Uso de Fluroquinolonas tópicas y sistémicas

7/28/2019 Uso de Fluroquinolonas tpicas y sistmicas

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DOI: 10.1542/peds.2011-1496; originally published online September 26, 2011;2011;128;e1034Pediatrics

John S. Bradley, Mary Anne Jackson and the Committee on Infectious DiseasesThe Use of Systemic and Topical Fluoroquinolones

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CLINICAL REPORT

The Use of Systemic and Topical Fluoroquinolones

abstractAppropriate prescribing practices for uoroquinolones are essentialas evolving resistance patterns are considered, additional treatmentindications are identied, and the toxicity prole of uoroquinolones inchildren becomes better dened. Earlier recommendations for systemic therapy remain; expanded uses of uoroquinolones for the treat-ment of certain infections are outlined in this report. Although uoro-quinolones are reasonably safe in children, clinicians should be awareof the specic adverse reactions. Use of uoroquinolones in childrenshould continue to be limited to treatment of infections for which nosafe and effective alternative exists. Pediatrics 2011;128:e1034e1045

OVERVIEWFluoroquinolones are highly active in vitro against both Gram-positiveand Gram-negative pathogens and have pharmacokinetic properties that are favorable for treating a wide array of infections. The prototypequinolone antibiotic agent, nalidixic acid, was approved by the US Foodand Drug Administration (FDA) for adults in 1964 and generally is con-sidered to be the rst generation of such agents. For more than 2decades, nalidixicacid also hasbeen approved by theFDAandavailablefor children aged 3 months and older. Subsequent chemical modica- tions of the rst quinolone compounds resulted in the development of a series of uoroquinolone agents with an increased antimicrobialspectrum of activity and better pharmacokinetic tissue-exposurecharacteristics.

Second-generation agents have a greater Gram-negative spectrum(with activity against Pseudomonas aeruginosa ) and include cipro-oxacin, levooxacin, noroxacin, and ooxacin. In 2004, ciprooxacinbecame the rst uoroquinolone agent approved for use in children 1 through 17 years of age.

Gemioxacin, a currently marketed third-generation agent, has beenapproved by the FDA for adults for the treatment of community-acquired pneumonia and acute exacerbations of chronic bronchitis.Compared with earlier agents, gemioxacin provides substantially in-creased activity against Streptococcus pneumoniae (while retainingactivity against many Gram-negative pathogens), Mycoplasma pneumoniae , and Chlamydophila pneumoniae.

A fourth generation of uoroquinolones, represented by moxioxacin,displays increased activity against anaerobes while maintaining theGram-positive and Gram-negative activity of the third-generationagents. Moxioxacin also provides excellent activity against many my-

John S. Bradley, MD, Mary Anne Jackson, MD, and theCOMMITTEE ON INFECTIOUS DISEASES

KEY WORDSuoroquinolones, pediatrics, infectious diseases, systemic therapy

ABBREVIATIONSFDAFood and Drug AdministrationUTIurinary tract infectionTMP-SMXtrimethoprim-sulfamethoxazole

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may be

appropriate.

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave led conict of interest statements with the AmericanAcademy of Pediatrics. Any conicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content of this publication.

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All clinical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reafrmed,revised, or retired at or before that time.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2011 by the American Academy of Pediatrics

Guidance for the Clinician inRendering Pediatric Care

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cobacteria including most strains of Mycobacterium tuberculosis currentlyisolated in the United States.

Animal toxicology data available with the rst quinolone compounds docu-mented their propensity to create in-ammation and subsequent destruc- tion of weight-bearing joints in juvenileanimals. 1,2 This observation effectivelysidelined further development orlarge-scale evaluation of this class of antibiotic agents in children.

A policy statement summarizing theassessment of risks and benets of uoroquinolones in pediatric patientswas published by the American Acad-emy of Pediatrics in 2006. 3 At that time,parenteral uoroquinolones werebelieved to be appropriate for the treatment of infections caused bymultidrug-resistant pathogens forwhich no alternative safe and effectiveparenteral agent existed. For outpatient management, oral uoroquinolo-nes were reasonable for treatment of infections when the only other optionswere intravenous treatment withother classes of antibiotic agents.

Since publication of the previousAmerican Academy of Pediatrics policystatement, the clinical value of uoro-quinolones for the treatment of spe-cic infections in children, particularly those caused by Gram-negative patho-gens, has been further documented.The use of topical uoroquinolone therapy for external otitis is now rec-ommended by the American Associa- tion of Otolaryngology. 4 In addition,results of the rst randomized,prospective studies on thesafetyof theuoroquinolones have been re-ported. 5,6 No published reports exist of physician-diagnosed cartilage damagein children in the United States, eitherfromcontrolledclinical trials of uoro-quinolones or from unsolicited report-ing to the FDA or drug manufacturers.Quinolones that are currently ap-proved by the FDA and available for use

in children are nalidixic acid for uri-nary tract infections (UTIs), ciprooxa-cin for inhalational anthrax and com-plicated UTI and pyelonephritis, andlevooxacin for inhalational anthrax.Only ciprooxacin and levooxacin are

available in a suspension formulation.Moxioxacin is currently under investigation for treatment of complicatedintraabdominal infections in children. 7

Other systemic quinolones that maybeavailable in other countries but not theUnited Statesare notaddressed in thisreport.

