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CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

The Use of Systemic and Topical Fluoroquinolones Mary Anne Jackson, MD, FAAP, Gordon E. Schutze, MD, FAAP, COMMITTEE ON INFECTIOUS DISEASES

Appropriate prescribing practices for fl uoroquinolones, as well as all abstract agents, are essential as evolving resistance patterns are considered, additional treatment indications are identifi ed, and the toxicity profi le of fl uoroquinolones in children has become better defi ned. Earlier recommendations for systemic therapy remain; expanded uses of fl uoroquinolones for the treatment of certain are outlined in this report. Prescribing clinicians should be aware of specifi c adverse reactions This document is copyrighted and is property of the American associated with fl uoroquinolones, and their use in children should continue Academy of Pediatrics and its Board of Directors. All authors have fi led confl ict of interest statements with the American Academy to be limited to the treatment of infections for which no safe and effective of Pediatrics. Any confl icts have been resolved through a process approved by the Board of Directors. The American Academy of alternative exists or in situations in which oral fl uoroquinolone treatment Pediatrics has neither solicited nor accepted any commercial represents a reasonable alternative to parenteral antimicrobial therapy. involvement in the development of the content of this publication. Clinical reports from the American Academy of Pediatrics benefi t from expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of Pediatrics may not refl ect the views of the liaisons or the organizations OVERVIEW or government agencies that they represent. The guidance in this report does not indicate an exclusive course of Fluoroquinolones are highly active in vitro against both Gram-positive treatment or serve as a standard of medical care. Variations, taking and Gram-negative , with pharmacokinetic properties that are into account individual circumstances, may be appropriate. favorable for treating a wide array of infections. The prototype quinolone All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffi rmed, agent, , was first approved by the US Food and revised, or retired at or before that time. Administration (FDA) for adults in 1964 and generally is considered to be the first generation of such agents. For more than 2 decades, DOI: 10.1542/peds.2016-2706 nalidixic acid represented the prototypic fluoroquinolone approved by PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). the FDA and was available for children 3 months and older, but it is no Copyright © 2016 by the American Academy of Pediatrics longer available. Subsequent chemical modifications resulted in a series FINANCIAL DISCLOSURE: The authors have indicated they of fluoroquinolone agents with an increased antimicrobial spectrum of have no fi nancial relationships relevant to this article to activity and better pharmacokinetic characteristics. disclose. , , and have a greater Gram-negative FUNDING: No external funding. spectrum (with activity against aeruginosa). In 2004, POTENTIAL CONFLICT OF INTEREST: The authors have ciprofloxacin became the first fluoroquinolone agent approved for use in indicated they have no potential confl icts of interest to children 1 through 17 years of age. disclose. is often referred to as a respiratory fluoroquinolone because it has increased activity against many of the respiratory pathogens, To cite: Jackson MA, Schutze GE, AAP COMMITTEE ON such as pneumoniae, , and INFECTIOUS DISEASES. The Use of Systemic and Topical Fluoroquinolones. Pediatrics. 2016;138(5):e20162706 Chlamydophila pneumoniae, while retaining activity against many of the

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 :e 20162706 FROM THE AMERICAN ACADEMY OF PEDIATRICS Gram-negative pathogens. A fourth- inhalational and . of arthrotoxicity was observed during generation agent, , A randomized, prospective, a 14-day treatment course at 90 mg/kg displays increased activity against double-blind multicenter study per day but not at 30 mg/kg per anaerobes while maintaining Gram- of moxifloxacin for complicated day. 8, 9 Apparent joint tenderness at positive and Gram-negative activity intraabdominal in the higher exposure resolved 6 weeks and also has excellent activity children, in which patients were after the last of ciprofloxacin. against Mycobacterium tuberculosis; randomly assigned to receive either Histopathologic evidence of cartilage however, there are limited safety and moxifloxacin plus comparator drug injury was noted in virtually all dosing data available in children. placebo or comparator drug plus animals given 90 mg/kg per day Animal toxicology data available moxifloxacin placebo, was completed of ciprofloxacin. At this exposure with the first quinolone compounds in July 2015, but no data are available level, the observed clinical signs all revealed their propensity to create at this time. Systemic quinolones occurred during and shortly after inflammation and subsequent licensed in the United States will be treatment but resolved by 2 months destruction of weight-bearing discussed in this report. In addition, after cessation, with no recurrent joints in canine puppies. 1, 2 This this review will contain no discussion signs noted during the 5-month observation effectively sidelined of the use of fluoroquinolones in follow-up period. Histopathologic further development or large-scale infants younger than 6 months. evidence of cartilage injury was also evaluation of this class of antibiotic observed at 30 mg/kg per day, the agents in children at that time. dose currently recommended for SAFETY children, and inflammation occurred A policy statement summarizing the in fewer than half the animals at this assessment of risks and benefits of Animal Models dose but persisted for 5 months after fluoroquinolones in pediatric patients The original toxicology studies with treatment, at full skeletal maturation. was published by the American quinolones documented cartilage The “no observed adverse event Academy of Pediatrics (AAP) in injury in weight-bearing joints in level” (NOAEL) was 10 mg/kg per 2006, and earlier recommendations canine puppies, with damage to day, a dose at which neither clinical remain, with updates as appropriate the joint cartilage proportional nor histopathologic evidence of 3 covered in this document. The to the degree of exposure. 