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Update on New Fluoroquinolones Boxed Warning & Increasing Fluoroquinolone Resistance JENNIFER DOAN, PHARM. D PHARMACY RESIDENT, UNITY HEALTH SEPTEMBER 30, 2016 1 Learning Objectives Recognize potential fluoroquinolone toxicities that may occur with systemic fluoroquinolone use Discuss the efficacy of systemic fluoroquinolone use for the following indications: Acute bacterial sinusitis Acute bacterial exacerbation of chronic bronchitis Uncomplicated urinary tract infections Understand increasing resistance with fluoroquinolone use 2 Fluoroquinolones Mechanism of Action: Inhibition of DNA replication by binding to topoisomerase II (DNA gyrase) and topoisomerase IV FDA-Approved Indications Community-acquired pneumonia Nosocomial pneumonia Chronic bronchitis (acute bacterial exacerbation) Acute bacterial rhinosinusitis Prostatitis Urinary tract infection (uncomplicated or complicated) Acute pyelonephritis Skin or skin structure infections (uncomplicated or complicated) 3 Potential Adverse Effects Photosensitivity Hypersensitivity QT prolongation Peripheral neuropathy Tendinitis or tendon rupture CNS effects Myasthenia gravis exacerbation 4 Photosensitivity & Hypersensitivity Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions involving areas exposed to light, can be associated with the use of fluoroquinolones after sun or UV light exposure Hypersensitivity: Serious and potentially fatal anaphylactic reactions may occur in patients who receive fluoroquinolone therapy 5 QT-Interval Prolongation Fluoroquinolones may lead to prolonged QT intervals due to inhibition of potassium channels Prolonged QTc interval >500 milliseconds is associated with an increased risk for Torsades de Pointes, a life-threatening cardiac arrhythmia Although QT prolongation is not common, caution should be warranted with fluoroquinolone use when being administered with other agents that cause QT prolongation 6 Peripheral Neuropathy Peripheral neuropathy: Nerve disorder that occurs in the arms or legs Symptoms: Pain, tingling, numbness, weakness These reactions may occur at any time during treatment and may persist for months to years after the agent is discontinued 7 Tendinitis or Tendon Rupture Symptoms: Pain, swelling, inflammation of a tendon or tendon rupture The risk of developing tendinitis or tendon rupture is further increased in: Patients who are older than 60 years old Patients who are taking corticosteroid drugs Patients who are kidney, heart, and lung transplant recipients 8 CNS Effects Fluoroquinolones have potential for CNS adverse effects such as: Depression, suicidal thoughts Hallucinations Confusion Anxiety Mild headache Drowsiness or insomnia Seizures – rare but may still occur (especially in patients with a lower seizure threshold) 9 Myasthenia Gravis Myasthenia gravis is a disease characterized by skeletal muscle weakness and may involve symptoms such as: Drooping eyelid, blurred or double vision Slurred speech, difficulty chewing/swallowing Weakness in arms/legs Case reports revealed that fluoroquinolone exposure may lead to life-threatening myasthenia gravis exacerbations in patients with underlying disease 10 November 2015 Antimicrobial Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee met to discuss the efficacy and safety of fluoroquinolone use in cases of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infection The suggestion of stronger warnings for systemic fluoroquinolones was discussed 11 Literature Review Before FDA-Approval Acute Bacterial Exacerbation of Chronic Bronchitis: The FDA reviewed 15 placebo-controlled trials and found that only six of the trials revealed statistically significant results Fluoroquinolone use may be considered in patients who have moderate-tosevere acute bacterial exacerbation of chronic bronchitis Acute Bacterial Sinusitis: The FDA reviewed 20 published placebo-controlled trials and found that only six of the trials revealed statistically significant results Lack of clinical criteria to differentiate between bacterial and viral acute rhinosinusitis has led to inappropriate antibacterial therapy Uncomplicated Urinary Tract Infection: The FDA reviewed 5 prospective, randomized, controlled trials for patients in an outpatient setting A good proportion of patients who received placebo treatment still achieved microbiological eradication 12 New Fluoroquinolone Boxed Warning Fluoroquinolones should be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections 13 Excessive Fluoroquinolone Use Consequences Excessive use of fluoroquinolone agents had led to widespread resistance among bacterial pathogens Resistance develops by either mutation