SAFETY

Animal Models

The original toxicology studies withquinolones documented cartilage injury in weight-bearing joints in juvenileanimals; damage to the joint cartilagewas proportional to the degree of ex-posure. 1,2 Each quinolone may demon-strate a different potential to causecartilage toxicity. 8 However, given asufciently high exposure, cartilagechanges will occur in all animal mod-els with all quinolones, including nali-

dixic acid.Although initial reports focused on articular cartilage, the results of subse-quent studies suggested the possibil-ity of epiphyseal plate cartilage injury, 9

which led to uoroquinolone clinicalstudy designs that lastedseveral years to assess growth potential. Recentdata suggest that quinolone toxicityoccurs as a result of concentrationspresent in cartilage that are suf-

ciently high to form chelate complexeswith divalent cations, particularlymagnesium, that result in impairmentof integrin function and cartilage ma- trix integrity in the weight-bearing joints, which undergo chronic traumaduring routine use. 10

In studies of ciprooxacin exposure tovery young beagle puppies (one of themost sensitive animal models for quin-olone toxicity), clinical evidence of ar-

throtoxicity was observed during a 14-day treatment course at 90 mg/kg perday but not at 30 mg/kg per day. Appar-ent joint tenderness at the higherexposure resolved 6 weeks after thelast dose of ciprooxacin.

Histopathologic evidence of cartilageinjurywas noted in virtuallyall animalsgiven 90 mg/kg per day. At this expo-sure level, the observed clinical signsall occurred during and shortly after treatment but resolved by 2 months,with no recurrent signs noted during the 5-month follow-up period. In con- trast, histopathologic evidence of cartilage injury was observed at 30 mg/kgper day, the dose currently recom-

mended for children. Histopathologicevidence of inammation occurred infewer than half the animals at thisdose but persisted for 5 months after treatment, at full skeletal matura- tion.5,11 The no-observed-adverse-event level was 10 mg/kg per day, adose at which neither clinical nor histopathologic evidence of toxicity waspresent.

Similar data, which documented a no-

observed-adverse-event level of 3mg/kg per day for intravenous dosingfor 14 days (approximately one-quarter the current FDA-approveddose of 16 mg/kg per day for childrenwho weigh 50 kg), were documentedbefore FDA approval of levooxacin foradults. Levooxacin has virtually 100%bioavailability; total drug exposure isequivalent between intravenous andoral formulations at the same

milligram-per-kilogram dose. 12

Recent data from investigation of alamb model, felt to approximate hu-man growth rates and activity moreclosely than juvenile beagle dogs orrats, have been published. This studyaddressed epiphyseal cartilage andgrowth velocity after a 14-day drug ex-posure to either gatioxacin or cipro-oxacin that was equivalent to thatachieved in children receiving thera-

FROM THE AMERICAN ACADEMY OF PEDIATR

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peutic doses. Gross examination of articular cartilage and microscopic ex-amination of epiphyseal cartilage didnot reveal abnormalities consistentwith cartilage injury or inammation. 13

Preclinical toxicology data are avail-able for all FDA-approved uoroquino-lones. These data document differ-ences in the animal speciessusceptible to cartilage effects as wellas differences between each quino-lone in the ability to create cartilage toxicity.

Human Studies

At the time of publication of the lastAmerican Academy of Pediatrics policystatement, retrospective studies,case-control series, and case reportsrepresented the published data onuoroquinolone safety in childrenavailable in the peer-reviewed litera- ture. 1417 Some reports included chil-dren with cystic brosis, who can de-velopdisease-related arthropathy, andsome included more toxic uoroquino-lone agents that were never approvedin the United States. These data pro-

videdconicting reports regarding thesafety of uoroquinolones in children.The results of 2 large, prospectivesafety studies are now available for re-view; 1 study was performed at the re-quest of the FDA by Bayer for cipro-oxacin, and the second study wasperformed by Johnson & Johnson forlevooxacin as part of their FDA-coordinated program of pediatricdrug development.

In 2008, the FDAs analysis of studydata for ciprooxacin in the treatmentof complicated UTI and pyelonephritisin children aged 1 through 17 yearsfrom 2004 was posted on the FDA Website. 5 A series of prospective, random-ized, double-blinded studies was per-formed to compare (1) intravenousceftazidime with intravenous cipro-oxacin, permitting oral step-down therapy, and (2) oral ciprooxacin

with oral cexime or trimethoprim-sulfamethoxazole (TMP-SMX). Theselarge studies were conducted in sev-eral countries ( Table 1) . Clinical endpoints were designed to capture anysign of cartilage or tendon toxicity byeliciting a detailed history of a wide va-riety of complaints referable to bones

and joints ( Table 2) . Comparing com-plaints and physical ndings between the ciprooxacin-treated group and the group treated with comparatorantimicrobial agents, a difference wasdetected only in the United States. Thedifference in rates of complaints var-ied between countries; the lowest

TABLE 1 Rate of FDA-Dened Arthropathy (See Table 2) 6 Weeks After Treatment With Ciprooxacinor Comparator, According to Selected Baseline Characteristics

Ciprooxacin ( N 335) Comparator ( N 349)

All patients, n /N (%) 31/335 (9.3) 21/349 (6.0)Country, n /N (%)

Argentina 8/77 (10.4) 7/79 (8.9)Canada 1/8 (12.5) 1/11 (9.1)