1, 2 Each toxicity was present, but a dose too statement indicated that the quinolone has a different potential to low for therapeutic benefit. parenteral fluoroquinolones were cause cartilage toxicity, 5 but given a appropriate for the treatment of sufficiently high exposure, cartilage Similar data were developed before infections caused by multidrug- changes will occur in all animal FDA approval of levofloxacin for resistant pathogens for which models with all quinolones. adults, documenting a NOAEL at no alternative safe and effective 3 mg/kg per day for IV dosing for Although initial reports focused parenteral agent existed. However, 14 days (approximately one-quarter on articular cartilage, subsequent for outpatient management, oral the current FDA-approved dose of studies suggested the possibility of fluoroquinolones were only indicated 16 mg/kg per day for children who epiphyseal plate cartilage injury, 6 when other options were intravenous weigh less than 50 kg). Levofloxacin leading to fluoroquinolone clinical (IV) treatment with other classes has virtually 100% bioavailability, study designs lasting several years to of antibiotic agents. In 2011, the with total drug exposure being assess growth potential. Data suggest AAP published an updated clinical equivalent between IV and oral that quinolone toxicity occurs as a report because of the increased formulations at the same milligram result of concentrations present in ophthalmologic and topical use of per kilogram dose. 10 fluoroquinolones as well as data cartilage that are sufficiently high to form chelate complexes with divalent on lack of toxicity when used in Data from a lamb model, with 4 cations, particularly magnesium, children. growth rates and activity more resulting in the impairment of Quinolones that are currently closely mirroring humans than integrin function and cartilage matrix approved for pediatric patients by juvenile beagle dogs or rats, have integrity in the weight-bearing joints, the FDA and available in an IV and been reported. Gross examination of which undergo chronic trauma oral suspension formulation are articular cartilage and microscopic during routine use. 7 ciprofloxacin for the indications examination of epiphyseal cartilage of inhalational anthrax, plague, In studies of ciprofloxacin exposure did not reveal abnormalities complicated urinary tract infections to very young beagle puppies (one of consistent with cartilage injury or (UTIs), and and the most sensitive animal models for inflammation after a 14-day drug levofloxacin for the indications of quinolone toxicity), clinical evidence exposure to either or

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e2 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 1 Rate of FDA-Defi ned Arthropathy 6 Weeks and 1 Year After Treatment With Ciprofl oxacin or none of the studies found growth a Comparator inhibition. Ciprofl oxacin (n Comparator (n = 349) = 335) Levofloxacin safety data were Arthropathy rate at 6-week follow-up,a n (%) 31 (9.3) 21 (6.0%) collected on a large cohort of 95% CI, % (–0.8 to 7.2) 2523 children who participated in Cumulative arthropathy rate at 1-year follow-up,a n (%) 46 (13.7) 33 (9.5%) prospective, randomized, unblinded 95% CI, % (–0.6 to 9.1) clinical efficacy trials. Data were b Selected musculoskeletal adverse events in patients with Ciprofl oxacin n Comparator n = 33 collected from a community-acquired arthropathy at 1-year follow-up = 46 patientsc patientsc Arthralgia 35 (76) 20 (61) trial in children 6 months Abnormal joint and/or gait examination 11 (24) 8 (24) to 16 years of age (a randomized Accidental injury 6 (13) 1 (3) 3:1, prospective, comparative trial Leg pain 5 (11) 1 (3) in 533 levofloxacin-exposed and Back pain 4 (9) 0 179 comparator-exposed evaluable Arthrosis 4 (9) 1 (3) Bone pain 3 (7) 0 subjects) and from 2 trials assessing Joint disorder 2 (4) 0 therapy for acute in Pain 2 (4) 2 (6) children 6 months to 5 years of Myalgia 1 (2) 4 (12) age (1 open-label noncomparative Arm pain 0 2 (6) study in 204 evaluable subjects Movement disorder 1 (2) 1 (3) and another randomized 1:1, Data are from ref 8. CI, confi dence interval. prospective, comparative trial in a The study was designed to show that the arthropathy rate for the ciprofl oxacin group did not exceed that of the comparator group by more than +6.0%. At both evaluations, the 95% CI indicated that it could not be concluded that 797 levofloxacin-exposed and 810 ciprofl oxacin had fi ndings comparable to the comparator. comparator-exposed evaluable b Events occurring in 2 or more patients. subjects). 13 In addition, after c A patient with arthropathy may have had more than 1 event. completion of the treatment trials, all subjects from both treatment arms ciprofloxacin that was equivalent to toxicity. Arthropathy rates were were also offered participation in an that achieved in children receiving 9.3% for ciprofloxacin versus unblinded, 12-month follow-up study therapeutic doses. 11 6% for the comparator group for safety assessments, including (Table 1). musculoskeletal events. Human Studies Adefurin et al 12 performed a systematic review of the safety The definitions of musculoskeletal In 2004, the FDA released data about data for 16 184 pediatric patients events for the safety of ciprofloxacin 8 from treated with ciprofloxacin by using (inflammation or rupture of an analysis of 100169, case reports and case series and a tendon as determined by which evaluated ciprofloxacin for reported 1065 (6.6%) adverse physical examination and/or MRI the treatment of complicated UTI or events. The most frequently reported or ultrasonography), arthritis pyelonephritis in children 1 through events were musculoskeletal (24%), (inflammation of a joint as evidenced 17 years of age. The study was a followed by abnormal liver function by redness and/or swelling of the prospective, randomized, double- tests (13%), nausea (7%), white joint), arthralgia (pain in the joint blind, active-controlled, parallel- blood cell