Cipro en Niños

8/12/2019 Cipro en Nios

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Arch Dis Chi ld2011;96:874880. doi:10.1136/adc.2010.208843874

Accepted 8 June 2011Published Online First23 July 2011

ABSTRACTObjective To determine the safety of ciprofloxacin inpaediatric patients in relation to arthropathy, any otheradverse events (AEs) and drug interactions.Methods A systematic search of MEDLINE, EMBASE,CINAHL, CENTRAL and bibliographies of relevant articleswas carried out for all published articles, regardlessof design, that involved the use of ciprofloxacin in anypaediatric age group 17 years. Only articles thatreported on safety were included.Results 105 articles met the inclusion criteria andinvolved 16 184 paediatric patients. There were 1065reported AEs (risk 7%, 95% CI 3.2% to 14.0%). Themost frequent AEs were musculoskeletal AEs, abnormal

liver function tests, nausea, changes in white blood cellcounts and vomiting. There were six drug interactions(with aminophylline (4) and methotrexate (2)). Theonly drug related death occurred in a neonate who hadan anaphylactic reaction. 258 musculoskeletal eventsoccurred in 232 paediatric patients (risk 1.6%, 95% CI0.9% to 2.6%). Arthralgia accounted for 50% of these.The age of occurrence of arthropathy ranged from7 months to 17 years (median 10 years). All cases ofarthropathy resolved or improved with management.One prospective controlled study estimated the risk ofarthropathy as 9.3 (OR 95% CI 1.2 to 195). Pooled safetydata of controlled trials in this review estimated the risk

of arthropathy as 1.57 (OR 95% CI 1.26 to 1.97).Conclusion Musculoskeletal AEs occur due tociprofloxacin use. However, these musculoskeletal eventsare reversible with management. It is recommended thatfurther prospective controlled studies should be carriedout to evaluate the safety of ciprofloxacin, with particularfocus on the risk of arthropathy.

INTRODUCTIONThe first quinolone discovered was nalidixic acidin 1962, as a by-product of antimalarial research.Its use was limited due to its narrow spectrum ofantibacterial activity, low serum levels and toxic-

ity issues.1Fluorination of the quinolone nucleusat position 6 resulted in introduction of second,third and fourth generations of fluoroquinolones,with ciprofloxacin in 1987 as a second generationfluoroquinolone.2 Ciprofloxacin is a broad spec-trum, bactericidal antibiotic which acts by bind-ing two of the four topoisomerases of bacteria.3

The use of ciprofloxacin and fluoroquinolones asa group in paediatric patients has been limited dueto arthropathy noticed in weight bearing jointsof juvenile animals. Cartilage damage causedby quinolones (nalidixic, oxolinic and pipemidicacids) was first reported in juvenile animals (bea-gle dogs 412 months of age).4 The arthropathycaused by quinolones has also been demonstrated

in other animal species such as mice,5dogs,6rats7and rabbits,8 and in in-vitro animal culture9andin-vitro human cell culture.10

Due to the good antibacterial activity and tissue

penetration, different investigators have used cip-rofloxacin in paediatric patients. The occurrenceof arthropathy is uncertain. Other adverse drugreactions and drug interactions have been reportedwith ciprofloxacin use in adults.11 However, thedrug toxicity profile has not been ascertained inpaediatric use. This systematic review aims topool together all the safety data about use of cip-rofloxacin in paediatrics, with a critical look at theoccurrence of arthropathy.

METHODS

Search strategy

We searched MEDLINE (1950 to November 2009),EMBASE (1950 to November 2009), the Cochranedatabase for systematic reviews, the CochraneCentral Register of Controlled Trials (CENT RAL),and the Cumulative Index to Nursing and AlliedHealth Literature (CINAHL) for any study withdocumented involvement of any paediatric agegroup (017 years) that used ciprofloxacin asintervention via any route of administration andfor any disease condition. There was no restric-tion on the type of study that was included, lan-guage of publication or inclusion of abstracts.Any study with involvement of a paediatric agegroup participant taking at least a single dose ofciprofloxacin was included. This was necessary to

Supplementaryappendices 1 and 2 are

published online only. To viewthese files please visit thejournal online (ht tp://adc.bmj .com)

1Academic Division ofChild Health, University ofNottingham, DerbyshireChildrens Hospital, Derby, UK2Department of PediatricPharmacology andPharmacogenetics, ClinicalInvestigation Center (CIC),9202 INSERM, Hpital RobertDebr, Paris, France

Correspondence toImti Choonara, AcademicDivision of Child Health,University of Nottingham,Derbyshire Childrens Hospital,Derby DE22 3DT UK;[email protected]

Ciprofloxacin safety in paediatrics: a systematicreview

Abiodun Adefurin,1Helen Sammons,1Evelyne Jacqz-Aigrain,2Imti Choonara1

What is already known on this topic

Ciprofloxacin is a broad spectrum, bactericidalantibiotic with good tissue penetration.Ciprofloxacin and fluoroquinolones as a group,

cause arthropathy in weight bearing joints ofjuvenile animals.The use of ciprofloxacin in paediatrics has been

limited due to the possibility of arthropathy.

