BMJ. 2008 Jul 19; 337(7662): 135.doi: 10.1136/bmj.a816PMCID: PMC2483892PMID: 18632714FDA adds “black box” warning label to fluoroquinolone antibioticsJanice Hopkins TanneAuthor information Copyright and License information PMC DisclaimerThe US Food and Drug Administration has told manufacturers of fluoroquinolones to warn doctors and patients of the raised risk of tendinitis and tendon rupture. The “black box” warning, the most stringent, must be added to drug labels and prescribing information, and manufacturers must also develop a treatment guide for patients.These measures, the FDA said on 8 July, would strengthen the existing warnings in the prescribing information for fluoroquinolones. The warnings apply to tablets, capsules, and injectable formulations for systemic use but not to ophthalmic or otic formulations.Public Citizen, a non-profit consumer rights organisation, said that the FDA had accomplished “two of the three steps Public Citizen has urged the agency to do for nearly two years.” The third step, which FDA did not take, was to send a warning letter to doctors “clearly describing possible adverse reactions, such as tendon pain, so that patients can be switched to alternative treatments before tendons rupture.”Public Citizen, together with the Illinois attorney general, petitioned the FDA in August 2006 to strongly warn the public about the risk of tendon rupture. When the FDA did not act it sued the agency in January to compel it to act.Public Citizen says that more than 100 cases of tendon rupture could have been avoided if the FDA had acted more quickly. It said, “From November 1997 through December 2007, there have been 407 reported cases of tendon rupture and 341 cases of tendinitis in patients using fluoroquinolone antibiotics. Because only a small fraction of cases are typically reported to the FDA, the actual number of ruptures and other tendon injuries attributable to the antibiotic is much higher.”The most common rupture was of the Achilles tendon.The drugs affected by the new warning include ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin.The FDA said the risk of tendinitis and tendon rupture was higher in people aged over 60, patients who had received kidney, heart, or lung transplants, and people taking steroid treatment. It said that doctors should tell patients to stop taking fluoroquinolones at the first sign of tendon pain, swelling, or inflammation, to avoid exercise and use of the affected area, and to contact a doctor promptly about changing to a non-fluoroquinolone antibiotic.Although most patients do not have problems, the FDA told doctors to consider the benefits and risks for each patient before prescribing a fluoroquinolone and to use them only for treating or preventing infections caused by bacteria. It also noted that patients may develop other serious adverse effects, including convulsions, hallucinations, depression, prolonged QTc (corrected QT interval) and torsades de pointes, and Clostridium difficile associated diarrhoea.

Global Evolution of Pathogenic Bacteria With Extensive Use of Fluoroquinolone AgentsMiklos Fuzi1* Jesus Rodriguez Baño2 Akos Toth31Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary2Unit of Infectious Diseases, Clinical Microbiology and Preventive Medicine, Department of Medicine, Hospital Universitario Virgen Macarena, University of Seville – Biomedicine Institute of Seville (IBiS), Seville, Spain3Department of Bacteriology, Mycology and Parasitology, National Public Health Center, Budapest, HungaryIt is well-established that the spread of many multidrug-resistant (MDR) bacteria is predominantly clonal. Interestingly the international clones/sequence types (STs) of most pathogens emerged and disseminated during the last three decades. Strong experimental evidence from multiple laboratories indicate that diverse fitness cost associated with high-level resistance to fluoroquinolones contributed to the selection and promotion of the international clones/STs of hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA), extended-spectrum ß-lactamase-(ESBL)-producing Klebsiella pneumoniae, ESBL-producing Escherichia coli and Clostridioides difficile. The overwhelming part of the literature investigating the epidemiology of the pathogens as a function of fluoroquinolone use remain in concordence with these findings. Moreover, recent in vitro data clearly show the potential of fluoroquinolone exposure to shape the clonal evolution of Salmonella Enteritidis. The success of the international clones/STs in all these species was linked to the strains’ unique ability to evolve multiple energetically beneficial gyrase and topoisomerase IV mutations conferring high-level resistance to fluorquinolones and concomittantly permitting the acquisition of an extra resistance gene load without evoking appreciable fitness cost. Furthermore, by analyzing the clonality of multiple species, the review highlights, that in environments under high antibiotic exposure virulence factors play only a subsidiary role in the clonal dynamics of bacteria relative to multidrug-resistance coupled with favorable fitness (greater speed of replication). Though other groups of antibiotics should also be involved in selecting clones of bacterial pathogens the role of fluoroquinolones due to their peculiar fitness effect remains unique. It is suggested that probably no bacteria remain immune to the influence of fluoroquinolones in shaping their evolutionary dynamics. Consequently a more judicious use of fluoroquinolones, attuned to the proportion of international clone/ST isolates among local pathogens, would not only decrease resistance rates against this group of antibiotics but should also ameliorate the overall antibiotic resistance landscape.

