INTRODUCTIONAcute infective conjunctivitis is a commonproblem in the primary care setting,accounting for up to 1% of GP consultationsin the UK.1,2 Standard treatment for acuteinfective conjunctivitis has traditionally beenwith topical antibiotics.3 There was littleevidence from primary care on which tobase treatment decisions until 2005, whenthree trials based on primary carepopulations were published.46 These trialsconfirmed a high rate of resolution inuntreated cases and a limited effect ofantibiotics within the primary care setting.Subsequently, clinical guidelines have beenupdated to limit the use of antibiotics.7 Inaddition, the differentiation between a viraland bacterial cause is difficult on clinicalgrounds, and it is generally impractical torequest and await microbiology resultsbefore initiating treatment.8Since 2005, GPs have responded to

evidence by reducing prescribing rates foracute infective conjunctivitis, but over-the-counter availability of chloramphenicol intheUKhas resulted in a 48% increase in theuse of topical chloramphenicol.9 Reliableidentification of subgroups that will benefitfrom antibiotics is important for guidingprescribing practice in both primary careand pharmacies. Previous studies have notbeen large enough for reliable subgroup

analysis. Individual patient data meta-analysis has been shown to be an efficientmethod for subgroup analysis when only alimited number of trials are available.10This study conducted a meta-analysis

using individual patient data, with the aim ofassessing the overall benefit of antibioticsas well as the benefit in different subgroupsof patients with acute infective conjunctivitisin a primary care setting.

METHODSelection of studiesThe Cochrane Central Register ofControlled Trials (CENTRAL), Embase,MEDLINE, and PubMed were searched forrandomised controlled trials up to andincluding April 2010. Methodological filterswere used for identifying randomisedcontrolled trials (RCTs) in Embase11 andMEDLINE;12 no other limits or filters wereused. The following search terms wereused: (keyword conjunctivitis, bacterial) or(acute or infect* or bacteria*) conjunctiv*)and (keyword anti-bacterial agents) or(antibiotic*). Trialswereeligible for inclusionif they were carried out within the primarycare setting and were randomised,comparing antibiotic with placebo or notreatment.A total of 332 potentially relevant trials

were identified; 325 of these were excluded

JM Jefferis, MA, BM, BCh, PGDipClinRes, NIHR,doctoral research fellow in opthalmology,Newcastle University, Newcastle. RPerera, MSc,DPhil, university lecturer in medical statistics;PWRose, FRCGP, MD, university lecturer ingeneral practice, Department of Primary HealthCare, University of Oxford, Oxford. PGlasziou, PhD,FRACGP, MRCGP, professor of evidence-basedmedicine, Bond University, Australia. HEveritt,BSc, MRCGP, MSc, PhD, clinical lecturer ingeneral practice, Community Clinical Sciences(CCS) Division, Faculty of Medicine, Health andBiological Sciences, Southampton University,Southampton. H vanWeeert, MD, PhD, professorof general practice and family medicine, AcademicMedical Centre, University of Amsterdam;

RPRietveld, MD, PhD, GP, Amsterdam, theNetherlands.

Address for correspondenceRafael Perera, Division of Public Health andPrimary Care, University of Oxford, Old RoadCampus, Headington, Oxford, OX3 7LF.

E-mail:Rafael.perera@dphpc.ox.ac.ukSubmitted: 20 January 2011; Editors response:21 February 2011; final acceptance: 29March 2011.British Journal ofGeneralPracticeThis is the full-length article (published online30 Aug 2011) of an abridged version published inprint. Cite this article as: BrJGenPract 2011; DOI:10.3399/bjgp11X593811.

Acute infective conjunctivitis inprimary care: who needs antibiotics?An individual patient data meta-analysis

Joanna Jefferis, Rafael Perera, Hazel Everitt, Henk van Weert, Remco Rietveld,Paul Glasziou and Peter Rose

Research

AbstractBackgroundAcute infective conjunctivitis is a commonproblem in primary care, traditionally managedwith topical antibiotics. A number of clinicaltrials have questioned the benefit of topicalantibiotics for patients with acute infectiveconjunctivitis.

AimTo determine the benefit of antibiotics for thetreatment of acute infective conjunctivitis inprimary care and which subgroups benefitmost.

DesignAn individual patient data meta-analysis.

MethodRelevant trials were identified and individualpatient data gathered for meta-analysis andsubgroup analysis.