What this study adds

Musculoskeletal adverse events (AEs) are the

most frequently reported AEs in paediatricpatients after ciprofloxacin use.All musculoskeletal AEs reported in the

literature have been reversible followingwithdrawal of ciprofloxacin.


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Arch Dis Chi ld2011;96:874880. doi:10.1136/adc.2010.208843 875

ascertain the extent of use of ciprofloxacin in paediatrics andto be able to pool any documented adverse events (AEs) involv-ing any paediatric age group. Hand searching of references ofarticles was also done. Studies that involved only adults wereexcluded. Search terms comprised both subject headings andfree text words. These included terms relating to ciprofloxacinor quinolones or fluoroquinolones; adverse effects or adversedrug reactions or side effects; arthropathy or cartilage toxicity

or chondrotoxicity or joint damage; and pharmacokinetics (seeonline supplementary appendix 1).

Outcome measuresThe prespecified outcomes were as follows:

Occurrence of arthropathy specified as joint pain, joint1.swelling, reduced movement of joint or radiographic evi-dence of joint damage and any other musculoskeletal AE.Occurrence of any other AEs from ciprofloxacin use.2.Occurrence of drugdrug interactions due to ciprofloxacin3.use.Death due to adverse drug reaction from ciprofloxacin4.use.

Data collection and analysisThe relevant data were extracted onto the data extractionform. Only studies that reported on the number of paediatricpatients within each study and reported on safety of cipro-floxacin in the paediatric patients were analysed. Participantsin the study were grouped into the following paediatric agegroups: preterm neonates (37 weeks gestation); infantsand toddlers (28 days to 23 months); children (211 years);and adolescents (1217 years). AEs were classified accord-ing to the WHO adverse reaction terminology classifica-tion into one of the several organ systems, and were further

analysed to determine which AEs actual ly occurred in any ofthe paediatric age groups (see online supplementary appen-dix 2). The ar thropathy reports were analysed for causalityin relation to the time of exposure to the drug, presence ofother disease and medications.12Details of the arthropathyincluded the time to development of arthropathy followingciprofloxacin use; the time to follow-up of patients after use

of ciprofloxacin; method of detecting arthropathy in patients;and any management of the arthropathy. A descriptive anal-ysis of extracted data was performed. Statistical analysis wascarr ied out using SPSS V.18 and GraphPad software.

RESULTSWe identified a total of 105 studies (figure 1), the majority ofwhich were case series or case reports13117(table 1). However,most of the patients (88%) were within case series or cohortstudies.

Dosage and formulationsThe dose ranged from 3.1 to 93.8 mg/kg/day (oral) and 3.2to 76.9 mg/kg/day (intravenous).68The usual dose in at least60% of studies was 1030 mg/kg/day in two divided dosesfor both oral and intravenous administration. The duration ofciprofloxacin ranged from single dose (pharmacokinetic stud-ies, therapy for cholera and prophylaxis for meningococcaldisease) to 880 days (a 12-year-old with osteomyelitis).68Themedian duration of use was 14 days.

Due to the lack of a commercially available paediatric for-

mulation, various formulations were used, including a pre-pared suspension from granular ciprofloxacin,161866 tablets,1925448198115ground tablets,82a suspension formulation fromBayer,1322pulverised tablets with sweet liquid,42and tabletscrushed and mixed in cherry syrup.70 Topical ciprofloxacinwas administered as drops to the eyes/ears.

Analysis of safetyAll reported AEs were analysed together (table 2). Sixty-eightstudies reported AEs, while 37 studies reported no AEs. Intotal, 16 184 paediatric patients were exposed to ciprofloxacinand there were 1065 reported AEs. This gave an estimated riskof 7 AEs in every 100 patients (7%, 95% CI 3.2% to 14.0%), or

1 AE in every 14 patients receiving ciprofloxacin.The most frequent AEs were musculoskeletal problems,abnormal liver function tests, nausea, changes in white bloodcell counts and vomiting (table 2). These are pooled safety dataof reported AEs by individual authors of the studies in ourreview. There was no dose dependent or duration dependentrisk of toxicity.

