Adverse Effects of Flouroquinolone Antibiotics
by Jeffrey Dach MD
Beatrice Golomb raised a warning flag for commonly used antibiotics such as Ciprofloxin and Levoquin, also known as Flouroquinolones, citing adverse effects which include Achilles Tendon rupture (left image) Her recent BMJ article reports four unfortunate victims of the adverse effects of flouroquinolone class of antibiotics.(1) Left Image: ruptured left Achilles Tendon courtesy of Wikimedia commons.
The most commonly reported adverse effect is tendon degeneration and tendon rupture. This is especially debilitating if it involves the Achilles tendon in back of the ankle. In addition, adverse effects involving muscle, cartilage and nerve tissue has been reported. Athletes as a group should be especially cognizant of these adverse effects, and avoid Cipro and other flouroquinolones whenever feasible.(2-5)
Dr Perlmutter brings attention to a recent publication in Neurology which brings to light the increasing occurrence of peripheral neuropathy as an adverse effect of flouroquinolone antibiotics.(6,7)
Flouroquinolones as Mitochondrial Toxins
Lyn Margulis’s work on the endosymbiotic theory proposed that mitochondria actually originated as bacteria incorporated into ancient eucaryotic cells. After decades of rejection, her theory was ultimately accepted. New molecular tools revealed that mitochondrial genes are similar to bacterial genes, and quite different from genetic material in the cell nucleus. John Archibald writes in The Scientist in 2014, The Cellular Revolution :
“The genetic material within the mitochondria and chloroplasts of present-day organisms was, even with 1970s-style technologies, demonstrably bacterial, highly distinct from that residing in the cell nucleus.”
Indeed, mitochondria share many of the same features of the bacterial world, and are thought to have “evolved” from bacterial life forms.(20-21) If this is true, then one might then suggest that antibacterial agents (antibiotics) such as flouroquinolones, whose mode of action is interference with bacterial DNA replication, would have a similar deleterious effect on mitochondrial DNA replication. Indeed, this is the case for flouroquinolone antibiotics which are mitochondrial toxins. (14-16)
Jeffrey Lawrence reported in 1996 on “Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells.” He found that cytotoxic effects of ciprofloxacin were caused by interference with mitochondrial topoisomerase II activity, resulted in a loss of mitochondial DNA.(16) Flouroquinolones target Type II topoisomerases and DNA Gyrases. The mechanism of action is summarized nicely by Dr Anderson in his 2001 article : (23)
(Flouroquinlones)… “corrupt the activities of two essential enzymes, DNA gyrase and topoisomerase IV, and induce them to kill cells by generating high levels of double-stranded DNA breaks.”
DNA Topoisomerase is involved in unwinding of DNA strands during cell replication. Here is a short one minute video explaining how DNA topisomerase I and II work.
Thanks and credit to Lisa Bloomquist and “Floxie Hope “ for the following diagrams and information:
Above diagram shows activity of DNA Topoisomerase.
Here is a quote from Lisa Bloomquist’s article:
“Many assert that fluoroquinolones only affect bacterial topoisomerases. It turns out that mitochondrial topoisomerases are affected too. Fluoroquinolones should be used as prudently and cautiously as all other topoisomerase interrupting drugs. All the other topoisomerase interrupting drugs are chemo drugs that are only used to treat cancers. To prescribe a drug that depletes mitochondrial DNA and affects human topoisomerases in order to treat urinary tract infections and traveler’s diarrhea is absurd, short-sighted and wrong.”
Cipro for UTI, Prostate, Sinus and Respiratory Infections
The flouroquinolones are commonly prescribed for various infections involving urinary tract, prostate, sinuses and respiratory tract. One might ask the next logical question. Are there natural alternatives to flouroquinolone antibiotics which do not carry these side effects?
Natural Alternatives to Fluoroquinolones
The answer is YES there are very effective plant derived natural anti-microbials which have been used for centuries to combat infections. Here we list only a few of many.
Allicin, the active ingredient in Garlic, is an effective antimicrobial agent. See these articles:
1) Garlic as Effective for Coronary Calcium Score and as antimicrobial.
2) Garlic as an Antimicrobial Agent
Berberine (Oregon Grape) is an effective antimicrobial agent. See this article: Berberine Antidote to a Modern Epidemic
Olive Leaf Extract is another very effective antimicrobial agent. See this article: The Amazing Olive Leaf.
Flouroquinolones as Anti-Cancer Agents
Recent revelations in molecular biology have revealed cancer as a metabolic disease in which the mitochondria are reprogrammed to voraciously consume massive amounts of glucose, serving as substrate and carbon source unrestrained cancer cell replication.