ResultsThree eligible trials were identified. Individualpatient data were available from all primarycare trials and data were available for analysisin 622 patients. Eighty per cent (246/308) ofpatients who received antibiotics and 74%(233/314) of controls were cured at day 7. Therewas a significant benefit of antibiotics versuscontrol for cure at seven days in all casescombined (risk difference 0.08, 95% confidenceinterval (CI) = 0.01 to 0.14). Subgroups thatshowed a significant benefit from antibioticswere patients with purulent discharge (riskdifference 0.09, 95% CI = 0.01 to 0.17) andpatients with mild severity of red eye (riskdifference 0.10, 95% CI = 0.02 to 0.18), while thetype of control used (placebo drops versusnothing) showed a statistically significantinteraction (P = 0.03).

ConclusionAcute conjunctivitis seen in primary care can bethought of as a self-limiting condition, withmost patients getting better regardless ofantibiotic therapy. Patients with purulentdischarge or a mild severity of red eye may havea small benefit from antibiotics. Prescribingpractices need to be updated, taking intoaccount these results.

Keywordsantibacterial agents; conjunctivitis; familypractice; meta-analysis.

e542 British Journal ofGeneral Practice, September 2011

on review of titles and abstracts by twoindependent assessors; seven wereretrieved for full text review, and whereclarification was needed the authors werecontacted; three of these articles met theinclusion criteria. Authors of individual trialswere contacted and asked for their rawdata. The following data were requestedfromeach trial investigator: outcomeonday7, culture results, age, symptom diaries orGP records, presence of purulent discharge,and severity of red eye.

OutcomemeasuresThe main outcome measure was cure atday 7. Bacterial culture positivity atpresentation was used as a secondaryoutcome measure to identify features thatpredicted positive bacterial growth. Thereason for usingpositive bacterial growth asa secondary outcomemeasure is that it hasbeen previously shown that there is astronger treatment effect in patients with apositive bacterial culture,4 and this is moreuseful in a clinical setting where bacterialculture is rarely undertaken. Cure at day 7was defined as no remaining symptomsrecorded in patient diaries at day 7 for trialsusing diaries, otherwise according to GPrecord on day 7 stating complete resolutionof conjunctivitis.For trials using diaries, patients with

missingdata at day 7were countedas curedat day 7 if their last diary record showedthem as cured (equivalent to last valuecarried forward). Analysis of diaries showedthat relapse rates after cure were very low(

using the command xtlogit, with trial as theindexing variable to account for differenceswithin trials. To explore the potentialpredictors of a positive culture, diagnosticsummary measures were calculated(sensitivity, specificity, positive likelihoodratio, negative likelihood ratio, and the oddsratio [OR] of the likelihood ratios) from thesimple frequency data (not accounting fortrial differences). An adjusted OR wascalculated to take account of trialdifferences, using a fixed-effect conditionallogistic regression model similar to the oneused to assess the effect interaction, but inthis case with a positive culture as thedependent variable (outcome).

RESULTSThe search yielded three RCTs conductedin the primary care setting.46 The data ofall three were available. The studycharacteristics are shown in Table 1.For the trial by Rietveld et al,4 data were

available for 163 of the 181 patients initiallyrandomised. For the trial byRoseet al,5 datawere available for 317 of the 326 patientsinitially randomised. The aim of this meta-analysis was to compare antibiotic therapyto placebo or no antibiotic therapy, andtherefore the delayed antibiotic arm of thestudy by Everitt et al (n = 109) was excludedfrom the meta-analysis.6 From theremaining 198 patients in the trial by Everittet al, data were available for 142. This givesa total number of 622 patients included inthis meta-analysis.Combining data from all three trials, 80%

(246/308) of patients who receivedantibiotics and 74% (233/314) of controlswere cured at day 7. The risk differencebetween antibiotic and control groups was0.08 (95%CI = 0.01 to 0.14), giving a numberneeded to treat of 13.Table 2 shows the effect of antibiotics on

the number of patients cured at day 7 fordifferent subgroups. The effect of using no

Table 1. Characteristics of principal trialsEveritt et al, 20066 Rietveld et al, 20054 Rose et al, 20055

Setting UK The Netherlands UKPrimary care Primary care Primary care

Participants 307 adults and children 181 adults 326 children aged 6 months to 12 yearsStudy design Open, factorial, randomised Double-blind, randomised Double-blind, randomised

control trial placebo-controlled trial placebo-controlled trialIntervention Immediate chloramphenicol eye Fusidic acid gel versus placebo Chloramphenicol 0.5% versus placebo

drops versus delayed chloramphenicoleye drops versus no eye drops

Determination of cure at day 7 Patient assessed cure as recorded in GP assessed at day 7 Parent assessed cure as recorded ina daily diary a daily diary

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Table 2. Subgroup analysis for the outcome cured at day 7Antibiotic group, Control group,a P-value for

