Side Effects of Cipro

June 21, 2006

by Andreas Schuld et al.

Andreas Schuld, Wendy Small, and Trent Harris of Parents of Fluoride Poisoned Children (PFPC) provide another excellent detailed examination of another fluoroquinolone in the news:

PFPC: Health Alert - CIPRO October 21, 2001 Dear All, Two months ago we reported on the withdrawal of Bayer's BAYCOL (Cerivastatin), a fluorinated drug (statin class) which had caused deaths and serious adverse health effects worldwide (1,2,3). BAYCOL had been found to cause muscle destruction/wasting - a condition known as rhabdomyolysis - and displayed compounded toxicity when used with other drugs. It had been linked to at least 31 deaths. We also showed how the adverse reactions documented with BAYCOL were largely identical to those of numerous other fluorinated drugs - all of which had been withdrawn from the market in recent years (3).

ANTHRAX AND CIPRO As a result of the current Anthrax scare another fluorinated drug called CIPRO has received extensive media coverage and the name has become familiar to millions almost overnight. As soon as the first cases of anthrax resulting from suspicious mail became known, there were wide reports of a hectic run on this drug. Mass hysteria seems present as governments, pharmacies and individuals everywhere are stockpiling this drug. Pharmacies are reporting record sales, and on-line prescription services and Internet sites are found selling the drug at more than $7.00 per pill. People everywhere, hyped into believing their flu-like symptoms are caused by anthrax exposure and mis-informed by irresponsible media reports, are taking CIPRO, and worse yet - are giving it to their children.

WHAT IS CIPRO? CIPRO is ciprofloxacin, a fluorinated quinolone, belonging to a class of fluorinated antibiotics which also include enoxacin, fleroxacin, temafloxacin, grepafloxacin, norfloxacin, sparfloxacin, tosufloxacin, lomefloxacin, ofloxacin, etc.. Ciprofloxacin has been in use since 1987 for a variety of other indications and is the most-widely used fluoroquinolone in humans and animals worldwide (4). In 2000 the FDA approved its use in treatment for inhalational anthrax under its "accelerated approval" regulations (5). It had actually taken the unusual step of urging Bayer - the sole manufacturer for all countries except India - to file for such approval, supposedly in order to protect the public from future terrorist attacks. The US Department of Defense had already ordered reserves of CIPRO during the 1991 Gulf War (6).