or acquisition of novel genetic information Fluoroquinolone resistance has been demonstrated in urinary infections, respiratory infections, gastrointestinal tract infections, skin and soft-tissue and bone and joint infections, sexually transmitted diseases, and ulcers 14 Common Organisms with Potential for Resistance Burkholderia cepacia Mycoplasma pneumoniae Campylobacter jejuni Neisseria gonorrhoeae Chlamydia trachomatis Pseudomonas aeruginosa Enterococcus faecium Staphylococcus aureus Escherichia coli Streptococcus pneumoniae Klebsiella pneumoniae 15 Antibiogram Chart 16 Preserving Fluoroquinolone Efficacy Develop an evidence-based approach to antimicrobial selection Assess the appropriateness of drug utilization by reviewing the activity of these agents and the patient’s disease state Ensure that patients who are candidates for fluoroquinolone use, are provided an indicated dose for an appropriate duration of time 17 Question The new FDA boxed warning opposes the use of fluoroquinolones in all cases of ABS, ACBECB, and uUTI due to the disabling and potentially permanent adverse effects that are associated with systemic fluoroquinolone use. A. True B. False 18 References Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams JW Jr. Makela M. Antibiotics for acute maxillary sinusitis in adults. Cochrane Database Syst Rev. 2014 Feb 11;(22):CD000243. doi:10.1002/14651858.CD0000243.pub3 Alonso Martínez JL, Rubio Obanos MT, Sampériz Legarre AL, Escolar Castellón F, Carrasco del Amo ME. Antibiotic treatment for acute episodes of chronic obstructive pulmonary disease. An Med Interna. 1992;9(8):377-80 Axelsson A, Chidekel N, Grebelious N, Jensen C. Treatment of acute maxillary sinusitis. A comparison of four different methods. Acta Otolaryngol. 1970;70(1):71-6 Baquero F. Antibiotic resistance in Spain: What can be done? Task Force of the General Directions for Health Planning of the Spanish Ministry of Health. Clin Infect Dis. 1996;23:819-23. Chou HW, Wang JL, Chang CH, Lai CL, Lai MS, Chan KA. Risks of cardiac arrhythmia and mortality among patients using new-generation macrolides, fluoroquinolones, and beta-lactam/beta-lactamase inhibitors: a Taiwanese nationwide study. Clin Infect Dis 2015;60:566577. Etminan M, Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: a pharmacoepidemiologic study. Neurology. 2014 Sep 30;83(14):1261-3. FDA Briefing Document. Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Gerdin DN. Clindamycin, cephalosporins, fluoroquinolones, and Clostridium difficile-associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis. 2004;38(5):646-8. 19 References Hadley JA, Mӧsges R, Desrosiers M, et al. Moxifloxacin five-day therapy versus placebo in acute bacterial rhinosinusitis. The Laryngoscope. 2010;120(5):1057-1062 IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf. 2001 Oct 1;34(10):839-47. Karageorgopoulos DE, Giannopoulou KP, Grammatikos AP, et al. Fluoroquinolones compared with β-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials. CMAJ. 2008;178(7):845-54. Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc. (accessed Aug 22, 2016). Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: A review focusing on newer agents. Clin Infect Dis. 1999;28(2):352-361. Manresa F, Blavia R, Martin R, Liñares J, Rodriguez B, Verdaguer R. Antibiotics for exacerbations of chronic bronchitis. Lancet. 1987;2(8555):394-5. McCusker ME, Harris AD, Perencevich E, Roghmann MC. Fluoroquinolone use and Clostridium difficile-associated diarrhea. Emerg Infect Dis. 2003 June;9(6):730-3. Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacoth. 2007;41(11):1859-1866. Nouria S, Marghi S, Belghith M, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo controlled trial. Lancet. 2001;358(9298):2020-25 20 References Owens RC, Ambrose PG. Antimicrobial safety: Focus on fluoroquinolones. Clinical Infectious Diseases. 2005;41(Supplement 2):S144S157. Rao GA, Mann JR, Shoaibi A, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death. Ann Fam med 2014;12(2):121-127. Saux NL. The treatment of acute bacterial sinusitis: No change is good medicine. CMAJ. 2008 Mar 25;178(7): 865-866. Seeger JD, West WA, Fife D, Noel GJ, Johnson LN, Walker AM. Achilles tendon rupture and its association with fluoroquinolone antibiotics and other potential risk factors in a managed care population. Pharmacoepidemiol Drug Saf. 2006;15(11):784-792. U.S Food and Drug Administration. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH. Increased risk of Achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch Intern Med. 2003;163(15):1801-1807. Wilton LV, Pearce GL, & Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol. 1996;41(4):277-284. 21