count derangements as evidenced by complaint), and group, multinational, multicenter (5.3%), vomiting (5.2%), and rash gait abnormality (limping or refusal pediatric trial. Ciprofloxacin oral (4.7%). Arthralgia (50% of the 258 to walk) were determined before suspension was compared with musculoskeletal adverse events) was starting the studies. The identity oral cefixime or - the most common musculoskeletal of study was known by (TMP-SMX) in 1 adverse event reported. These data parents, study personnel, and the stratum, and in the second stratum showed an estimated risk of 16 subject’s care providers because ciprofloxacin (IV alone or IV followed musculoskeletal adverse events per reports of musculoskeletal events by oral suspension) was compared 1000 patients receiving ciprofloxacin and any other adverse events were with a number of comparator (1.6%; 95% confidence interval: collected during the follow-up regimens, including IV ceftazidime 0.9% to 2.6%), or 1 event for every period. An analysis of these events alone or IV ceftazidime followed by 62.5 patients. All cases of arthropathy occurred at 1, 2, and 12 months after oral cefixime or TMP-SMX. Clinical resolved or improved with medical treatment. The analysis of disorders end points were designed to capture management, which included drug involving weight-bearing joints any sign of cartilage or tendon withdrawal in some cases, and documented a statistically greater

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 e3 rate between the levofloxacin-treated neuropathy, abnormal bone summary, although isolated studies group and comparator group at 2 development, scoliosis, walking of fluoroquinolone antimicrobial months (1.9% vs 0.7%; P = .025) difficulty, myalgia, tendon disorder, agents have suggested possible and at 12 months (2.9% vs 1.6%; hypermobility syndrome, and pain musculoskeletal toxicity in children, P = .047). A history of joint pain in the spine, hip, and shoulder) were there is no evidence for long-term accounted for 85% of all events, with slightly higher in the comparator harm at this time. no findings of joint abnormality when group (0.1%) than in the levofloxacin Other potential adverse reactions assessed by physical examination. group (0.07%). A total of 174 of of fluoroquinolone-class antibiotic Computed tomography or MRI was 207 (84%) reviewed subjects were agents, although very uncommon performed for 5 of the patients with identified by the growth-impaired or in children, include central musculoskeletal symptoms; no signs possible growth-impaired criteria. nervous system adverse effects of structural injury were identified. Children from levofloxacin and (seizures, headaches, dizziness, No evidence of joint abnormalities comparator treatment groups had lightheadedness, sleep disorders, was observed at 12 months in the similar growth characteristics at hallucinations) and peripheral levofloxacin group. the 5-year assessment, with equal neuropathy. In data from clinical percentages of children from each trial 100169, the rate of neurologic treatment group having (1) no A long-term follow-up study (5 events described were similar change in height percentile, (2) years) in selected subjects from this between ciprofloxacin-treated 14 an increase in percentile, or (3) cohort was published recently. and comparator-treated children. 8 a decrease in percentile. Of the 9 The selection of the children for Reported rates of neurologic events children that had less growth than this long-term follow-up study was in the levofloxacin safety database predicted (6 of 104 [6%] from the based on meeting 1 of the following were statistically similar between levofloxacin group, 3 of 70 [4%] from criteria: (1) growth impaired or fluoroquinolone- and comparator- the comparator group), none were possibly growth impaired, defined treated children. 16, 17 as a documented height <80% of the believed by the drug monitoring expected height increase 12 months safety committee to have drug- Cardiotoxicity (see Additional after treatment; (2) assessed by the attributable growth changes. This Risks/Conditions), disorders investigator as having abnormal 5-year follow-up study enrolled 48% of glucose homeostasis (hypo- bone or joint symptoms during the of study participants from US sites and hyperglycemia), hepatic original 12-month follow-up; (3) compared with 20% from US sites dysfunction, renal dysfunction persisting musculoskeletal adverse enrolled in the original clinical trials. (interstitial nephritis and crystal events at the end of the original nephropathy), and hypersensitivity 12 months of follow-up; and (4) A rare complication associated reactions have also been reported. follow-up requested by the drug with agents, Practitioners should be aware safety monitoring committee because tendon rupture, has a predilection that fluoroquinolone-associated of concerns for possible tendon/ for the Achilles tendon (and is often photosensitivity has been described, joint toxicity associated with a bilateral) and is estimated to occur at and patients should be counseled protocol-defined musculoskeletal a rate of 15 to 20 per 100 000 treated to use appropriate sun-protection disorder. Of the 2233 subjects patients in the adult population. 15 measures. Rashes were more participating in the previously Advanced age, along with antecedent commonly noted in association with described 12-month follow-up steroid therapy and a particular the use of >7 days of in study, 124 of 1340 (9%) from the subset of underlying diseases, women younger than 40 years. levofloxacin group and 83 of the 893 including hypercholesterolemia, (9%) subjects in the comparator gout, rheumatoid arthritis, end- RESISTANCE group were enrolled (207 total stage renal disease/dialysis, and subjects), and 49% from each group renal transplantation, have been Resistance has been a concern since completed the study. Although an identified as risk factors and the approval of quinolone agents, increase in musculoskeletal events prompted an FDA warning about given the broad spectrum of activity in the levofloxacin group had been this serious adverse event for all and the large number of clinical noted at 12 months after treatment, quinolone agents. Although rare indications. Multiple mechanisms the cumulative long-term outcomes cases of Achilles tendon rupture can of resistance have been described, of children with musculoskeletal follow overuse injuries in children, including leading to adverse events reported during to date there have been no reports of changes in the target enzymes DNA the 5-year safety study (including Achilles tendon rupture in children gyrase and DNA , as ongoing arthropathy, peripheral in association with quinolone use. In well as pumps and alterations