Numbers n/N n/N RD (95% CI) NNT RR (95% CI) interactionb

All cases 622 246/308 223/314 0.08 (0.01 to 0.14) 13 1.11 (1.02 to 1.21)Type of control 622Placebo 480 185/235 181/245 0.03 (0.04 to 0.11) 34 1.05 (0.95 to 1.15)Non-placebo 142 61/73 42/69 0.23 (0.08 to 037) 5 1.40 (1.13 to 1.73) 0.03Culture result 547Negative 255 92/127 89/128 0.02 (0.09 to 0.12) 50 1.02 (0.88 to 1.19)Positive 292 119/141 113/151 0.08 (0.01 to 0.17) 13 1.11 (0.99 to 1.24) 0.33Discharge 619Non-purulent 266 94/126 93/140 0.08 (0.03 to 0.19) 13 1.12 (0.96 to 1.31)Purulent 353 151/181 127/172 0.09 (0.01 to 0.17) 12 1.12 (1.00 to 1.25) 0.72Severity 599Mild redness 365 158/186 134/179 0.10 (0.02 to 0.18) 10 1.13 (1.02 to 1.25)Moderate or severe redness 234 77/110 77/124 0.06 (0.06 to 0.18) 17 1.10 (0.91 to 1.33) 0.40Age, years 384

placebo in the control group is compared tothe placebo control. The subgroups thatsignificantly benefited from antibiotics werethose with a purulent discharge and thosewith a mild severity of red eye. The type ofcontrol used (placeboor nodrops) showedastatistically significant interaction. The trialthat used no placebo showed a significanteffect of antibiotics compared to control(risk difference [RD] = 023, 95% CI = 0.08 to0.37), while the combination of the two trialsthat used a placebo showed a non-

significant effect of antibiotics compared tocontrol (RD = 003, 95% CI = 004 to 011).Figure 1 shows the RDs between antibioticand no antibiotic group for cure at day 7 foreach subgroup. The level of heterogeneityacross the trials is indicated in Figure 1 by I2.Sensitivity analyses based on the

assumptions that all missing data were forpatients who were (a) cured or (b) not curedshowed a reduction of effect in the no-placebo group (Everitt et al trial only) whenmissing data were treated as not cured (RD

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Table 3. Predictors of a positive cultureOdds ratio

Culture Culture Sensitivity, Specificity, Unadjusted, Adjusteda

positive, n/N negative, n/N % % LR+ LR LR+/LR (95% CI)Purulent discharge 233/311 110/281 75 61 1.91 0.41 4.6 1.7

(1.08 to 2.58)Severity (moderate+) 100/295 131/277 34 53 0.72 1.25 0.6 1.4

(0.89 to 2.12)Age

= 0.14; 95% CI = 0 to 0.28). This is moreconsistent with the null hypothesis than inthe primary analysis. The rest of the resultswere robust to the choice of imputed valuesfor the missing data.Table 3 shows the predictors of a positive

culture result at presentation. Specificityand sensitivity are shown, as are the positiveandnegative likelihood ratios. Thepredictivevalues of combined factors are also shown.

DISCUSSIONSummaryThe individual patient data meta-analysis ofantibiotic use for acute conjunctivitis inprimary care shows that there is a smalloverall significant effect of antibiotics versuscontrol,with anumberneeded to treat of 13.However, most patients recovered by day 7whether they received antibiotics or not.Taking only the two trials that used aplacebo control, there was no overallsignificant effect of antibiotics versuscontrol. Patient subgroups identified asgaining a benefit from antibiotic were thosewith purulent discharge andmild severity ofred eye. Predictors of bacterial culturepositivity at presentation were purulentdischarge and age less than 5 years.It was found that patients with a mild

severity of red eye were more likely tobenefit from antibiotics compared to thosewith a moderate or severe red eye. Thiscould be because viral and allergic causesof conjunctivitis, as well as alternativediagnoses such as episcleritis, may give amore dramatically red eye.17 It may also bethat in patients with only mild red eye, thediagnosis of acute conjunctivitis hingesmoreon thepresenceofmorespecific signsand symptoms, such as purulent discharge.Previous studies have described purulent

discharge as an indicator of a bacterialcause,1518 with the presumption that thiswould help clinicians decide which patientswould benefit from antibiotics. In this study,purulent discharge did predict benefit fromantibiotics, and also predicted a positivebacterial culture. However, bacterial culturepositivity was not an indicator of benefitfrom antibiotics in this study. This mayreflect the inaccuracy of cultures,particularly in the primary care settingwhere transport times may confound theresults. It may also be due to an insufficientsample size. However, in either case, theeffect is likely to be small and the findingsdemonstrate that even when the cause ofconjunctivitis is bacterial, most patients willget better without the use of antibiotics.As well as cure rate at day 7, which was

the main outcome measure in this study, it

is also important to know whetherantibiotics may shorten the duration ofsymptoms. To address this, survivalanalyses were carried out on the twodatasets using patient diaries. Results wereconsistent with those reported in thismeta-analysis, with no difference in recovery timefor the trial by Rose et al,5 but a cleardifference in the trial by Everitt et al,6 whichused no placebo.