ADVERSE EFFECTS: As mentioned in the info on BAYCOL, temafloxacin and grepafloxacin are two other fluoroquinolones now withdrawn from the market because they had caused severe liver and renal damage - and deaths, just like fluorinated drugs from other, different classifications (3). The same information also exists for CIPRO. Fatal liver failure associated with ciprofloxacin was reported in the Lancet in 1994 (7, 8 - 150 more related refs). Ciprofloxacin has been implicated in several cases of acute renal failure and is the most established fluoroquinolone to cause such renal dysfunction (4, 9, 10, 11 - 96 related refs). FLUORIDE The most common side-effects reported due to CIPRO (2-16%) are gastrointestinal in nature and equal those reported when children accidentally ingest "too much" fluoride from their toothpaste - such as nausea, diarrhea, vomiting, and abdominal pain. Why? Ciprofloxacin administration results in elevated serum fluoride levels (12). In a series of tests evaluating the safety of ciprofloxacin in children, serum fluoride levels increased after 12 hours in 79% of the children; on day 7 the 24-hour urinary fluoride excretion was higher in 88.9% of children observed (12). Just as in the case of Baycol and other fluorinated drugs, CIPRO can cause musculo-skeletal disorders such as rhabdomyolysis. RHABDOMYOLYSIS Since the introduction of fluoroquinolones on the market in 1987 more than 200 cases of rhabdomyolysis, tendinitis, tendon rupture etc. have been reported in the literature (4,13,14,15). In October 1994 the Japan Pharmaceutical Affairs Bureau was first to amend the product information for fluoroquinolones to state that rhabdomyolysis may occur (16). In 1996 the FDA also issued directives to manufacturers to include warning statements on all fluoroquinoline product inserts to alert patients and caregivers to the potential for tendinitis and tendon rupture (17). Also in 1996 the Sri Lanka Drug Evaluation Sub-Committee decided that the product information of fluoroquinolone antibiotics should include a warning stating: "The onset of tendon pain calls for immediate withdrawal of fluoroquinolone antibiotics." (18) Achilles tendon rupture was shown to occur even after withdrawal of the drug. Pathologically there was ultrastructure alteration in tendinocytes. Just as in other cases of fluoride poisoning, studies in animals show that magnesium deficiency aggravate the induced tendinopathy (14,19). DRUG INTERACTIONS/DEATH: Just as with BAYCOL, drug interactions with ciprofloxacin have resulted in fatal outcomes due to potentiation of another drug's effects such theophylline (4,20), methadone (21), or warfarin (22). Just like BAYCOL and other fluorinated drugs, ciprofloxacin is a potent inhibitor of the thyroid hormone-regulated P 450 enzyme system in the liver. Of all fluoroquinolones, ciprofloxacin and enoxacin have shown the greatest inhibitory capacity (4). P450 IA2 prevents the metabolism/inactivation of methylxanthines, thereby causing increased serum concentrations of drugs like theophylline and caffeine, which in turn causes excess CNS and cardiac stimulation. As mentioned above, CIPRO also elevates serum fluoride levels. The liver has been identified as a target organ of fluoroquinolone toxicity in animal studies (23). Already in the 1930s the same was shown by Bayer's scientists such as Litzka or Knoll's Kraft who found that ALL organic fluoride compounds tested (including those used for fluoroquinolone production) interfered with thyroid hormone activity in liver and muscle tissue. Meanwhile, they also showed "anti-bacterial" activity. This led to the development of many fluorinated medications, including the numerous compounds then used very successfully in the treatment of hyperthyroidism (24,25). Kraft invented many fluorinated "medications". When it was discovered that some of these organic compounds had the same detrimental effects on teeth and bone as inorganic fluoride - although much less actual F- was involved - he even filed patents on behalf of Knoll's using these compounds in dental preparations (26,27). Pregnant women should never take ciprofloxacin. CIPRO transfers through the placenta. It inhibits P450 1A2 which has been shown to be critical for neonatal survival by influencing the physiology of respiration in neonates. Mice lacking this cytochrome died shortly after birth and showed symptoms of severe respiratory distress (28). Respiratory distress is a side-effect of ciprofloxacin also in adults (9). CIPRO also transfers through breastmilk. RESISTANCE TO BACTERIA Taking Ciprofloxacin can spur germs to mutate so that future bacterial infections become untreatable. During the last decades a dramatic increase in bacterial strains multiresistant to antibiotics, particlularly CIPRO - has been reported (30, 31, 32). This increase has led to the occurrence of incurable bacterial infections with a fatal outcome, and a particularly serious problem in connection with hospital-acquired infections. For example, Clostridium difficile has become one of the most common acquired organisms in hospitals and long term care institutions. The organism typically infects patients whose normal intestinal flora has been disturbed by the administration of a broad-spectrum antibiotic such as CIPRO. The diarrhea and inflammatory colitis associated with infection represent a serious medical and surgical complication leading to increased morbidity and mortality, and prolonging hospital stays by an average of nearly three weeks. This is especially true for the elderly and for patients with serious underlying diseases who are the most likely to develop the infection. C. difficile associated diarrhea represents a major economic burden to the healthcare system, conservatively estimated at $3-6 billion per year in excess hospital costs in the U.S. alone (33). The emergence of this "antibiotic resistance" is a result of the overwhelming use of antibiotics in human and veterinary medicine. High rates of fluoroquinolone resistance have been reported in many countries (30). For example, in Asia CIPRO no longer can be used to treat gonorrhea, because the disease has become resistant to the drug (34). While the FDA in August 2000 approved CIPRO as the first-line treatment against anthrax, a few months later (October 2000) it asked Bayer to remove BAYTRIL - its equivalent for animals. The FDA proposed banning the fluoroquinolones, which chicken and turkey farmers have given to birds in their water since 1995 to help shield the animals from infection. The agency acted after linking the drugs to a jump in Campylobacter bacteria immune to the medications. Nearly 18 percent of one common strain that infects humans are now immune to the very same drugs which were considered the last line of defense against the infection. Campylobacter is the leading bacterial cause of food poisoning in the United States. Typically contracted through raw or undercooked meat, the germs afflict more than 2 million people and kill some 500 each year in the US, according to the CDC. While Abbot voluntarily withdrew its version of the antibiotic (SaraFlox), Bayer decided to challenge the FDA. The company had the option to comply with the proposed ban or seek a hearing to determine whether such a move was justified. Bayer refused to comply with the ban, a move that kicked off a lengthy process that could take years (35). Meanwhile Bayer gets to poison the world, AND make huge profits from it... The AMA has advised its members to prescribe CIPRO very cautiously, saying the worldwide problem of antibiotic resistance poses future dangers worse than the anthrax attacks of today (Orlando Sentinel, October 20, 2001). PHOTOSENSITIVITY Photosensitization can result when light interacts with chemical agents in the skin and eyes. This process can produce undesirable clinical consequences, such as phototoxicity (i.e. exaggerated sunburn), photoallergy, or photocarcinogenicity. People receiving CIPRO or any other fluoroquinolone are warned on the product inserts not to expose themselves to direct sunlight. Rashs develop on the areas exposed. Upon UVA-irradiation the "fluorine" of numerous fluoroquinolones such as lomefloxacin and fleroxacin, are "lost" as fluoride (36). "We have discovered that anions can activate visual photoreceptors in the dark. One anionic activator is the commonly used dental agent fluoride. The data on in vitro preparations indicate that these anions modulate photoreceptor biochemistry and may effect photoreceptors sensitivity..." [Lewis A - "Fundamental studies in the molecular basis of laser induced retinal damage" Annual report (Final) March 1 1979 - March 15, 1985 US DTIC records (unclassified) AD#177817 (1985)] MEDLINE has many articles on fluoride and photoreceptor activation (G protein-coupled) (35).

