salmanellosis, Meningococcal meningitis showed in incidence of arthropathy in pediatric group. Further studies are planned in selected pediatric age groups with quinolones before concluding for official use of quinolones (except those already approved) in pediatric infections.

Tendinopthy:

In 1982 Fluoroquinolone associated Tendinopathy and tendon rupture have been reported. More than 1000 cases of quinolone induced tendinitis have been reported as per French surveillance in 1997. Clinically manifested as congestion and /or inflammation and oedema of tendon leading to pain and swelling and in more than 50% of cases it was bilateral and then tendon ruptures. 400 cases with in 18 months of treatment with Ofloxacin, Norfloxacin, Ciprofloxacin and Pefloxacin. In more than 70% patients aged 60yrs or above and in 10% of patients receiving concurrent steroid medication. Achilles tendon rupture reported to have occurred 120 days after the start of treatment and can occur even after withdrawal of the drug. Pathologically there was ultrastructure alteration in tendinocytes. In animals, Mg deficiency aggravated tendinopathy.

Drug Interactions

Primary drug- Quinolones. Interact with

X Warfarin = enhanced anticoagulation

X H2 Antagonists = quinolone absorption

X Cyclosporin = toxicity

X Rifampicins = decreases serum concentration of quinolone

X NSAIDs = Convulsions

X Insulin & oral hypoglycemics = hypoglycemia"

As you can see T R Ramanujam's research barely scratches the surface regarding the toxicity of these drugs. One of the most common and pronounced adverse drug reactions to fluoroquinolones is often manifested as severe joint, muscle and tendon pain. Ranging from a dull ache to a severe pain in various joints with the Achilles tendon most often times affected. Since 1982 it has been made known to the medical community that such events occur. It was not until 1996, fourteen years later, did anyone bother to address this issue. Public Citizen petitioned the FDA to add warnings and to issue "Dear Doctor" letters to physicians warning them of the danger presented. Of course the FDA only went so far as to add a couple sentences stating such damage was possible. The warning is buried within the monographs and hardly discernable. As a result more than twenty years later this is still considered by the medical community to be a "rare" phenomenon. If fact recently one physician had thought that he had discovered a "rare" side effect and had planned on writing a paper addressing it despite the fact that Casperian et al had done so twenty years earlier.

Research indicates a tremendous amount of multiple case reports of tendinitis (particularly Achilles tendinitis) and tendon rupture in patients receiving as little as ONE dose of fluoroquinolones, months and in some cases years after such therapy. Such tendinopathy can occur within a few days, weeks, or even months following a course of fluoroquinolone therapy. Tendon rupture can occur without a history of specific trauma. There are numerous theories as to how this occurs but the exact mechanics of such damage, twenty years later, still remains a mystery. Unlike other etiologies, bilateral tendinitis is common.

Fluoroquinolone induced tendinopathy is well described in France and, to a much lesser extent, by US rheumatologic and orthopedic journals, but there is scant information in primary care literature. Current research indicates that the primary care physician has not been exposed to the risk that he or she is subjecting their patients to. You can be assured that your primary care physician has no knowledge of this devastating adverse event. Fluoroquinolone induced tendinopathy is underreported, both in literature and to the FDA. Tendinopathy, arthralgia and myalgia have all been associated with fluoroquinolone therapy. Although the exact incident remains unknown due to the under reporting, together with the physicians failure to recognize, treat and report such events, some authors have estimated this to occur in 15 to 20 patients per 100,000 treated patients. No doubt that this number is far greater than this. From 1987 to 1997 the FDA had received 201 reported cases of tendon disorders. One has to seriously question how many other such events may have occurred that was either misdiagnosis or not reported by the physician or the patient.

The etiology of these lesions remains unknown. Numerous animal studies point to several factors that are suspected of causing such damage. The sudden onset of some tendinopathies points to direct toxicity. Few histological studies exist. Jorgensens et al proposed that such damage is vascular in nature as a result of insufficient blood supply. LeHuec et al indicates a reaction to a foreign body. A 1997 study by Movin et al revealed irregular collagen fiber arrangement. The concomitant use of corticosteroids and fluoroquinolones has long been recognized as a risk factor for developing tendinopathies of this nature. This has been presumably due to accelerated degeneration of collagen fibers. High load bearing tendons, such as the Achilles, quadriceps and rotator cuff tendons, are frequently described in the literature as being involved in tendinopathy.

Such tendinopathies may manifest as follows:

Grossly swollen tendon sheath

Acutely inflamed digital flexor tendon sheath

Trigger finger (the locking of one or several fingers)

DeQuervain's tenosynovitis (disabling wrist pain)

Ganglia (carpal tunnel syndrome)

Tennis Elbow

Shoulder Pain

Hip Pain

Knee Pain

Posterior, Plantar and Forefoot Heel Pain

Achilles tendon pain

Rotary Cuff Pain

With the newer generations of fluoroquinolones an even more devastating side effect has manifested. That being peripheral neuropathy. Even though such events have been linked in medical research to Nalidixic Acid (circa 1962), forty years later Dr. Cohen has published his findings relating to these events, giving you the impression that something new has been discovered. That is not the case. Severe, devastating, crippling and at times permanent disability has been linked to this class of drugs since their inception in 1939.