Figure 1 Algorithm of the analysis of the studies in the systematic review.


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Drug related death occurred in a neonate who experiencedan anaphylactic reaction following intravenous ciprofloxacin.An additional 23 paediatric patients had to discontinue cipro-floxacin due to serious AEs (table 3).

There were six drug interactions with ciprofloxacin. Fourpatients had drug interactions with aminophylline47 (twopatients were irritable/restless, one had tremors and onehad hot flushes). Two patients had delayed elimination ofmethotrexate.55However, there was no drug interaction withaminophylline in seven preterm babies.21

ArthropathyThirty-two studies reported arthropathy, while 73 studiesreported no arthropathy (37 studies reporting no AEs + 36studies of those reporting AEs that reported no arthropathy).There was no evidence that dose or duration had an effect onarthropathy.

In total, 16 184 paediatric patients were exposed to cipro-floxacin; 258 musculoskeletal events occurred in 232 paediat-ric patients (some patients had more than one musculoskeletalAE). This gave an estimated risk of 16 musculoskeletal AEs per1000 patients receiving ciprofloxacin (1.6%, 95% CI 0.9% to2.6%) or one musculoskeletal AE in every 62.5 patients. A sum-mary of the reported symptoms and/or signs of arthropathy ispresented in table 4. Only 10 of the 32 studies gave detailedinformation regarding time and onset, duration of follow-up,method of detecting arthropathy and management.

The youngest documented case of arthropathy was in a7-month-old infant.60Age of occurrence was documented in47 paediatric patients; median age was 10 years. The time

to follow-up of the patients after use of ciprofloxacin was1 week to 50 months.80109Of 47 studies reporting the time

to follow-up of the patients, 31 studies (66%) followed up foran average time of 90 days. The time to development of anyform of arthropathy was reported in 12 studies and rangedfrom 15 min to 30 days (median 6 days).7381There were threeadditional cases of arthralgia that occurred on the first day oftreatment.16 101 Management included continuation of druguse, discontinuation of drug with/without rechallenge, use ofanalgesics to relieve arthralgia, dose reduction or a combina-tion of any of these measures. All cases of arthropathy withreport on management resolved or improved. However, therewas a report of arthralgia remaining unchanged in 1 out of

31 reported arthralgia cases in a study. However, we are notcertain i f any management was instituted or for how long thearthralgia persisted.74

Arthralgia accounted for 130 (50%) events. Four patients dis-continued therapy due to arthralgia, which resolved in threepatients (no report of the outcome in the last patient).47 68Radiological confirmation of arthropathy using MR1 waspositive in two studies involving six cystic fibrosis patients,who had joint effusions, abnormal thickness of articularcartilage, non-homogeneous structure of cartilage or alteredtwo-layer appearance of cartilage.7991 In addition to clinicalexamination and radiological investigation, seven studies (531cases and 674 controls) investigated the effects of ciprofloxa-

cin on growth of patients after following up the patients for650 months.2832336375109116None of these studies found

Table 1 Summary of 105 studies that reported on safety of

ciprofloxacin in paediatrics

Type of study Frequency (N=105)Number of patients

(N=16 184)

Case series 46 8876

Case report 24 24

RCT 15 1787

Cohort study 12 5368

Pharmacokinetic 5 79

Non-RCT 3 50

Route of administration Frequency (N=105) Number of patients

(N=16 184)

Oral 39 1871

Intravenous 25 329

Intravenous and oral 19 6489

Not reported 16 6905

Topical 6 590

Age group Frequency (N)* Number of patients

Children 67 NA

Adolescents 53 NA

Infants 40 NA

Preterm neonates 19 NA

Neonates (GA not stated) 18 NA

Term Neonates 9 NA

*Total number of studies for age group is not 105 studies because multiple age

groups were included within some studies .The number of patients in each age group could not be ascer tained because most

studies involved more than one age group and the number wit hin each age group

was not reported.

GA, gestational age; NA, not available; RCT, randomised controlled tr ial.