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e4 FROM THE AMERICAN ACADEMY OF PEDIATRICS in membrane porins. 18 The role hospitals (Houston, Kansas City, San the rapid component of the delayed of plasmid-mediated quinolone Diego, and Philadelphia) document rectifier potassium current I(Kr), resistance determinants such as ciprofloxacin resistance to E coli expressed by HERG (the human qnr genes, continues to increase. to range from 5% to 14% for 2014 ether-a-go-go–related gene). The phenotype conferred by these (G.E. Schutze, MD, M.A. Jackson, MD, Moxifloxacin has the greatest risk to genes generally shows a low-level J. Bradley, MD, and T. Zaoutis, MD, prolong the QT interval and should resistance to fluoroquinolones, personal communication, 2015) with be avoided in patients with long QT but it also appears to encourage rates that appear to be stable for the syndrome, those with hypokalemia additional fluoroquinolone resistance last 3 years. As fluoroquinolone use or hypomagnesemia, those with mechanisms that lead to high-level in pediatrics increases, it is expected organic heart disease including resistance. 19 Several surveillance that resistance will increase, as congestive heart failure, those studies have shown that after the has been documented in adults. receiving an antiarrhythmic agent introduction of fluoroquinolones into There is a clear risk of resistance from class Ia or class III (eg, quinidine clinical practice, resistance rapidly in patients exposed to repeated and procainamide or amiodarone develops, although less commonly treatment courses. Susceptibility and sotaolo, respectively), those in pediatric patients given the data in patients with who are receiving a concurrent reduced use of these revealed a sharp increase in drug that prolongs the QTc interval in children. In large-scale pediatric resistance to Pseudomonas strains independently, and those with studies of levofloxacin for acute when comparing rates from 2001 hepatic insufficiency–related otitis media, the emergence of and 2011. 27 There is a correlation metabolic derangements that levofloxacin-resistant pneumococci between fluoroquinolone use and may promote QT prolongation. was not shown after treatment, the emergence of ciprofloxacin Levofloxacin also appears to prolong suggesting that the emergence and levofloxacin resistance among the QT interval, although at a lower of resistance during treatment is Gram-negative bacilli in hospitalized risk than moxifloxacin. Ciprofloxacin not a common event. 20 In adult children. 28 As expected, when the use appears to confer the lowest risk. 33 patients, Pseudomonas resistance of the fluoroquinolones (in particular No cases of cardiotoxicity or torsades to both fluoroquinolones and other levofloxacin) increased, the de pointes in children associated with antimicrobial agents is problematic. 21 susceptibility of Gram-negative bacilli fluoroquinolones have been reported Data on resistance in to ciprofloxacin and levofloxacin to date. 34 isolated from adults with UTIs who significantly decreased. 29 were seen in emergency departments in the EMERGEncy ID NET, a USE OF FLUOROQUINOLONES IN network of 11 geographically diverse ADDITIONAL RISKS/CONSIDERATIONS PEDIATRIC INFECTIONS university-affiliated institutions, The incidence of Clostridium difficile– suggest a low but stable rate of associated disease in children resistance of approximately 5%, 22 Although most clinicians use continues to increase across the although in specific locations, rates of a polymyxin/trimethoprim United States. The AAP Committee on resistance for outpatients are closer ophthalmologic solution or Infectious Diseases emphasizes the to 10%. 23, 24 Similar published data polymyxin/ ophthalmic risks related to the development of do not exist for children, although ointment for the treatment of acute C difficile–associated disease, which in current reports that include bacterial conjunctivitis, an increasing includes exposure to antimicrobial outpatient data, stratified by age, number of topical fluoroquinolones therapy. 30 Current data suggest that rates of fluoroquinolone resistance in are approved by the FDA for this , oral , E coli in children have been generally indication in adults and children and fluoroquinolone-class well below 3%. 24, 25 older than 12 months, including are associated with an increased levofloxacin, ofloxacin, moxifloxacin, risk of both community-acquired Recent data from Canadian hospitals gatifloxacin, ciprofloxacin, and and hospital-acquired C difficile– revealed that antimicrobial ( Table 2). Conjunctival associated disease. 31, 32 resistance rates continue to be tissue pharmacokinetic studies that higher in older age groups as Cardiotoxicity of fluoroquinolones use conjunctival biopsies in healthy compared with children and that is well described in adults and adult volunteers with besifloxacin, there is considerable variability in relates to the propensity of such gatifloxacin, and moxifloxacin age-specific resistance trends for to prolong the QT interval have been performed. All 3 agents different pathogens. 26 Data available through blockage of the voltage- reached peak concentrations from 4 large tertiary care children’s gated potassium channels, especially after 15 minutes. 35 Although drug