OTHER CIPRO SIDE EFFECTS (29): Abnormal dread or fear, achiness, bleeding in the stomach and/or intestines, blood clots in the lungs, blurred vision, change in color perception, chills, confusion, constipation, convulsions, coughing up blood, decreased vision, depression, difficulty in swallowing, dizziness, double vision, drowsiness, eye pain, fainting, fever, flushing, gas, gout flare up, hallucinations, hearing loss, heart attack, hiccups, high blood pressure, hives, inability to fall or stay asleep, inability to urinate, indigestion, intestinal inflammation, involuntary eye movement, irregular heartbeat, irritability, itching, joint or back pain, joint stiffness, kidney failure, labored breathing, lack of muscle coordination, lack or loss of appetite, large volumes of urine, light-headedness, loss of sense of identity, loss of sense of smell, mouth sores, neck pain, nightmares, nosebleed, pounding heartbeat, ringing in the ears, seizures, sensitivity to light, severe allergic reaction, skin peeling, redness, sluggishness, speech difficulties, swelling of the face, neck, lips, eyes, or hands, swelling of the throat, tender, red bumps on skin, tingling sensation, tremors, unpleasant taste, unusual darkening of the skin, vaginal inflammation, vague feeling of illness, weakness, yellowed eyes and skin. CIPRO causes fluoride poisoning. Will any practitioner know how to deal with this, considering that the ADA has shielded all from proper knowledge of fluoride toxicity? Andreas Schuld, Wendy Small, Trent Harris Parents of Fluoride Poisoned Children (PFPC) Vancouver, BC, Canada pfpc@istar.ca 1) "Poison Control: Fluorides, the deadly toxin within" (http://www.prn.usm.my/bulletin/nst/2001/nst34.html) 2) 7AM - News: "Cures That Kill?" (http://www.7amnews.com/2001/features/081801.shtml) 3) Dr. Mercola - "Baycol - Another Fluoride Drug Bites the Dust" (PFPC News, August 18, 2001) (http://www.mercola.com/2001/aug/18/fluoride_drugs.htm) 4) Clinical Toxicology Review - "What Are Fluoroquinolones?" CTR, Massachusetts Poison Control System, Vol. 20, No. 3 (1997) 5) FDA TALK PAPER " APPROVAL OF CIPROÆ FOR USE AFTER EXPOSURE TO INHALATIONAL ANTHRAX" Food and Drug Administration, U.S. Department of Health and Human Services Public Health Service 5600 Fishers Lane Rockville, MD 20857 (2000) 6) CNN - Reuter's, July 27, 2000 7) Fuchs S, Simon Z, Brezis M - "Fatal hepatic failure associated with ciprofloxacin" Lancet 242:738-739 (1994) 8) 150+ Related References : CIPRO - Liver (http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/ query?form=4&db=m&term=cipro&liver) 9) Hootkins R, Fenves AZ, Stephens MK - "Acute renal failure secondary to oral ciprofloxacin therapy: a presentation of three cases and a review of the literature" Clin Nephrol 32(2):75-8 (1989) 10) Reece RJ, Nicholls AJ - "Ciprofloxacin-induced acute interstitial nephritis" Nephrol Dial Transplant 11(2):393 (1996) 11) 90+ Related References : CIPRO - Renal failure (http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/ query?form=4&db=m&term=cipro&renal&failure) 12) Pradhan KM, Arora NK, Jena A, Susheela AK, Bhan MK - "Safety of ciprofloxacin therapy in children: magnetic resonance images, body fluid levels of fluoride and linear growth" Acta Paediatr 84(5):555-60 (1995) 13) Australian Adverse Drug Reactions Bulletin - Vol. 16, No. 2 (May 1997) 14) Ramanujam TR - "Fluoroquinolones - A Review" (2001) (http://www.mcsindia.org/doctors/Epharma/january.asp) 15) Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399) (http://www.citizen.org/publications/release.cfm?ID=6595) 