As mentioned in my previous article, Cancer as a Metabolic Disease, many drug and natural plant substances target the mitochondria in cancer cells, accounting for their effectiveness as anti-cancer agents. One might ask the next question: Since flouroquinolones target the mitochondria, perhaps they would serve as anti-cancer agents. A number of studies have confirmed, YES, this is indeed the case. (17-19)
Articles with Related Interest:
Jeffrey Dach MD
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Davie Fl 33314
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Links and references:
1) Fluoroquinolone adverse effects Golomb BMJ 2015
Fluoroquinolone-induced serious, persistent, multisymptom adverse effects.
Golomb BA, Koslik HJ, Redd AJ. BMJ Case Rep. 2015 Oct 5;2015.
significant disability in previously
healthy, highly functional individuals
These findings buttress and extend prior reports involving FQ-induced tendon, muscle, central nervous, psychiatric, peripheral nervous, gastrointestinal, autonomic and endocrine FQ-induced serious and persistent AEs.
FQs be avoided for non-life-threatening, mild, moderate and uncomplicated infections.
full free pdf
2) Fluoroquinolone-associated tendinopathy.
Tsai, Wen-Chung, and Yun-Ming Yang. “Fluoroquinolone-associated tendinopathy.” Chang Gung Med J 34.5 (2011): 461-467.
The fluoroquinolones (FQs) are used to treat a wide range of infections because of their excellent gastrointestinal absorption, superior tissue penetration and broad-spectrum activity. Recently, FQ-associated tendinopathy and tendon rupture have been reported, especially in the elderly and patients with diabetes and renal failure. However, these adverse effects do not appear to be widely known among physicians. Because of the frequent use of FQs in clinical practice, physicians should be aware of their potential for severe disability from tendon rupture. Achilles tendinopathy or rupture is among the most serious side effects associated with FQ use, with reports markedly increasing, especially with the use of ciprofloxacin. The histopathologic findings include degenerative lesions, fissures, interstitial edema without cellular infiltration, necrosis and neovascularization. There are possible molecular mechanisms accounting for FQ-associated tendinopathy. First, ciprofloxacin mediates inhibition of cell proliferation and G2/M cell cycle arrest in tendon cells by down-regulation of cyclin B and cyclin-dependent kinase 1. Second, ciprofloxacin inhibits the spead and migration of tenocytes by down-regulation of focal adhesion kinase phosphorylation. Third, ciprofloxacin enhances the enzymatic activity of matrix metalloproteinase-2 with degradation of type I collagen. Management of FQ-associated tendinopathy includes immediate discontinuation of FQs, rest, non-steroidal anti-inflammatory drugs, physical modalities and eccentric strengthening exercise. Tendon rupture may require surgical intervention.
free full text
3) Fluoroquinolone-induced tendinopathy: etiology and preventive measures.
Kaleagasioglu, Ferda, and Ercan Olcay. “Fluoroquinolone-induced tendinopathy: etiology and preventive measures.” The Tohoku journal of experimental medicine 226.4 (2012): 251-258.
Tendinopathy is a serious health problem and its etiology is not fully elucidated. Among intrinsic and extrinsic predisposing factors of tendinopathy, the impact of therapeutic agents, especially fluoroquinolone (FQ) group antibiotics, is recently being recognized. FQs are potent bactericidal agents widely used in various infectious diseases, including community acquired pneumonia and bronchitis, chronic osteomyelitis, traveler’s diarrhea, typhoid fever, shigellosis, chronic bacterial prostatitis, uncomplicated cervical and urethral gonorrhea and prophylaxis of anthrax. FQs have an acceptable tolerability range. However, many lines of evidence for developing tendinitis and tendon rupture during FQ use have resulted in the addition of a warning in patient information leaflets. FQ-induced tendinopathy presents a challenge for the clinician because healing response is poor due to low metabolic rate in mature tendon tissue and tendinopathy is more likely to develop in patients who are already at high risk, such as elderly, solid organ transplant recipients and concomitant corticosteroid users. FQs become photo-activated under exposure to ultraviolet light, and this process results in formation and accumulation of intracellular reactive oxygen species (ROS). The subsequent FQ-related oxidative stress disturbs mitochondrial functions, leading to apoptosis. ROS overproduction also has direct cytotoxic effects on extracellular matrix components. Understanding the mechanisms of the FQ-associated tendinopathy may enable designing safer therapeutic strategies, hence optimization of clinical response. In this review, we evaluate multi-factorial etiology of the FQ-induced tendinopathy and discuss proposed preventive measures such as antioxidant use and protection from natural sunlight and artificial ultraviolet exposure.