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 e5 TABLE 2 Most Common Infections for Which Fluoroquinolones Are Effective Therapy Infection Primary (s)a Fluoroquinolone Systemic antibiotic requirementb UTI Escherichia coli, , species, Ciprofl oxacinc Citrobacter species, Serratia species Acute otitis media, , Haemophilus infl uenzae Levofl oxacind Pneumonia S pneumoniae, Mycoplasma pneumoniae ( preferred for Levofl oxacind Mycoplasma infections) Gastrointestinal infections species, Shigella species Ciprofl oxacinc Topical antibiotic requiremente Conjunctivitis S pneumoniae, H infl uenza Besifl oxacin, levofl oxacin, gatifl oxacin, ciprofl oxacin, moxifl oxacin, ofl oxacin Acute otitis externa, tympanostomy tube– P aeruginosa, , mixed Gram-positive/Gram- Ciprofl oxacin,f ofl oxacin associated otorrhea negative organisms a Assuming that the pathogen is either documented to be susceptible or presumed to be susceptible to fl uoroquinolones. b If oral therapy is appropriate, use other classes of oral antibiotics if organisms are susceptible. c Dose of ciprofl oxacin. Oral administration: 20–40 mg/kg per day, divided every 12 hours (maximum dose: 750 mg/dose); IV administration: 20–30 mg/kg per day, divided every 8–12 hours (maximum dose: 400 mg/dose). d Dose of levofl oxacin. Oral or IV administration: for children 6 months to 5 years of age, 16–20 mg/kg per day divided every 12 hours; for children 5 years and older, 10 mg/kg per day once daily (maximum dose: 750 mg/dose). e Systemic toxicity of fl uoroquinolones is not a concern with topical therapy: the use of topical agents should be determined by suspected pathogens, effi cacy for mucosal infection, tolerability, and cost. Other systemic therapy may be required for more severe infection. f Available with and without corticosteroid. concentrations are only 1 indicator of effective than acetic acid solutions. High-quality studies that evaluated potential clinical efficacy, the utility Aminoglycoside-containing otic quinolone versus nonquinolone of agents with higher concentrations preparations were reported to cause topical solutions are limited. A is tempered by the observation of a ototoxicity if the tympanic membrane systematic review of 13 meta- potential increase in ocular adverse was not intact; fluoroquinolone- analyses confirmed that topical events, such as eye pain, 35 and containing preparations represent antibiotic agents were superior to slower corneal reepithelialization a safer alternative to treat both placebo and noted a statistically with specific agents. 36 Bacterial otorrhea associated with tympanic significant advantage of quinolone eradication and clinical recovery membrane perforation and agents over nonquinolone agents of 447 patients aged 1 through tympanostomy tube otorrhea. Eleven in the rate of microbiologic 17 years with culture-confirmed trials included aural toilet as a (P = .035). Safety profiles were bacterial conjunctivitis were routine intervention, but the authors similar between groups. 40 Similarly, evaluated in a post hoc multicenter acknowledged that this treatment is Mösges et al 42 reviewed 12 relevant study investigating besifloxacin not likely to be available in a typical randomized controlled clinical and moxifloxacin ophthalmic primary care office setting. 38 The studies involving 2682 patients drops.37 Although better clinical and paucity of high-quality studies of and concluded that quinolone microbiologic response was noted for antimicrobial agent–based topical therapy achieved a higher cure besifloxacin compared with placebo, therapy limited conclusions in rate (P = .01) and superior similar outcomes were noted when this review. A small, prospective, eradication rate (P = .03) than a compared with moxifloxacin. Both randomized, open-label study in 50 non–fluoroquinolone-containing agents were reported to be well patients with tympanostomy tube antibiotic-steroid combination. tolerated. otorrhea or a tympanic membrane The clinical significance of these 2 perforation showed comparable reviews is reduced, however, when External Otitis, Tympanostomy Tube– outcomes with either topical considering that bacterial persistence Associated Otorrhea antibiotic therapy or topical plus in the ear canal after treatment does systemic antibiotic agents. 39 For Recommendations for optimal care not necessarily imply persistent children with severe acute otitis for patients with otitis externa acute otitis externa symptoms. externa, systemically administered are outlined in a review of 19 A conclusion that quinolone and antimicrobial agents should be randomized controlled trials, nonquinolone agents are similar in considered in addition to topical including 2 from a primary care both microbiologic and clinical cure therapy. 40 setting, yielding 3382 participants. 38 rates was reached in a study in more Topical antibiotic agents containing Which topical antibiotic agent is than 200 children, 90 of whom were corticosteroids appeared to be more best for external otitis is unclear. 41 evaluated for microbiologic response

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e6 FROM THE AMERICAN ACADEMY OF PEDIATRICS in a multicenter, randomized, States. A prospective, open- adults for single-drug treatment of parallel-group, evaluator-blinded label, noncomparative study of community-acquired pneumonia. study comparing once-daily levofloxacin was performed in 205 These “respiratory tract” ofloxacin drops with a 4-times- children 6 months and older, 80% fluoroquinolones show in vitro daily sulfate/polymyxin of whom were younger than 2 years. activity against the most commonly B sulfate/hydrocortisone otic Tympanocentesis was performed isolated pathogens: S pneumoniae, suspension. Microbial eradication at study entry and at least at 3 to 5 H influenzae (nontypeable), and was documented in 95% and days into therapy for children who as well as 94%, respectively; clinical cure had treatment failure or persistent M pneumoniae, C pneumoniae, was achieved in 96% and 97%, effusion. Bacterial eradication of and . 50 – 52 respectively. 43 Treatment with middle-ear pathogens occurred in Although these agents are not the fluoroquinolone agents has been well 88% of children, including 84% drugs of choice for pneumonia in tolerated. infected by pneumococci and previously healthy adults, they 100% infected by Haemophilus are recommended for adults with Acute Otitis Media, Sinusitis, and influenzae. Levofloxacin treatment underlying comorbidities and for Lower Respiratory Tract Infections was well tolerated, with vomiting those who have been exposed to Newer fluoroquinolones show in 4% of patients documented antibiotic agents within the previous enhanced in vitro activity against as the most common adverse 3 months and are, therefore, more S pneumoniae, compared with effect.48 An evaluator-blinded, likely to be infected with antibiotic- ciprofloxacin. The clinical need for active-comparator, noninferiority resistant pathogens. 