Fluoroquinolone pollution of food, water and soil, and bacterial resistanceReviewPublished: 08 September 2014Volume 13, pages 21–36, (2015)Cite this articleEnvironmental Chemistry LettersAims and scopeSubmit manuscriptAura Rusu, Gabriel Hancu & Valentina Uivarosi2100 Accesses73 Citations3 AltmetricExplore all metricsAbstractFluoroquinolones are a valuable synthetic antibacterial class widely used in the treatment of infectious diseases both in humans and animals. Until recently, it has been thought that bacterial resistance to fluoroquinolones develops very slowly. Nowadays, there are multiple studies that reveal the alarming occurrence of bacterial resistance and there is a high risk of becoming therapeutically useless. The emergence of this phenomenon comes from injudicious usage in therapy, the presence of residues and their metabolites in food of animal origin and also in sewage, compost and domestic waste, which end up in soil and water sources. In the present paper, we reviewed important issues regarding fluoroquinolones impact on the environment in connection with the development of bacterial resistance: (1) the presence of fluoroquinolones as pollutants in soil, surface waters, and food. Fluoroquinolones are persistent with high specificity to interact with soil compared to other antibiotics. Pollution of water sources raises concerns regarding the effects of small concentrations (ng L-1) on human health and also of the environment. The non-therapeutic use in animal farms conducts to food pollution; the cultivated plants could concentrate the fluoroquinolones (over 100 µg L-1); (2) the increase of bacterial resistance to fluoroquinolones occurring with specific mutations in the target enzymes as well by the plasmid-mediated resistance and active efflux of the cell; (3) international regulations of the fluoroquinolone residues in food that are far to encompass all compounds; (4) fluoroquinolones residues analysis with standardized methods should provide limits of detection lower than maximum residue limit values; and (5) trends and perspectives: (a) a wider process of harmonization of regulations; (b) the fluoroquinolones restriction, necessary for low levels of bacterial resistance; (c) the soil and waste water purification methods; (d) the practice of soil planting scheme as an alternative; and (e) an environmental label in order to facilitate the selection of drugs.

Fluoroquinolones (FQs) are highly potent bactericidal antibiotics with broad-spectrum activity against Gram-negative/positive bacteria. The Food and Drug Administration (FDA) anticipated the presence of a long-lasting incapacity of Fluoroquinolone Associated Toxicity (FQAT), which is not officially documented yet. This review aimed to précis the existing information on FQA long-term toxicity, such as cardiotoxicity, aortic aneurysm, tendon rupture, nephrotoxicity, hepatotoxicity, peripheral neuropathy, vagus nervous dysfunction, reactive oxygen species (ROS), phototoxicity, glucose hemostasis, and central nervous system (CNS) toxicity. We are focused on the CNS toxicity of FQs, either due to the direct action of the FQs on CNS receptors or by other drug co-administration, including nonsteroidal anti-inflammatory disease (NSAIDs) and theophylline. Due to the nature of the R7 side chain, FQs containing unsubstituted 7-piperazine and 7-pyrrolidine have the most significant effect. The gamma-aminobutyric acid-A (GABAA) receptor and CNS effects are inhibited through at least three possible mechanisms. Firstly, by the pharmacological action of the quinolone directly. Secondly, FQ-NSAIDs interact pharmacodynamically in which the interaction between the FQ and a receptor is significantly altered by the presence of another drug that interacts with the same receptor. An example may be the interaction between NSAIDs and some FQs. Thirdly, a pharmacokinetic drug-drug interaction leads to a higher concentration of quinolone or the other drug. An example may be the interaction between theophylline and benzodiazepines with some FQs.