Costa Rica 4/21 (19.0) 0/20 (0.0)Germany 1/13 (7.7) 1/11 (9.1)Mexico 0/56 (0.0) 0/60 (0.0)Peru 2/87 (2.3) 3/88 (3.4)United States 13/62 (21.0) 8/71 (11.3)South Africa 2/11 (18.2) 1/9 (11.1)

Race, n /N (%)White 18/130 (13.8) 13/134 (9.75)Black 0/5 (0.0) 1/7 (14.3)Asian 0/3 (0.0) 1/6 (16.7)Hispanic 8/102 (7.8) 3/109 (2.8)Uncoded 5/95 (5.3) 3/93 (3.2)

Gender, n /N (%)Male 6/62 (9.7) 4/65 (6.2)Female 25/273 (9.2) 17/284 (6.0)

TABLE 2 Rate of FDA-Dened Arthropathy 6 Weeks and 1 Year After Treatment With Ciprooxacinor a Comparator

Ciprooxacin(N 335)

Comparator(N 349)

Arthropathy rate at 6 wk of follow-up, n (%) 31 (9.3) 21 (6.0)95% condence interval a ( 0.8 to 7.2)

Cumulative arthropathy rate at 1 y of follow-up, n (%) 46 (13.7) 33 (9.5)95% condence interval a ( 0.6 to 9.1)

Selected musculoskeletal adverse events b in patientswith arthropathy at 1 y of follow-up

No. of patients 46 c 33c

Arthralgia, n (%) 35 (76) 20 (61)Abnormal joint and/or gait exam, n (%) 11 (24) 8 (24)Accidental injury, n (%) 6 (13) 1 (3)Leg pain, n (%) 5 (11) 1 (3)Back pain, n (%) 4 (9) 0 (0)Arthrosis, n (%) 4 (9) 1 (3)Bone pain, n (%) 3 (7) 0 (0)Joint disorder, n (%) 2 (4) 0 (0)Pain, n (%) 2 (4) 2 (6)Myalgia, n (%) 1 (2) 4 (12)Arm pain, n (%) 0 (0) 2 (6)Movement disorder, n (%) 1 (2) 1 (3)

a The study was designed to demonstrate that the arthropathy rate for the ciprooxacin group did not exceed that of thecomparator group by more than 6.0%. At both evaluations, the 95% condence interval indicated that it could not beconcluded that ciprooxacin had ndings comparable to those of the comparator.b

Events that occurred in 2 or more patients.c A patient with arthropathy may have had more than 1 event.



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rates were reported from Mexico (0%ciprooxacin, 0% comparator), and the highest rates were reported from the United States (21% ciprooxacin,11% comparator). The study used anoninferioritydesign to assess muscu-

loskeletal complaints between the 2 treatment groups across all countries,and as analyzed, the groups were suf-ciently different to suggest potentialmusculoskeletal toxicity with cipro-oxacin ( Table 2) .

The levooxacin safety data collectionwas prospective and randomized butnot blinded. The published safety pro-le of levooxacin included a large co-hort of 2523 children from 3 large multicenter efcacy trials. Data werecollected from a community-acquiredpneumonia trial in children aged 6months to 16 years (a randomized 3:1,prospective, comparative trial with533 levooxacin-exposed and 179comparator-exposed evaluable subjects) and from 2 trials that assessed therapy of acute otitis media in chil-dren aged 6 months to5 years (1 open-label noncomparative study with 204

evaluable subjects and another ran-domized 1:1, prospective, comparative trial with 797 levooxacin-exposed and810 comparator-exposed evaluablesubjects). 6 In addition, after comple- tion of the treatment trials, all subjectsfrom both treatment arms were alsooffered participation in an unblinded,long-term, 12-month follow-up studyfor safety assessments, and 2233 of 2523 families participated. From these

trials, a selected group of children whowere judged to benet from additionalfollow-up because of the presence of tendon/joint abnormalities or failure to achieve expected vertical growthover the year of observation were con- tinued in the musculoskeletal long- term follow-up study, which consistedof yearly visits for 4 additional years.

The denitions of musculoskeletalevents for tendinopathy (inammation

or rupture of a tendon as determinedby physical examination and/or MRI orultrasound), arthritis (inammation of a joint as evidenced by redness and/orswelling of the joint), arthralgia (painin the joint as evidenced by complaint),

and gait abnormality (limping or re-fusal to walk) were determined beforestarting the studies. The identity of study medication was known by par-ents, study personnel, and the subjects care providers as reports of musculoskeletal events and any otheradverse events were collected during the follow-up period. An analysis of these events occurred 1, 2, and 12months after treatment. The analysis

of disorders that involved weight-bearing joints revealed a statisticallygreater rate between the levooxacin-and comparator-treated groups at 2months (1.9% vs 0.7%; P .025) and at12 months (2.9% vs 1.6%; P .047). Ahistory of joint pain accounted for 85%of all events, and there were no nd-ings of joint abnormality when as-sessed by physical examination. Com-puted tomography or MRI was

performed for 5 of the patients withmusculoskeletal symptoms; no signsof structural injury were identied. Noevidence of joint abnormalities wasob-served at 12 months in the levooxacingroup.