16) Information on Adverse Reactions to Drugs No.128, October 1994 17) FDA Medical Bulletin - Vol. 26, No.3 (October 1996) 18) 27th Meeting of the Drug Evaluation Sub-Committee, Ministry of Health, Colombo (November 1996) 19) Shakibaei M, de Souza P, van Sickle D, Stahlmann R - "Biochemical changes in Achilles tendon from juvenile dogs after treatment with ciprofloxacin or feeding a magnesium-deficient diet" Arch Toxicol 75(6):369-74 (2001) 20) Clinical Toxicology Review, Vol. 20, No. 3 (1997) 21) Herrlin K, Segerdahl M, Gustafsson LL, Kalso E - "Methadone, ciprofloxacin, and adverse drug reactions" Lancet 356(9247):2069-70 (2000) 22) Ellis RJ, Mayo MS, Bodensteiner DM - "Ciprofloxacin-warfarin coagulopathy: a case series" Am J Hematol 63(1):28-31 (2000) 23) Guzman A, Garcia C, Demestre I - "Subchronic toxicity of the new quinolone antibacterial agent irloxacin in beagle dogs" Arzneimittelforschung 50(5):485-94 (2000) 24) Kraft K - "•ber die Synthese einiger aromatischer Fluorverbindungen" Knoll Research, Chem Ber. 84(2):150-156 (1951) (describes manufacturing processes of numerous organic fluorides, after it was shown that all organic fluoride compounds displayed stronger anti-thyroid activity than the mere "fluoride ion") 25) Kraft K, Dengel F - "•ber die Synthese einiger aromatischer Fluorverbindungen, II. Mitteilung" Chem Ber 85(6):577-582 (1952) (more reports on organic fluoride investigations..."in regards to their characteristics in lowering BMR as well as anti-bacterial activity") 26) Zutavern EP, Kraft K - "Verfahren zur Herstellung von organischen Salzen der Fluorwasserstoffs†ure" German Patent No. 855118, granted Dec. 5, 1950 (Knoll AG) (Kraft patent on the same organic fluoride compounds used previously in the treatment of hyperthyroidism, now patented as anti-caries agents!) 27) Eichler O, Kraft K - "Verfahren zur Herstellung einer alkalischen, seifenfreien, reagibles Fluor neben Calciumcarbonat enthaltenden Zahnpasta" German Patent No. 971375, granted Aug. 28, 1951 (Knoll AG) (patent describing the use of ethanol-amino-hydrofluorides in toothpaste...) 28) Pineau T, Fernandez-Salguero P, Lee SS, McPhail T, Ward JM, Gonzalez FJ - "Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2" Proc Natl Acad Sci U S A 92(11):5134-8 (1995) 29) Cipro Monograph (http://www.healthsquare.com/pdrfg/pd/monos/cipro.htm) 30) Coronado VG, Edwards JR, Culver DH, Gaynes RP - "Ciprofloxacin resistance among nosocomial Pseudomonas aeruginosa and Staphylococcus aureus in the United States. National Nosocomial Infections Surveillance (NNIS) System" Infect Control Hosp Epidemiol 16(2):71-5 (1995) 31) Smith KE, Besser JM, Hedberg CW, Leano FT, Bender JB, Wicklund JH, Johnson BP, Moore KA, Osterholm MT - "Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998" N Engl J Med 340(20):1525-32(1999) 32) CDC Special Report : "Emerging Mechanisms of Fluoroquinolone Resistance" David C. Hooper Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 33) Kurtz CI, Fitzpatrick R - "Anionic polymers as toxin binders and antibacterial agents" US Patent 6,290,946, GelTex Pharmaceuticals, Inc. (2000) 34) Orlando Sentinel, October 20, 2001 35) Bayer Balks at Banning Poultry Antibiotic - FDA, citing resistance, seeks removal" By Adam Marcus HealthScout Reporter, Dec. 1, 2000 36) Chignell CF - "Mechanisms of chemically induced photosensitivity" Crisp Data Base National Institutes Of Health, CRISP/99/ES50046-20 (1998). 37) Photoreceptor/fluoride - 50+ References http://www.ncbi.nlm.nih.gov/htbin-