53 Failures in such agents to treat respiratory tract multicenter study comparing the treatment of pneumococcal infections has largely been driven by levofloxacin with amoxicillin- pneumonia have been reported the emergence of multidrug-resistant clavulanate (1:1) involving 1305 with levofloxacin at 500 mg daily strains of this pathogen, such as evaluable children older than 6 as a result of the emergence of serotype 19A pneumococcus. Current months documented equivalent resistance while receiving therapy otitis media and acute bacterial clinical cure rates of 75% in or resistance from previous sinusitis guidelines from the AAP each treatment arm. Because exposures to fluoroquinolones.54 and Pediatric Infectious Diseases tympanocentesis was not required, An increased dose of levofloxacin Society/Infectious Diseases Society microbiologic cure rates could not be (750 mg daily, given for 5 days) is of America guidelines on community- determined.17 currently approved by the FDA for acquired pneumonia in children adults with pneumonia. The increase support the use of levofloxacin as an Pneumonia in drug exposure at the higher dose is recognized to overcome the alternative therapy for those with Although initially approved by the most common mechanism for the severe allergy and for those FDA for the treatment of pneumonia development of fluoroquinolone infected with suspected multidrug- and acute exacerbation of chronic resistance. 55 resistant pneumococcus (ie, patients bronchitis in adults, ciprofloxacin in whom amoxicillin and amoxicillin- therapy has not been uniformly 44–46 Of the fluoroquinolones, only clavulanate have failed). successful in the treatment of levofloxacin has been studied Pharmacokinetic data for children 6 pneumococcal pneumonia in adults prospectively in children months and older are well defined at dosages initially studied 30 years with community-acquired for levofloxacin, the only currently ago. Failures are most likely the pneumonia, documenting efficacy available fluoroquinolone studied result of increasing pneumococcal in a multinational, open-label, for respiratory tract infections in resistance to ciprofloxacin and other 47 noninferiority-design trial, compared children. fluoroquinolones documented since with standard antimicrobial agents their first approval. 49 Ciprofloxacin is Acute Bacterial Otitis Media for pneumonia.16 For children 6 currently not considered appropriate months to 5 years of age, levofloxacin Clinical studies of levofloxacin and therapy for community-acquired (oral or IV) was compared with gatifloxacin have been conducted pneumonia in adults because of its amoxicillin-clavulanate (oral) or in children with recurrent or resistance profile. persistent otitis media but in those (IV). For children 5 years with not simple acute bacterial Fluoroquinolones with enhanced and older, levofloxacin (oral) was otitis media. Although studies of activity against S pneumoniae compared with clarithromycin (oral) several fluoroquinolones have compared with ciprofloxacin and levofloxacin (IV) was compared been reported, only levofloxacin is (levofloxacin, moxifloxacin, with ceftriaxone (IV) in combination currently available in the United gemifloxacin) have been used in with either erythromycin (IV) or

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 e7 clarithromycin (oral). Clinical cure efficacy trials by using a number of strains isolated from 1999 to 2003 rates were 94.3% in the levofloxacin- fluoroquinolone agents for infections were resistant to both ampicillin treated group and 94.0% in the caused by Salmonella and Shigella and TMP-SMX. A 2005 outbreak comparator group, with similar species, but only 2 of the 12 trials of multidrug-resistant Shigella rates of cure in both the younger reported data on fluoroquinolones sonnei infection involving 3 states and older age groups. Microbiologic compared with nonquinolone was reported in the Morbidity and etiologies were investigated, with agents. Patients were treated for Mortality Weekly Report61 ; 89% of Mycoplasma being the most frequently (8 studies, including strains were resistant to both agents, diagnosed pathogen, representing 7 for multidrug-resistant strains), but 100% of strains were susceptible 32% of those receiving levofloxacin invasive nontyphoid to ciprofloxacin. Recently, however, in both older and younger age groups (1 study), and shigellosis (3 studies). fluoroquinolone resistance has been and approximately 30% of those Clinical and microbiologic success noted to be increasing at an alarming receiving comparator agents in with fluoroquinolone therapy for rate in Asia and Africa, and these both age groups. Pneumococci were these infections was similar when resistant isolates are also starting to infrequently documented to be the comparing children with adults. be seen in the United States as well. 62, cause of pneumonia in study patients, Recent data, however, show that 63 Treatment options for multidrug- representing only 3% to 4% of those fluoroquinolone resistance among resistant shigellosis, depending on who received levofloxacin and 3% to isolates responsible for enteric fever the antimicrobial susceptibilities 5% of those receiving the comparator. in South Asia is very high (>90%), of the particular strain, include Of note, the clinical response rate of and the use of these drugs has been ciprofloxacin, , 83% in children younger than 5 years, severely limited because of this. 57, 58 and parenteral ceftriaxone. diagnosed by serologic testing with Therefore, fluoroquinolones would Nonfluoroquinolone options should Mycoplasma infection and treated not be an appropriate option in be used if available. with amoxicillin-clavulanate, was visitors returning from South Asia Although ciprofloxacin has been similar to that in children treated with enteric fever. regarded as an effective agent for with levofloxacin (89%), suggesting A prospective, randomized, double- traveler’s diarrhea in the past, a high rate of spontaneous