A report on the 5-year safety assess-ment of the 2233 children who re-ceived levooxacin treatment was re-cently completed by the manufacturer,Johnson & Johnson. Specied criteria

for review included (1) documentedheight that was less than 80% of theexpected height increase, (2) abnor-mal bone or joint ndings, and (3) anyother concerns for possible tendon/ joint toxicity identied by the datasafety monitoring board during treat-ment or in the 12 months after treat-ment. A total of 174 of 207 (84%) re-viewed subjects were identied by thepredetermined growth criteria (124

levooxacin-treated and 83 comparator- treated subjects), and 49% of eachgroup completed the entire 5-yearfollow-up. Although an increase inmusculoskeletal events in the levo-oxacin group had been noted 12

months after treatment, the cumulative long-term outcomes of childrenwith musculoskeletal adverse eventsreported during the 5-year safetystudy (including ongoing arthropathy,peripheral neuropathy, abnormalbone development, scoliosis, walkingdifculty,myalgia, tendon disorder, hy-permobility syndrome, and pain in thespine, hip, and shoulder) were slightlyhigher in the comparator treatment

group (2% levooxacin, 4% comparator). Among all study participants identied by the growth criteria ( n 174),equal percentages of children fromeach treatment group were docu-mented to fall into the previously de-ned categories at the 5-year visit: nochange in height percentile; improve-ment; or deterioration in growth char-acteristics. This 5-year follow-up studyenrolled 48% of study participants

from US sites compared with 20%fromUS sites enrolled in the original clinical trials (unpublished data on le, J&Jprotocol LOFBO-LTSS-001, clinical studyreport, March 23, 2011).

A rare complication associated withquinolone antibiotic agents, tendonrupture, has a predilection for theAchilles tendon (often bilateral) and isestimated to occur at a rate of 15 to 20per 100 000 treated patients in the

adult population. Advanced age, alongwith antecedent steroid therapy and aparticular subset of underlying dis-eases, including hypercholesterol-emia, gout, rheumatoid arthritis, end-stage renal disease/dialysis, and renal transplantation, have been identiedas risk factors and prompted an FDAwarning about this serious adverseevent for all quinolone agents. Achilles tendon rupture in the pediatric popu-




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lation, in general, is extremely rare,and although tendonitis in athletes isobserved, this event usually followsoveruse. To date, there have been noreports of this rare complication in apediatricpatient who wasexposed to aquinolone, which precludes assess-ment of the risk of this complication inchildren.

Other potential toxicities of uoroquinolone-class antibiotic agentsdo not occur commonly in children butinclude central nervous system ad-verse effects (seizures, headaches,dizziness, lightheadedness, sleep dis-orders), peripheral neuropathy, hy-persensitivity reactions, photosensi- tivity and other rashes, disorders of glucose homeostasis (hypoglycemiaand hyperglycemia), prolongation of QT interval, and hepatic dysfunction.

In the prospective ciprooxacin studyrequested by the FDA, the rate of neu-rologic events was similar betweenciprooxacin- and comparator-treatedchildren ( Table 3) .5 Reported rates of neurologic events in the levooxacinsafety database were statistically sim-ilar between uoroquinolone- andcomparator-treated children. 18,19

RESISTANCE

Quinolone resistance has been a con-cern since the rst approval of theseagents, given the broad spectrum of activity and the large number of clini-

cal indications. Multiple mechanismsof resistance have been described, in-cluding mutations that lead to changesin the target enzymes DNA gyrase andDNA topoisomerase, as well as efuxpumps and alterations in membrane

porins. 20 Newly described plasmid-encoded quinolone-resistance pro- teins have the ability to spreadrapidly. 21

Surveillance studies have tracked u-oroquinolone resistance in S pneumoniae strains isolated primarilyfrom adult patients with respiratory tract infections and in Escherichia coli isolated from adult patients with UTIs.A number of studies also have as-sessed resistance in other enteric ba-cilli,2225 Pseudomonas aeruginosa ,26

Neisseria gonorrhoeae ,27 Neisseria meningitidis ,28 and Streptococcus pyogenes .29,30 One recent study in NorthAmerica addressed uoroquinoloneresistance in both Gram-negative andGram-positive isolates, specicallyfrom children younger than 7 years. 31

Previous concerns that continuingwidespread use of respiratory uoro-quinolones would lead to substantialincreases in pneumococcal resistanceand subsequent lack of usefulness of this class of agents for respiratory tract infections 32 34 have, fortunately,not been conrmed by current pub-lished surveillance data, particularlyfor pneumococcal isolates from chil-dren. 31,35,36 The Active Bacterial CoreSurveillance of the Centers for DiseaseControl and Prevention documented

virtually no levooxacin resistance inchildren younger than 2 years between1999 and 2004. 37 In large-scale pediat-ric studies of levooxacin for acute otitis media, emergence of levooxacin-resistant pneumococci was notdocumented in children with persist-ing pneumococcal colonization after treatment, which suggests that emer-gence of resistance during treatmentis not a common event. 38 Possible rea-

sons for the lack of increasingmultidrug-resistant serotypes in bothchildren and adults in populations inNorth America and Europe include thealmost universal use of conjugatepneumococcal vaccine in children

since 2000 as well as the lack of wide-spread use of uoroquinolones inchildren. 37,3941

In adult patients, Pseudomonas resistance to both uoroquinolones andotherantimicrobial agents is problem-atic. 42 Data on resistance in E coli iso-lated from adults with UTIs who wereseen in emergency departments in theEMERGEncy ID NET, a network of 11geographically diverse university-afliated institutions, suggest a lowbut stable rate of resistance of approx-imately 5%, 24 although in specic loca- tions, rates of resistance for outpa- tients are closer to 10%. 22,43 Similarpublished data do not exist for chil-dren, although in recent reports thatincluded outpatient data, stratied ac-cording to age, the rates of uoroquin-olone resistance in E coli in childrenhave been generally well below 3%. 23,43