The Office of Attorney General, State of Illinois filed a petition with the FDA (filed May 18, 2005) requesting black box warnings for all the Fluoroquinolone Drugs, only to be ignored by the FDA.  Soon there after Public Citizen petitioned the FDA to Include a Black Box Warning on Fluoroquinolone Antibiotics (HRG Publication #1781) on August 29, 2006.  It has been almost two years since the Attorney General filed her petition and we have yet to have any action taken by the FDA.

Since that time we have added Gemifloxacin (Factive) to our list of fluoroquinolones with severe side effects (severe rashes and toxicity) as well as Gatifloxacin (Tequin) which the manufacturer pulled from production due to severe and fatal hypo/hyperglycemic reactions.  Once again Public Citizen petitioned the FDA to Immediately Ban the Antibiotic Gatifloxacin (Tequin) (HRG Publication #1768) due to these reactions.  Even though Tequin is no longer being manufactured, the remaining stockpile is still in clinical use today.  The FDA still has not responded to these three petitions as of the writing of this article in 2007. 

We believe that the Fluoroquinolones should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria, in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication, the use of drugs within this class is unlikely to provide benefit to the patient and increases the risk of the development of serious and irreversible adverse drug reactions. As with any potent antimicrobial drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during therapy.

Due to the continuing efforts, not only of the Fluoroquinolone Toxicity Research Foundation, but also numerous medical researchers such as Dr. Cohen and others, the FDA has recently added new warnings to the drugs found within this class bringing the following to the attention of both the patient and the physician, forty years after the fact:

Recent label changes to all of the fluoroquinolones include warnings regarding:

Irreversible Peripheral neuropathy

Tendon Effects such as spontaneous tendon rupture both during and AFTER therapy

Caffeine accumulation resulting in CNS stimulation

Pseudomembranous colitis (life-threatening diarrhea)

QTc interval prolongation (ventricular arrhythmias including torsades de pointes)

Commitment use of Non-steroidal anti-inflammatory agents (provoking convulsions)

A review of the various letters sent to the manufacturers of the drugs within this class, appears to indicate that the FDA considers these adverse drug reactions to be class effects and not limited to a specific fluoroquinolone. Neggram, (Nalidixic Acid, the ‘Father’ of the quinolones) introduced in the sixties, appears to have undergone the most extensive revisions with the newer drugs receiving the minimal of warnings.

Several of the label changes found within some of the drugs currently in clinical practice failed to state that Peripheral Neuropathy is an irreversible condition or that the drug should be discontinued upon the manifestation of Peripheral Neuropathy. The reasoning behind this discrepancy is difficult to determine. One would think if indeed these serious adverse reactions were a class effect then all drugs within this class would receive identical warnings. However this does not appear to be the case. Most striking is the total absence of any of these warnings for the eye and ear drops containing these drugs commonly used in clinical practice within the pediatric population.

Within the package insert for Ciprofloxacin regarding Peripheral neuropathy we find the following:

 "Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including Ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition."

Yet the package inserts for Moxifloxacin, Bayer’s replacement for Ciprofloxacin (as Ciprofloxacin has gone generic) we find the following warning devoid of the statement "…in order to prevent the development of an irreversible condition." As well as the advice that the patient should discontinue such therapy upon manifestation of Peripheral Neuropathy: "Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones."

Within the package insert for Ciprofloxacin regarding Tendon Effects we find the following which appears to be consistent amongst all the fluoroquinolones: "Ruptures of the shoulder, hand, and Achilles and other tendon ruptures tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including Ciprofloxacin. Post-marketing surveillance reports indicate that the this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including Ciprofloxacin."

The following warnings are also proven to be inconsistent amongst the various drugs within this class concerning: Caffeine accumulation Pseudomembranous colitis QTc interval prolongation. It may very well take several years before the treating physician is even exposed to these warnings, as no "Dear Doctor" letters have been sent to the best of our knowledge. The patient remains at considerable risk for the duration as the direct result of such malfeasance. Peripheral neuropathy results in a life long disability. Spontaneous tendon rupture, first reported in 1982 (Bailey et al) continues to be unrecognized by the treating physician who fails to recognize, treat and report such events.

The various manufacturers have done a great disservice both to the patient and the physician by their failure to provide adequate warnings regarding the above mentioned adverse drug reactions VIA the issuing of a "Dear Doctor" letter. Yet recently a "Dear Doctor" letter was issued by a drug manufacturer in which the physician was instructed to inform their patients that the failure to drink an adequate amount of water while taking this particular medicine (not a fluoroquinolone) could result in choking. We are truly baffled as to why such a warning was deemed necessary (advising a patient to drink adequate amounts of water while taking a pill), yet providing warnings regarding irreversible disease states such as Peripheral Neuropathy as well as potentially fatal reactions such as Rhabdomyolysis, Pseudomembranous Colitis, Steven Johnson Syndrome, Torsades de Pointes does not warrant such a letter.