Table 2 Summary of reported adverse events (AEs) from 68 studies

AEs Frequency

Musculoskeletal 232*

Abnormal liver function tests 139

Nausea 75

Blood cell count derangements 57

Vomiting 56

Rash 51

Injection site reaction 47

Headache 41

Hearing/eye associated AEs 42

Abdominal pain/discomfort 38

Diarrhoea 36

Psychiatric disorders 18

Dizziness/decreased consciousness 13

Pruritus 2

Irritability/anxiety/nervousness 12

Photosensitivity 10

Acute renal failure/impaired renal function 9

Abdominal distension 8

Allergy/anaphylactoid reaction 7

Oral cavity abnormalities 6Bleeding 6

Hemiparesis/hypotonia/hyperreflexia/ataxia 5

Fever/hot flushes 5

Rigors/shivering/tremors 4

Interstitial nephritis 4

Others 34

Not specified 98

Total 1065

*232 patients had 258 musculoskeletal events.Others include AEs which occur red once, twice or thrice only. These include sei-

zures, haemolytic uraemic syndrome, pseudomembranous colitis, gastro-oesoph-

ageal reflux disease, urinary retention, greenish discolouration of teeth, malaise,

weight loss, dysuria, heart failure, sinoatrial nodal arrest and tachycardia.

Not specified AEs reported as unknown.


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any significant difference in growth of the ciprofloxacinexposed patients compared with the control arm.

The majority of the musculoskeletal events (223, 86%) wereclassified as possibly related to ciprofloxacin. Rechallengewith ciprofloxacin was done in eight patients, but was positivein only a 9-year-old cystic fibrosis patient who had received17 mg/kg/day for 15 days and noticed arthralgia of elbow andknees on the sixth day post-therapy.8391101No informationwas given about how long arthralgia lasted on rechal lenge andif any management was instituted.

Controlled studiesOnly two studies estimated the risk of development ofarthropathy in paediatr ic patients receiving ciprofloxacin com-pared to a control group. A prospective cohort study of 264cases and 249 controls matched for age and presence of cysticfibrosis, followed up patients for 15 days after the last dose oftreatment.101An estimated crude OR for musculoskeletal AEsin the fluoroquinolone group (ciprofloxacin, ofloxacin and per-floxacin) compared to other antibiotics was 9.3 (95% CI 1.2 to195, p=0.02). Considering cyst ic fibrosis patients alone withinthe same study (approximately 90 patients in each group), theOR for musculoskeletal AEs in the fluoroquinolone group com-pared to other antibiotics was 1.2 (95% CI 0.1 to 35, p=0.99).

The ORs estimated were not adjusted for possible influence ofage and sex.

Second, a retrospective cohort study using a pharmacydatabase of patients exposed to fluoroquinolones and azithro-mycin, checked for potential joint or tendon disorder diagnosedwithin 60 days of exposure to drug.103The joint or tendon dis-orders were verified from medical records of the patients bythree blinded specialists. The study had over 4500 patientsreceiving ciprofloxacin and over 1500 patients receiving oflox-acin compared to over 15 000 patients receiving azithromycin.

The estimated RR for verified tendon or joint disorder for cip-rofloxacin was 1.04 (95% CI 0.72 to 1.51) and for ofloxacin was1.04 (95% CI 0.55 to 1.84). The age and sex adjusted RR were1.08 (95% CI 0.74 to 1.58) for ciprofloxacin and 1.13 (95% CI0.63 to 2.03) for ofloxacin.

Safety data of all randomised controlled trials, non-ran-domised controlled trials and cohort studies in our reviewwere pooled together. Analysis of 23 controlled studies (7 con-trolled studies were excluded because ciprofloxacin or anotherfluoroquinolone was administered in the comparator arm)comprising 6481 cases and 17 441 controls showed that thereis a 57% increased risk of arthropathy in patients who receivedciprofloxacin compared to the comparator arm (OR 1.57, 95%CI 1.26 to 1.97).131519 28 3363 75 76 79 101 103 105 109111 112 116Further analysis of five controlled studies that included onlycystic fibrosis patients (227 cases and 391 controls) estimateda 67% increased risk of arthropathy (OR 1.67, 95% CI 1.13 to2.45).171979101105

DISCUSSIONOur systematic review about the safety of ciprofloxacin is thefirst review that has pooled together all reported suspected AEsdue to ciprofloxacin use in paediatric patients. Ciprofloxacin iscontraindicated in paediatrics because juvenile animals devel-oped arthropathy after use.4However, our review has identi-fied over 16 000 children who have received ciprofloxacin. Itis likely that the number of children who have received cipro-

floxacin in practice is significantly greater than this.Our review confirms that musculoskeletal toxicity is the

most frequently reported AE following the use of ciprofloxa-cin. There is, however, a wide range of toxicity that has beenreported and it is important to recognise that, like all anti-infective agents, ciprofloxacin can be associated with a broadspectrum of AEs. The toxicity profile in table 2 is pooled safetydata of reported suspected AEs by individual authors; how-ever, these AEs may not be adverse drug reactions in all cases.From our review, there is an estimated risk of one musculosk-eletal AE in every 62.5 patients, and a 57% increased risk ofarthropathy in patients exposed to ciprofloxacin. The muscu-loskeletal AEs appear reversible with management.