resolution blind comparative trial of acute, resistance rates are increasing of disease caused by Mycoplasma invasive diarrhea in febrile children for specific pathogens in many species in preschool-aged children, in Israel was conducted by Leibovitz parts of the world. Resistance to poor accuracy of diagnosis by et al 59 comparing ciprofloxacin species is particularly serologic testing, or a clinical end- with intramuscular ceftriaxone in a problematic in patients with a point evaluation after a treatment double-dummy treatment protocol. history of international travel. course that could not identify possible A total of 201 children were treated Recent data from Campylobacter differences in response that may and evaluated for clinical and isolates from international travel have been present in the first days of microbiologic cure as well as for revealed fluoroquinolone resistance therapy. safety. Pathogens, most commonly of approximately 61%. 64 Therefore, Levofloxacin is now recognized as the Shigella and Salmonella species, were fluoroquinolones would not be preferred oral agent for children as isolated in 121 children. Clinical and an appropriate option in the young as 6 months of age with highly microbiologic were equivalent treatment of traveler’s diarrhea penicillin-resistant isolates (minimum between groups. 59 unless a pathogen is defined and inhibitory concentration of ≥4 antimicrobial susceptibilities are In the United States, although μg/mL).44 Although fluoroquinolones confirmed. cases of typhoid fever and invasive may represent effective therapy, they salmonellosis are uncommon, there are not recommended for first-line UTI are approximately 500 000 cases of therapy for community-acquired shigellosis, with 62 000 of the cases Standard empirical therapy for respiratory tract infections in occurring in children younger than 5 uncomplicated UTI in the pediatric children, because other better-studied years.60 Treatment is recommended, population continues to be a and safer antimicrobial agents are primarily to prevent the spread antibiotic agent, available to treat the majority of the of infection. Ampicillin and TMP- because TMP-SMX– and amoxicillin- currently isolated pathogens. SMX resistance is increasing, and resistant E coli are increasingly multidrug-resistant strains are common. The fluoroquinolones Gastrointestinal Infections becoming common; the National remain potential first-line agents Alghasham and Nahata 56 Monitoring only in the setting of pyelonephritis summarized the results of 12 System reported that 38% of or complicated UTI when typically

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e8 FROM THE AMERICAN ACADEMY OF PEDIATRICS recommended agents are not wound healing (patients older than are suitable, fluoroquinolones may appropriate on the basis of 60 years, those taking corticosteroid represent the only treatment option. susceptibility data, allergy, or drugs, and those with kidney, heart, P aeruginosa can cause skin adverse event history. AAP policy or lung transplants [black box infections (including folliculitis) continues to support the use of warning for all fluoroquinolones]) after exposure to inadequately ciprofloxacin as oral therapy for may increase the risk of chlorinated swimming pools or 70 UTI and pyelonephritis caused by musculoskeletal adverse effects. hot tubs. The disease is self-limited P aeruginosa or other multidrug- and the majority of children will resistant Gram-negative Other Uses not require antimicrobial therapy, in children 1 through 17 years of but if they do, oral fluoroquinolone 3 age. If ciprofloxacin is started as Ciprofloxacin and levofloxacin agents offer a treatment option empirical therapy, but susceptibility are among the acceptable that may be preferred over data indicate a pathogen that is antimicrobial agents for use in parenteral nonfluoroquinolone susceptible to other appropriate postexposure prophylaxis against antimicrobial therapy. In addition, classes of antimicrobial agents, the as well as for fluoroquinolones may be considered child’s therapy can be switched to a the treatment of many forms of as part of an antimicrobial regimen in nonfluoroquinolone. anthrax (eg, cutaneous, inhalation, cases of infections after penetrating systemic) in children 1 month skin/soft tissue injuries in the setting Mycobacterial Infections or older.71 Ciprofloxacin is one of water exposure when P aeruginosa of the antimicrobial options in or Aeromonas hydrophila may play a The fluoroquinolones are active postexposure prophylaxis and/or significant role. in vitro against mycobacteria, treatment of plague as well. 72, 73 including M tuberculosis and many A recent systematic review nontuberculous mycobacteria. 53, 65 Ciprofloxacin is effective in of empirical fluoroquinolone Increasing multidrug resistance eradicating nasal carriage of Neisseria therapy for children with fever in M tuberculosis has led to the meningitidis (single dose, 500 mg and neutropenia found excellent increased use of fluoroquinolones for adults and 20 mg/kg for those outcomes with short-term safety. as part of individualized, multiple- older than 1 month) and preferred It should be emphasized, however, drug treatment regimens, with in nonpregnant adults. It can also be that these data were from studies levofloxacin and moxifloxacin considered in younger patients as an in patients with low-risk fever and showing greater bactericidal activity alternative to 4 days of rifampin if neutropenia (leukemia/lymphoma), than ciprofloxacin. 66 Treatment ciprofloxacin-resistant isolates of N of whom only a small proportion regimens that include 1 to 2 years meningitidis have not been detected would be expected to have a serious 75 of fluoroquinolones for multidrug- in the community. occult bacterial infection. Ongoing resistant and extensively drug- investigations will help define the resistant tuberculosis have not been Good penetration into the role for these antimicrobial studied prospectively in children. cerebrospinal fluid by certain agents in patients with fever and Prevailing evidence supports the fluoroquinolones (eg, levofloxacin) neutropenia. use of fluoroquinolones in the is reported, and concentrations often treatment of multidrug-resistant exceed 50% of the corresponding SUMMARY tuberculosis infections in children.67, 68 plasma drug concentration. The extended administration of In patients with tuberculosis, Fluoroquinolones are broad- the fluoroquinolones in adults with cerebrospinal fluid penetration, spectrum agents that should be multidrug-resistant tuberculosis measured by the ratio of the plasma considered selectively for use in has not shown serious adverse area under the concentration a child or adolescent for specific effects, and there is no evidence to time curve from 0 to 24 to the clinical situations, including the date suggesting that this is different cerebrospinal fluid area under following: (1) infection caused by in children. 