For hospitalized children in a major tertiary care pediatric center, only 3%of 271 bloodstream isolates of E coli and Klebsiella species collected over 4years (19992003) were resistant touoroquinolones. 44 With the exceptionof children with cystic brosis, overallresistance in pediatric Gram-negativeisolates, including P aeruginosa , hasbeen lower than 5%. 31 Data availablefrom 3 large tertiary care childrenshospitals document ciprooxacin re-sistance for E coli to range from 4% to7% for 2010 (B. Connelly, MD [Cincin-nati Childrens Hospital and MedicalCenter, Cincinnati, OH], M. A. Jackson,MD [Mercy Childrens Hospital, KansasCity, MO], andJ. Bradley, MD [Rady Chil-drens Hospital, San Diego, CA], verbalcommunication, May 2011), and therates have seemed stable for the last 3years.

TABLE 3 Rate of FDA-Dened NeurologicAdverse Events by 6 Weeks AfterTreatment With Ciprooxacin orComparator

NeurologicAdverse Events

Ciprooxacin(N 335),

n (%)

Comparator(N 349),

n (%)

Any event 9 (3) 7 (2)Dizziness 3 ( 1) 1 ( 1)Nervousness 3 ( 1) 1 ( 1)Insomnia 2 ( 1) 0 (0)Somnolence 2 ( 1) 0 (0)Abnormal dreams 0 (0) 2 ( 1)Convulsion 0 (0) 2 ( 1)Hypertonia 0 (0) 1 ( 1)Abnormal gait 0 (0) 1 ( 1)



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As uoroquinolone use in pediatricsincreases, it is expected that resistance will increase, as has been docu-mented in adults. Appropriate use of uoroquinolones in children shouldlimit the development and spread of resistance.

USE OF FLUOROQUINOLONES FORPEDIATRIC INFECTIONS

ConjunctivitisAn increasing number of topical uo-roquinolones have been investigatedand approved by the FDA for treatmentof acute conjunctivitis in adults andchildren older than 12 months, includ-ing levooxacin, moxioxacin, gati-oxacin, ciprooxacin, and besioxa-cin (Table 4 ). Conjunctival tissuepharmacokinetic evaluation was con-ducted in healthy adult volunteers;

besioxacin, gatioxacin, and moxi-oxacin were compared by using conjunctival biopsy. All 3 agents reachedpeak concentrations after 15 min-utes. 45 Bacterial eradication and clini-cal recovery of 447 patients aged 1 through 17 years with culture-conrmed bacterial conjunctivitis wasevaluated in a posthoc multicenterstudy that investigated besioxacin

and moxioxacin ophthalmic drops. 46Although better clinical and microbio-logical response was noted for besi-oxacin compared with placebo, sim-ilar outcomes were noted whencompared with moxioxacin. Bothagents were reported to be well tol-erated. Although drug concentrations are only 1 indicator of potentialclinical efcacy, the utility of agentswith higher concentrations is tem-

pered by the observation of a potential increase in ocular adverseevents, such as eye pain, 45 andslower corneal reepithelializationwith specic agents. 47

External Otitis, TympanostomyTubeAssociated Otorrhea

Recommendationsfor optimal care forpatients with otitis externa were out-lined in a review of 19 randomized con- trolled trials, including 2 from a pri-mary care setting, which yielded 3382participants. Topical antibiotic agentscontaining corticosteroids seemed tobe more effective than acetic acidsolutions. Aminoglycoside-containing

otic preparations were reported tocause ototoxicity if the tympanic mem-brane was not intact; uoroquinolone-containing preparations represent asafer alternative for treating bothotorrhea associated with tympanicmembrane perforation and tympanostomy tube otorrhea. Eleven trials in-cluded aural toilet as a routine inter-vention, but the authors acknowledged that this treatment is not likely to be

available in a typical primary care of-ce setting. 48 The paucity of high-quality studies of antimicrobial-based topical therapy limited conclusions in this review. A small, prospective, ran-domized, open-label study of 50 patients with tympanostomy tubeassociated otorrhea or a tympanicmembrane perforation resulted incomparable outcomes with either top-ical antibiotic therapy or topical plus

systemic antibiotic agents. 49 For chil-dren with severe acute otitis externa,systemically administered antimicro-bial agentsshould be considered in ad-dition to topical therapy. 50

Which topical antibiotic agent is bestfor external otitis is unclear. High-quality studies that evaluated quino-lone versus nonquinolone topical solu- tions have been limited. A systematicreview of 13 meta-analyses conrmed

TABLE 4 Most Common Infections for Which Fluoroquinolones Are Effective Therapy (See Text)

Infection Primary Pathogen(s) a Fluoroquinolone

Systemic antibiotic requirement b

UTI Escherichia coli Ciprooxacin c

Pseudomonas aeruginosa Enterobacter speciesCitrobacter species

Serratia speciesAcute otitis media; sinusitis Streptococcus pneumoniae Levooxacin d

Haemophilus inuenzae Pneumonia Streptococcus pneumoniae Levooxacin

Mycoplasma pneumoniae (macrolidespreferred for Mycoplasma infections)

Gastrointestinal infections Salmonella species Ciprooxacin c

Shigella speciesTopical antibiotic requirement e,f

Conjunctivitis Streptococcus pneumoniae BesioxacinHaemophilus inuenzae Levooxacin