The term arthropathy has been used broadly for variousmusculoskeletal AEs. Juvenile animals were noted to havegait stiffness, particularly in the hind limbs; reluctance to risefrom a sitting, lateral or sternal recumbence position; exuda-tion of synovial fluid; and blistering and ulcerative erosions ofarticular cartilage in the limb joints.4118However, our reviewsuggested that arthralgia was the commonest symptom ofarthropathy (50%) in paediatric patients, affecting mostlythe knee joint. Tendon or joint disorders and reduced move-ment also accounted for a significant proportion of arthropa-thy cases (19% and 15%, respectively). Although the specifictendon disorder could not be ascertained, tendin itis or tendonrupture could be implied as this represents the most frequentpresentations in the literature.119121The only specific report of

tendon disorder in our review was a case of Achilles tendinitisin a patient (age not specified).106Tendon disorders have been

Table 3 Summary of serious adverse events necessitating

withdrawal and/or discontinuation of therapy

AENumber of

patients (n=23)

Rash 5

Arthralgia 4

Vomiting and diarrhoea 2

Allergy 2

Anaphylactoid reaction 2

Epistaxis 1

Angioneurotic oedema 1

Cardiac failure 1

Sinus nodal arrest 1

Toxic megacolon 1

Nausea 1

Interstitial nephritis 1

Benign intracranial hypertension 1

Table 4 Summary of reported musculoskeletal events from 32

studies

Musculoskeletal events Frequency (%)

Arthralgia 130 (50.0)

Tendon or joint disorder 48 (19.0)

Reduced movement/stiffness 39 (15.0)

Joint swelling 8 (3.0)

Radiological confirmed arthropathy 6 (2.3)

Myalgia 4 (1.6)

Arthritis 3 (1.2)

Pain in extremity 1 (0.4)

Osteitis 1 (0.4)

Unknown 18 (7.0)

Total 258* (100)

*258 musculoskeletal events occurred in 232 patients.


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thought to occur more frequently in patients over 60 years.122However, our review suggests it is also reported in paediatricpatients, and clinicians should be aware of such possibility.

Various molecular mechanisms have been postulated forarthropathy, such as inhibition of synthesis of collagen andglycosaminoglycans, inhibition in mitochondrial functionresulting in generation of free radicals and oxidative stress orchelation of magnesium ions, all culminating in cartilage and

tendon damage.5123There appear to be differences in features of arthropathy in

animals compared to humans. Two studies reported on thehistopathology of the articular cartilage of three patients atpostmortem examination, but no arthropathic lesions werenoted.64 91 However, animal studies showed exudation ofsynovial fluid, blistering and ulcerative erosion of articu-lar cartilage at postmortem examination, even after clinicalrecovery.4

Animal studies have suggested that arthropathy occursearlier in younger animals.118However, our review showed amedian age of 10 years (range 7 months to 17 years) among47 age documented paediatric patients. Although most of thestudies included in our review involved children (211 years), atleast 389 neonates were exposed, with none developing mus-culoskeletal AEs. The differences in growth between animalsand humans have been suggested as a possible explanation forsuch differences. The number, location and time of appearanceof secondary ossification centres vary between animal speciesand humans.

Arthropathy in animals appears to be dose related, withincreased risk in higher doses and after longer duration oftreatment.124125However, our data does not point to any dosedependent or duration dependent relationship in humans.

In conclusion, our review identified only one prospectivecohort study showing an increased risk of arthropathy, and weestimated an increased r isk in those exposed to ciprofloxacin.

The concern of arthropathy in paediatric patients, based onstudies in juvenile animals is therefore appropriate; however,the risk of arthropathy is relatively low and reversible withmanagement. The risk of ciprofloxacin-induced arthropathyneeds to be considered in relation to the benefits of using cip-rofloxacin in children with acute infections. The role of cipro-floxacin in paediatric and neonatal sepsis can only be clarifiedby further prospective studies evaluating both the benefitand the risk of toxicity, with a particular focus on the risk ofarthropathy.

Acknowledgements This work is part of the TINN network (CollaborativeProject), supported by the European Commission under the Health CooperationWork Programme of the 7th Framework Programme (grant agreement number223614).

Funding TINN project, an FP7 project sponsored by the European Commission.

Competing interests None.

Provenance and peer review Not commissioned; externally peer reviewed.

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