4) Beware of fluoroquinolones: You, your patient, and the FDA By Matthew DeLaney, MD|April 7th, 2014
full free pdf Musculoskeletal Complications Fluoroquinolones Athletic Hall 2011
Hall, Mederic M., Jonathan T. Finnoff, and Jay Smith. “Musculoskeletal complications of fluoroquinolones: guidelines and precautions for usage in the athletic population.” PM&R 3.2 (2011): 132-142.
5) full pdf Ciprofloxacin induced chondrotoxicity and tendinopathy Adikwu 2012
Adikwu, Elias, and Nelson Brambaifa. “Ciprofloxacin induced chondrotoxicity and tendinopathy.” American Journal of Pharmacology and Toxicology 7.3 (2012): 94-100.
free full text
6) Neurology. 2014 Sep 30;83(14):1261-3.
Oral fluoroquinolone use and risk of peripheral neuropathy: a pharmacoepidemiologic study. Etminan M1, Brophy JM2, Samii A2.
To quantify the risk of peripheral neuropathy (PN) with oral fluoroquinolone (FQ) use.
METHODS:We conducted a case-control study within a cohort of men aged 45 to 80 years in the United States followed from 2001 to 2011. Cases were defined as those with the first physician visit diagnosis of PN, polyneuropathy, or drug-induced polyneuropathy. Four controls were matched to each case by age, follow-up, and calendar time using density-based sampling. As a sensitivity analysis, we also quantified the risk of PN with finasteride use, a drug that is not expected to increase the risk of PN. Rate ratios (RRs) for current users of FQs were computed using conditional logistic regression, which was adjusted for chronic renal failure, chronic liver disease, hypothyroidism, postherpetic neuralgia, and the use of nitrofurantoin and metronidazole.
RESULTS:We identified 6,226 cases and 24,904 controls. Current users of FQs were at a higher risk of developing PN (RR = 1.83, 95% confidence interval [CI] 1.49-2.27). Current new users had the highest risk (RR = 2.07, 95% CI 1.56-2.74). No risk was observed for current users of finasteride (RR = 1.21, 95% CI 0.97-1.51).
CONCLUSIONS:Current users, especially new users of FQs, are at a higher risk of developing PN. Despite the increase in the use of FQs, clinicians should weigh the benefits against the risk of adverse events when prescribing these drugs to their patients.
7) Fluoroquinolones and Peripheral Neuropathy by David Perlmutter MD neurologist
8) Dangers of Fluoride-Based Antibiotics, Plus Natural Solutions
by Paul Fassa May 6, 2013
9)Surviving Cipro Web Site
A Guide to Fluoroquinolone Toxicity Syndrome and Finding a Cure
10) More references on adverse effects of flouroquinolones.
If your doctor hands you a prescription for a fluoroquinolone antibiotic (this could be not only Cipro or Levaquin but also Avelox or generics ciprofloxacin, levofloxacin, and moxifloxacin, or others), be very certain that your condition warrants the risks that come along with taking these drugs.
Fluoroquinolones have fluoride as a central part of the drug. Fluoride is a known neurotoxin, and drugs with an attached fluoride can penetrate into very sensitive tissues.
13) Upadhyay, Abhinav et al. “Combating Pathogenic Microorganisms Using Plant-Derived Antimicrobials: A Minireview of the Mechanistic Basis.” BioMed Research International 2014 (2014): 761741. PMC. Web. 8 Oct. 2015.
14) full free pdf
Simões, Manuel, Madalena Lemos, and Lúcia C. Simões. “Phytochemicals Against Drug-Resistant Microbes.” Dietary Phytochemicals and Microbes. Springer Netherlands, 2012. 185-205.
Flouroquinolones as mitochondrial toxins
mitochondrial DNA: see diagram in downloads
14) Study Finds that Ciprofloxacin Depletes Mitochondrial DNA February 24, 2015 BY Floxie Hope by Lisa Bloomquist
15) Book: Floxie Hope Lisa Bloomquist Buy on AMazon Floxie Hope: A Journey Through Fluoroquinolone Antibiotic Toxicity
16) Lawrence, Jeffrey W., et al. “Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells.” Molecular pharmacology 50.5 (1996): 1178-1188.