GatioxacinCiprooxacinMoxioxacinOoxacin

Acute otitis externa; tympanostomy tubeassociated otorrhea

Pseudomonas aeruginosa Ciprooxacin g

Staphylococcus aureus OoxacinMixed Gram-positive/Gram-negative organisms

a Assuming that the pathogen is either documented to be susceptible or presumed to be susceptible for uoroquinolones.b If oral therapy is appropriate, use other classes of oral antibiotics if organisms are susceptible.c Dose of ciprooxacin: oral administration, 20 to 40 mg/kg per day, divided every 12 hours (maximum dose: 750 mg perdose); intravenous administration, 20 to 30 mg/kg per day, divided every 8 to 12 hours (maximum dose: 400 mg per dose).d Dose of levooxacin: oral or intravenous administration, 16 to 20 mg/kg per day divided every 12 hours (for children 6monthsto 5 yearsof age) or10 mg/kgper dayoncedaily(forchildren 5 yearsof ageand older)(maximum dose:750 mgperdose).e Systemic toxicity of uoroquinolones is not a concern with topical therapy; use of topical agents should be determinedaccording to suspected pathogens, efcacy for mucosal infection, tolerability, and cost.f Other systemic therapy may be required for more severe infection.g Available with and without corticosteroid.




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that topical antibiotic agents were su-perior to placebo and noted a statisti-cally signicant advantage of quino-lone agents over nonquinolone agentsin the rate of microbiological cure(P .035), although theclinical importof this advantage is likely of limitedvalue. Safety proles were similar between groups. 50 A conclusion that quin-olone and nonquinolone agents aresimilar in both microbiological andclinical cure rates was reached in astudy of more than 200 children, 90 of whom were evaluated for microbiolog-ical response in a multicenter, random-ized, parallel-group, evaluator-blindedstudy that compared once-daily ooxa-cin drops to 4-times-daily neomycinsulfate/polymyxin B sulfate/hydrocortisone otic suspension. Microbial erad-ication was documented in 95% and94%, respectively; clinical cure wasachieved in 96% and 97%, respectively.Treatment was well tolerated withboth regimens. 51

Acute Otitis Media, Sinusitis, andLower Respiratory Tract Infections

Newer uoroquinolones display en-hanced in vitro activity against S pneumoniae compared with ciprooxacin.The clinical need for such agents to treat respiratory tract infections haslargely been driven by the emergenceof multidrug-resistant strains of thispathogen. Pharmacokinetic data forchildren 6 months of age and older arewell dened for levooxacin, the only

currently available uoroquinolone that has been studied for respiratory tract infections in children. 52 The phar-maceutical manufacturer is currentlynot intending to present data to theFDA to obtain approval for the use of levooxacin for acute bacterial otitismedia or community-acquired pneu-monia in children (S.Maldonado, John-son & Johnson, written communica- tion, May 2011).

Acute Bacterial Otitis Media

Clinical studies of levooxacin andgatioxacin have been conducted inchildren with recurrent or persistentotitis media but not simple acute bacterial otitis media. Although the resultsof studies of several uoroquinoloneshave been reported, only levooxacinis currently available in the UnitedStates. A prospective, open-label, non-comparative study of levooxacin wasperformed in 205 children 6 months of age and older, 80% of whom wereyounger than 2 years. Tympanocente-sis was performed at study entry andat least at 3 to 5 days into therapy forchildren for whom treatment failed orwho had persistent effusion. Bacterialeradication of middle-ear pathogensoccurred in 88% of children, including84% infected by pneumococci and100% infected by Haemophilus inuenzae . Levooxacin treatment was well tolerated; vomiting in 4% of thepatients was documented as themost common adverse effect. 53 Anevaluator-blinded, active-comparator,noninferiority, multicenter study that

involved 1305 evaluable children older than 6 months and compared levo-oxacin to amoxicillin-clavulanate(1:1) found equivalent clinical curerates of 75% in each treatment arm.However, because tympanocentesiswas not required, microbiologicalcure rates could not be determined. 19

Pneumonia

Although initially approved by the FDAfor the treatment of pneumonia andacute exacerbation of chronic bronchitis in adults, ciprooxacin therapy hasnot been uniformly successful in treat-ment of pneumococcal pneumonia inadults at dosages initially studied 30years ago. Failures are most likely aresult of the increasing pneumococcalresistance to ciprooxacin and otheruoroquinolones documented since their rst approval. 54 Ciprooxacin is

currently not considered appropriate therapy for community-acquired pneu-monia in adults.

Fluoroquinolones with enhanced activ-ity against S pneumoniae comparedwith ciprooxacin (levooxacin, moxi-oxacin, gemioxacin) have been usedin adults for single-drug treatmentof community-acquired pneumonia.These respiratory tract uoroquino-lones have demonstrated in vitro activ-ity against the most commonly iso-lated pathogens: S pneumoniae ,Haemophilus inuenzae (nontype-able), and Moraxella catarrhalis , aswell as M pneumoniae , C pneumoniae ,and Legionella pneumophila .5557 Al- though these agents are not the drugsof choice for pneumonia in previouslyhealthy adults, they are recommendedfor adults with underlying comorbidi- ties and for those who have been ex-posed to antibiotic agents within theprevious 3 months and, therefore,are more likely to be infected withantibiotic-resistant pathogens. 58 Fail-ures in the treatment of pneumococcalpneumonia have been reported with

levooxacin at 500 mg daily as a resultof emergence of resistance on therapyor resistance from previous expo-sures to uoroquinolones. 59 An in-creased dose of levooxacin750 mgdaily, given for 5 daysis currentlyapproved by the FDA for adults withpneumonia. The increase in drug expo-sure at the higher dose is designed toovercome the most common mecha-nism for the development of uoro-

quinolone resistance. 60

Of the uoroquinolones, only levooxa-cin has been studied prospectively inchildren with community-acquiredpneumonia; efcacy in a multinational,open-label, noninferiority-design trialcompared with standard antimicro-bial agents for pneumonia was docu-mented. For children aged 6 months to5 years, levooxacin (oral or intrave-nous) was compared with amoxicillin/