69 A recent study that the curve (0–24), was greater for a multidrug-resistant pathogen for focused on the use of levofloxacin levofloxacin (median: 0.74; range: which there is no safe and effective for tuberculosis infection in an adult 0.58–1.03) than for gatifloxacin alternative and (2) options for liver transplant patient population (median: 0.48; range: 0.47–0.50) treatment include either parenteral did show a risk of tenosynovitis in or ciprofloxacin (median: 0.26; nonfluoroquinolone therapy or 18% of those treated, highlighting range: 0.11–0.77). 74 In cases of oral fluoroquinolone therapy that the clinician needs to be aware multidrug-resistant, Gram-negative and oral therapy is preferred. In that additional risk factors for poor meningitis for which no other agents other clinical situations outlined

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 e9 previously, fluoroquinolones may and indicate why a fluoroquinolone is Richard L. Gorman, MD, FAAP – National Institutes also represent a preferred option the most appropriate antibiotic agent of Health (eg, topical fluoroquinolones in for a child’s infection. Natasha Halasa, MD, MPH, FAAP – Pediatric Infectious Diseases Society the treatment of tympanostomy Joan L. Robinson, MD – Canadian Paediatric tube–associated otorrhea) or an Society acceptable alternative to standard ACKNOWLEDGMENTS Jamie Deseda-Tous, MD – Sociedad therapy because of concerns for We thank Dr John S. Bradley, MD, Latinoamericana de Infectologia Pediatrica antimicrobial resistance, toxicity, or FAAP, for his critical review and Geoffrey R. Simon, MD, FAAP – Committee on Practice Ambulatory Medicine characteristics of tissue penetration. input into this manuscript. Jeffrey R. Starke, MD, FAAP – American Thoracic If a fluoroquinolone is selected for Society therapy on the basis of the above LEAD AUTHORS considerations, practitioners should Mary Anne Jackson, MD, FAAP ABBREVIATIONS be aware that both ciprofloxacin and Gordon E. Schutze, MD, FAAP levofloxacin are costly. AAP: American Academy of COMMITTEE ON INFECTIOUS DISEASES, Pediatrics Although adverse reactions are 2016–2017 FDA: Food and Drug Administra- uncommon, because of the potential Carrie L. Byington, MD, FAAP, Chairperson tion for risks of , Yvonne A. Maldonado, MD, FAAP, Vice Chairperson IV: intravenous Elizabeth D. Barnett MD, FAAP TMP-SMX: trimethoprim-sulfa- central nervous system effects, James D. Campbell, MD, FAAP and cardiac, dermatologic, and H. Dele Davies, MD, MS, MHCM, FAAP methoxazole hypersensitivity reactions in adults, Ruth Lynfi eld, MD, FAAP UTI: in July 2016 the FDA added a Flor M. Munoz, MD, FAAP safety announcement with updated Dawn Nolt, MD, FAAP Ann-Christine Nyquist, MD, MSPH, FAAP box warnings restricting use of Sean O’Leary, MD, MPH, FAAP fluoroquinolone antibiotics in adults Mobeen H. Rathore, MD, FAAP REFERENCES with acute sinusitis, , Mark H. Sawyer, MD, FAAP 1. Tatsumi H, Senda H, Yatera S, and uncomplicated UTI to situations William J. Steinbach, MD, FAAP Takemoto Y, Yamayoshi M, Ohnishi in which no other alternative Tina Q. Tan, MD, FAAP Theoklis E. Zaoutis, MD, MSCE, FAAP K. Toxicological studies on pipemidic treatment is available. No compelling acid. V. Effect on diarthrodial joints of published evidence to date supports experimental animals. J Toxicol Sci. FORMER COMMITTEE MEMBERS the occurrence of sustained injury 1978;3(4):357–367 to developing bones or joints in John S. Bradley, MD, FAAP 2. Gough A, Barsoum NJ, Mitchell L, children treated with available Kathryn M. Edwards, MD, FAAP Gordon E. Schutze, MD, FAAP McGuire EJ, de la Iglesia FA. Juvenile fluoroquinolone agents; however, canine drug-induced arthropathy: FDA analysis of ciprofloxacin safety EX OFFICIO clinicopathological studies on data suggests the possibility of David W. Kimberlin, MD, FAAP – Red Book Editor articular lesions caused by oxolinic increased musculoskeletal adverse Michael T. Brady, MD, FAAP – Red Book Associate and pipemidic acids. Toxicol Appl events. Although studies were not Editor Pharmacol. 1979;51(1):177–187 Mary Anne Jackson, MD, FAAP – Red Book blinded, with the potential for bias, 3. Committee on Infectious Diseases. children treated with levofloxacin Associate Editor Sarah S. Long, MD, FAAP – Red Book Associate The use of systemic fl uoroquinolones. both immediately after treatment Editor Pediatrics. 2006;118(3):1287–1292 and at a 12-month follow-up had an Henry H. Bernstein, DO, MHCM, FAAP – Red Book 4. Bradley JS, Jackson MA; Committee increased rate of musculoskeletal Online Associate Editor on Infectious Diseases. 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Riecke K, Lozo E, ShakiBaei M, et al. verbally review common, anticipated, Administration Marc Fischer, MD, FAAP – Centers for Disease Fluoroquinolone-induced lesions in the potential adverse events, such Control and Prevention epiphyseal growth plates of immature as rash, diarrhea, and potential Bruce G. Gellin, MD, MPH – National Vaccine rats. Presented at: 40th Interscience musculoskeletal or neurologic events, Program Offi ce Conference on Antimicrobial Agents

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Downloaded from www.aappublications.org/news by guest on October 1, 2021 The Use of Systemic and Topical Fluoroquinolones Mary Anne Jackson, Gordon E. Schutze and COMMITTEE ON INFECTIOUS DISEASES Pediatrics originally published online October 31, 2016;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2016/10/27/peds.2016-2706

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