Strengths and limitationsA key strength of this study is that using theindividual patient data from three trialsyielded622patients, giving thestudygreaterpower thananyof the individual studies, andenabling subgroup analysis. There was alow level of heterogeneity across thestudies, allowing the data to be combined.However, there are also some limitations.The quality of the three studies includedwas variable. All three studies detailed theirrandomisation techniques. The trials byRose et al5 and Rietveld et al4 were blindedand used adequate masking. In the Rose etal trial,5 nine of the 326 patients were lostwith respect to 7-day follow-up. In theRietveld et al trial,4 18 of the 181 patientswere lost to follow-up. In the Everitt et altrial,6 therewere no data on cure at day 7 for56 of the 198 patients. It should also benoted that a large number of patients (30%)in the control arm of the Everitt et al trialwent on to receive antibiotics.Two of the studies included in this meta-

analysis used a placebo in the control arm,while one did not. Figure 1 shows asignificant effect of antibiotics versuscontrol in the trial using no placebo, but notin the two trials using a placebo. Thishighlights the need for using a placebo inrandomised controlled drug trials, but alsosuggests that there could be a hygiene orirrigation effect of putting non-antibioticdrops into the eye. This is an interestingfinding and would be an area for furtherresearch. Although a lack of evidenceprohibits clear guidelines here, cleaning theeyes is a cheap and simple procedure andcould be part of management advice givenby GPs.All the studies here were carried out in

primary care populations. This thereforelimits the implications of this study tounselected primary care populations.

Comparison with existing literatureA previous Cochrane Review of the use ofantibiotics for conjunctivitis also showed ajust significant benefit of antibioticsoverall.19 However, this review includedstudies from secondary care as well as

e546 British Journal ofGeneral Practice, September 2011

FundingNo funding was received for this work.

ProvenanceFreely submitted; externally peer reviewed.

Competing interests

All authors have completed the UnifiedCompeting Interest form atwww.icmje.org/coi_disclosure.pdf (availableon request from the corresponding author)and declare that they have no conflicts ofinterests that may be relevant to thesubmitted work.

Discuss this articleContribute and read comments aboutthis article on the Discussion Forum:http://www.rcgp.org.uk/bjgp-discuss

primary care and included some olderstudies that were not thought to be of highquality. Three more-recent studies, notcarried out in primary care, have shown asignificant effect of antibiotics forconjunctivitis.2022 It is difficult to comparethe present studies with these three recenttrials in secondary care, as their focus wasmicrobiological rather than clinical. Allthree trials confined their analyses toculture-positive patients, and henceexcluded over half the randomised patients.The spectrum of illness seen in secondarycare, and the focus onmicrobiological cure,is likely to account for these differences.The small effect of antibiotics in acute

conjunctivitis that has been shown here issimilar to that found in systematic reviewslooking at sore throat and otitis media.23,24

Recent evidence also suggests that the useof antibiotics for acute otitis media mayincrease the recurrence rate.25 TheNationalInstitute for Health and Clinical Excellencehas drawn up guidelines to limit the use ofantibiotics for self-limiting respiratory tractinfections in primary care.26,27 In light of thepresent findings, similar guidelines need to

be drawn up for the use of antibiotics inacute infective conjunctivitis. These resultssupport the recent statement that it was amistake to make chloramphenicol availableover the counter because of the low efficacyof the drug in treating conjunctivitis.28

Implications for practiceThis individual patient data meta-analysisdemonstrates that topical antibiotics are oflimitedbenefit in acute infective conjunctivitisand most patients will get better withoutthem. There is a limited set of patients whomay benefit from antibiotics, includingpatients with purulent discharge andpatients with mild severity of red eye.However, even in these groups the benefit ofantibiotics is limited. Judicious use ofantibiotics is important to reduce the risks ofantibiotic resistance in the population.Prescribing practices and over-the-counterpolicies need to be updated to reflect thesefindings. Furthermore, patient expectationsof antibiotic use need to be addressed, asthey are likely to be a strong driving forcebehind prescribing decisions.

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