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clavulanate (oral) or ceftriaxone (intravenous). For children 5 years of ageand older, levooxacin (oral) was com-pared with clarithromycin (oral), andlevooxacin (intravenous) was com-pared with ceftriaxone (intravenous) in

combination with either erythromycin(intravenous) or clarithromycin (oral).Clinical cure rates were 94.3% in thelevooxacin-treated group and 94.0%in the comparator group, and therewere similar rates of cure in both theyounger and older age groups. Micro-biological etiologies were investi-gated, and Mycoplasma was the mostfrequently diagnosed pathogen (by se-rologic testing), representing 32% of

those receiving levooxacin in botholder and younger age groups and ap-proximately 30% of those receivingcomparator agents in both agegroups. Pneumococci were infre-quently documented to be the cause of pneumonia in study patients, repre-senting only 3% to 4% of those whoreceived levooxacin and 3% to 5% of those receiving comparator. It shouldbe noted that the clinical response

rate of 83% in children younger than 5years diagnosed by serologic testingwith Mycoplasma infection and treated with amoxicillin/clavulanatewas similar to that in children treatedwith levooxacin (89%), which indi-cates a high rate of spontaneous reso-lution of disease caused by Myco- plasma species in preschool-agedchildren, poor accuracy of diagnosisby serologic testing, or a clinical end-

point evaluation after a treatmentcourse that could not identify possibledifferences in response that may havebeen present in the rst days of therapy. 18

Although uoroquinolones may repre-sent effective therapy, they arenot rec-ommended for rst-line therapy of re-spiratory tract infection in children,because other better-studied andsafer antimicrobial agents are avail-

able to treat the majority of the cur-rently isolated pathogens.

Gastrointestinal Infections

Alghasham and Nahata 61 summarized the results of 12 efcacy trials thatused a number of uoroquinoloneagents for infections caused by Salmo- nella and Shigella species. However,data from only 2 of the 12 trials thatcompared uoroquinolones to non-quinolone agents were reported. Pa- tients were treated for typhoid fever(8 studies, including 7 for multidrug-resistant strains), invasive nonty-phoid salmonellosis (1 study), andshigellosis (3 studies). Clinical and

microbiological success with uoro-quinolone therapy for these infections was similar for children andadults. A recent report suggestedcaution in the use of uoroquinolonesin visitors returning from India with ty-phoid fever, because antimicrobial-resistant Salmonella typhi strains, in-cluding strains with decreasedsusceptibility to uoroquinolones,have been noted. 62

A prospective, randomized, double-blind comparative trial of acute, inva-sive diarrhea in febrile children wasconducted by Leibovitz et al, 63 whocompared ciprooxacin with intra-muscular ceftriaxone in a double-dummy treatment protocol. Two hun-dred and one children were treatedand evaluated for clinical and microbi-ological cure as well as for safety.Pathogens were isolated in 121 chil-

dren, mostcommonly Shigella and Sal- monella species. Clinical and microbi-ological cure were equivalent betweengroups. No arthropathy was detectedduring or up to 3 weeks after comple- tion of therapy. 63

In the United States, although cases of typhoid fever and invasive salmonello-sis are uncommon, there are up to280 000 cases of shigellosis per year,most of which occur in preschool-aged

children with relatively mild disease.Treatment is recommended primarily to prevent spread of infection. Ampicil-lin and TMP-SMX resistance is increas-ing, and multidrug-resistant strainsare becoming common; the National

Antimicrobial Resistance MonitoringSystem (NARMS) reported that 38% of the strains isolated from 1999 2003were resistant to both ampicillinand TMP-SMX. A 2005 outbreak of multidrug-resistant Shigella sonnei in-fection involving 3 states was reportedin the Morbidity and Mortality Weekly Report 64; 89% of the strains were resistant to both agents, but 100% of thestrains were susceptible to ciprooxa-

cin. Treatment options for multidrug-resistant shigellosis, depending on theantimicrobial susceptibilities of theparticular strain, include ciprooxa-cin, azithromycin, and parenteralceftriaxone.