We have previously shown that 4-quinolone drugs cause a selective loss of mitochondrial DNA (mtDNA) from mouse L1210 leukemia cells. The loss in mtDNA was associated with a delayed loss in mitochondrial function. Here, we report that the 4-quinolone drug ciprofloxacin is cytotoxic to a variety of cultured mammalian cell lines at concentrations that deplete cells of mtDNA. The IC50 values for ciprofloxacin varied from 40 to 80 micrograms/ml depending on the cell line tested. Cytotoxicity required continuous exposure of cells to drug for 2-4 days, which corresponded to approximately three or four cell doublings. Shorter times of drug exposure did not cause significant cytotoxicity. In addition, cells became drug resistant when they were grown under conditions that bypassed the need for mitochondrial respiration. Resistance was not due to a decrease in cellular drug accumulation, suggesting that ciprofloxacin cytotoxicity is caused by the loss of mtDNA-encoded functions. Analysis of mtDNA from ciprofloxacin-treated cells revealed the presence of site-specific, double-stranded DNA breaks. Furthermore, exonuclease protection studies indicated that the 5′-, but not the 3′-, ends of the drug-induced DNA breaks were tightly associated with protein. These results suggest that ciprofloxacin may be causing cytotoxicity by interfering with a mitochondrial topoisomerase II-like activity, resulting in a loss of mtDNA.
Cipro Kills Cancer Cells
17) Aranha, Olivia, David P. Wood, and Fazlul H. Sarkar. Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clinical Cancer Research 6.3 (2000): 891-900.
18) Int J Oncol. 2003 Apr;22(4):787-94.
Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis. Aranha O1, Grignon R, Fernandes N, McDonnell TJ, Wood DP Jr, Sarkar FH.
For hormone resistant prostate cancer (HRPC), chemotherapy is used but the mortality is 100% with a mean survival time of 7-8 months. Our previous studies have shown the chemotherapeutic effect of ciprofloxacin in bladder cancer. At doses 50-400 micro g/ml ciprofloxacin, the concentrations that are normally achieved at doses currently used for the treatment of anti-bacterial infections, inhibited bladder cancer cell growth and induced S/G2M arrest with modulation of key cell cycle regulatory genes and ultimately activated apoptotic processes. In this study, we investigated the effect of ciprofloxacin on androgen independent prostate carcinoma, PC3 cells and compared our results with non-tumorigenic prostate epithelial cells. The main advantage of this fluroquinolone antibiotic is its relative non-toxicity as compared to current chemotherapy, which is not very effective, for the treatment of advanced hormone resistant prostate cancer. PC3 cells as well as normal prostate epithelial cells (MLC8891) were treated with 25-400 micro g/ml ciprofloxacin, and cell counting was done during 3 days of treatment. The cell death was determined using DAPI staining of cell nuclei, 7AAD-staining followed by flow cytometric analysis as well as by activation of caspase-3, a member of the ICE family of enzymes involved in the apoptotic cascade. The cell lysates were analyzed by immunoblotting techniques for the expression of key genes targeted by ciprofloxacin (p21WAF1, Bax and Bcl-2). Translocation of bax was visualized using a fluorescence staining procedure followed by laser confocal microscopic imaging. Treatment of prostate cancer cells with ciprofloxacin resulted in a dose- and time-dependent inhibition of cell growth (70-100% with 50-400 micro g/ml of the drug). There was a concomitant induction of cell cycle arrest at the S and G2/M phases of the cell cycle as well as induction of apoptosis. The CDK inhibitor p21WAF1 was down-regulated as early as 12 h following ciprofloxacin treatment (100-200 micro g/ml for 12-24 h). There was a significant increase in the Bax/Bcl-2 ratio with translocation of Bax, a pro-apoptotic protein, to mitochondria with concomitant activation of caspase 3. These results suggest the potential usefulness of the fluroquinolone, ciprofloxacin as a chemotherapeutic agent for advanced prostate cancer. The fluroquinolone ciprofloxacin showed anti-proliferative and apoptosis inducing activity on prostate cancer cells but not on non-tumorigenic prostate epithelial cells. These effects of ciprofloxacin were mediated by cell cycle arrest at S-G2/M phase of the cell cycle, Bax translocation to mitochondrial membrane and by increasing the Bax/Bcl-2 ratio in PC3 prostate cancer cells. Based on our in vitro results, further in-depth in vivo animal or human investigations are warranted.
19) FRE FREE PDF Apoptosis by Fluoroquinolones Lung Cancer Asian Pacific JCancer Mondal 2004
Mondal, E. R., S. K. Das, and P. Mukherjee. “Comparative Evaluation of Antiproliferative Activity and Induction of Apoptosis by some Fluoroquinolones with a Human Non-small Cell Lung Cancer Cell Line in Culture.” Asian Pacific Journal of Cancer Prevention 5 (2004): 196-204.
By John Archibald December 1, 2014 The Scientist”The genetic material within the mitochondria and chloroplasts of present-day organisms was, even with 1970s-style technologies, demonstrably bacterial, highly distinct from that residing in the cell nucleus.”
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
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