Although ciprooxacin has been re-garded as an effective agent for travel-ers diarrhea in the past, resistanceratesareincreasing forspecic patho-gens in many parts of the world. Resis-

tance in Campylobacter species is particularly problematic in countries suchas Taiwan, Thailand, and Sweden,where rates of 57%, 84%, and up to 88%, respectively, have beenreported. 65,66

Urinary Tract Infection

Standard empiric therapy for uncom-plicated UTI in the pediatric populationcontinues to be a cephalosporin antibi-otic agent, because TMP-SMX- andamoxicillin-resistant E coli are increas-ingly common. The uoroquinolonesremain a potential rst-line agent onlyin the setting of pyelonephritis or com-plicated UTI when typically recom-mended agents are not appropriate on the basis of susceptibility data, allergy,or adverse-event history. The previousAmerican Academy of Pediatrics policystatement (2006) supported the use of




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ciprooxacin as oral therapy for UTIand pyelonephritis caused by P aeruginosa or other multidrug-resistantGram-negative bacteria in childrenaged 1 through 17 years and remainscurrent. 3

Mycobacterial Infections

The uoroquinolones are active invitro against mycobacteria, includingM tuberculosis and many nontubercu-lous mycobacteria. 58,67 Increasing multidrug resistance in M tuberculosis has lead to the increased use of uoro-quinolones as part of individualized,multiple-drug treatment regimens;levooxacin and moxioxacin have

demonstrated greater bactericidal activity than has ciprooxacin. 68 Treat-ment regimens that include uoro-quinolones for 1 to 2 years formultidrug-resistant and extensivelydrug-resistant tuberculosis have notbeen prospectively studied in children.However, the benet of treatment of tuberculosis with an active compoundwhen other active alternatives are notavailable is greater than the potentialfor arthropathy. No joint toxicity hasyetbeen reported in children who havereceived long-term therapy for tuber-culosis, but data on safety have notbeen collected systematically.

Other Uses

Ciprooxacin is effective in eradicatingnasal carriage of Neisseria meningitidis (single dose: 500 mg for adults and20 mg/kg for children older than 1month), is preferred in nonpregnantadult women, and can be consideredfor younger patients as an alternative to rifampin, depending on results of arisk/benet assessment.

Good penetration into the cerebrospi-nal uid by certain uoroquinoloneshas been reported, and concentrations often exceed 50% of the corre-sponding plasma drug concentration.In cases of multidrug-resistant Gram-

negative meningitis in which no otheragents are suitable, uoroquinolonesmay represent the only treatmentoption. 69

P aeruginosa cancause skin infections(including folliculitis) after exposure to inadequately chlorinated swimmingpools or hot tubs. For children who re-quire systemic therapy, uoroquino-lone agents offer an oral treatment option that may be preferred overparenteralnonuoroquinolone antimi-crobial therapy.

SUMMARY

Use of a uoroquinolone in a child oradolescent may be justied in special

circumstances in which (1) infection iscaused by a multidrug-resistant patho-gen for which there is no safe and ef-fective alternative and (2) the optionsfor treatment include either parenteral nonuoroquinolone therapy ororal uoroquinolone therapy, and oral therapy is preferred. In other clinicalsituations outlined previously, uoro-quinolones may also represent apreferred option (eg, topical uoro-

quinolones in the treatment of tympa-nostomy tubeassociated otorrhea)or an acceptable alternative to stan-dard therapy because of concerns forantimicrobial resistance, toxicity, orcharacteristics of tissue penetration.

No compelling published evidence todate supports the occurrence of sus- tained injury to developing bones or joints in children treated with avail-able uoroquinolone agents; however,

FDA analysis of ciprooxacin safetydata, as well as posttreatment and 12-month follow-up safety data for levo-oxacin, suggest the possibility of in-creased musculoskeletal adverseeffects in children who receive uoro-quinolones compared with agents of other classes. Many drugs in commonpediatric use lack specic FDA ap-proval for children. In the case of uo-roquinolones, as is appropriate with

all antimicrobial agents, practitionersshould verbally review common, antic-ipated potential adverse events, andindicate why a uoroquinolone is themost appropriate antibiotic agent fora childs infection.

LEAD AUTHORSJohn S. Bradley, MDMary Anne Jackson, MD

COMMITTEE ON INFECTIOUS DISEASES,20102011Michael T. Brady, MD, ChairpersonHenry H. Bernstein, DOCarrie L. Byington, MDKathryn M. Edwards, MDMargaret C. Fisher, MDMary P. Glode, MDMary Anne Jackson, MD

Harry L. Keyserling, MDDavid W. Kimberlin, MDYvonne A. Maldonado, MDWalter A. Orenstein, MDGordon E. Schutze, MDRodney E. Willoughby, MDFormer Committee MemberJohn S. Bradley, MDLiaisonsBeth Bell MD, MPH Centers for Disease

Control and Prevention Robert Bortolussi, MD Canadian Paediatric

Society Marc A. Fischer, MD Centers for Disease

Control and Prevention Bruce Gellin, MD National Vaccine Program

Ofce Richard L. Gorman, MD National Institutes of

Health Lucia Lee, MD Food and Drug Administration R. Douglas Pratt, MD Food and Drug

Administration Jennifer S. Read, MD National Institutes of

Health Jeffrey R. Starke, MD American Thoracic

Society Jack Swanson, MD Committee on Practice

Ambulatory Medicine Tina Q. Tan, MD Pediatric Infectious Diseases

Society

EX OFFICIOCarol J. Baker, MD Red Book Associate Editor Sarah S. Long, MD Red Book Associate Editor H. Cody Meissner, MD Red Book Associate

Editor Larry K. Pickering, MD Red Book Editor

CONSULTANTLorry G. Rubin, MD

STAFFJennifer Frantz, MPH



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DOI: 10.1542/peds.2011-1496; originally published online September 26, 2011;2011;128;e1034Pediatrics

John S. Bradley, Mary Anne Jackson and the Committee on Infectious DiseasesThe Use of Systemic and Topical Fluoroquinolones

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