Did introduction of pneumococcal vaccines in the Netherlands decrease the need for respiratory antibiotics in children? Analysis of 2002 to 2013 data

Transcription

1 Reserch rticles Did introduction of pneumococcl vccines in the Netherlnds decrese the need for respirtory ntibiotics in children? Anlysis of 2002 to 2013 dt G Gefenite (g.gefenite@lumnus.rug.nl) 1,2, M J Bijlsm 1, H J Bos 1, E Hk 1,2 1. Deprtment of Phrmcy, Unit of PhrmcoEpidemiology & PhrmcoEconomics (PE2), University of Groningen, Groningen, the Netherlnds 2. Deprtment of Epidemiology, University Medicl Centre Groningen, University of Groningen, the Netherlnds Cittion style for this rticle: Gefenite G, Bijlsm MJ, Bos HJ, Hk E. Did introduction of pneumococcl vccines in the Netherlnds decrese the need for respirtory ntibiotics in children? Anlysis of 2002 to 2013 dt. Euro Surveill. 2014;19(44):pii= Avilble online: Article submitted on 24 July 2013 / published on 06 November 2014 To estimte the effect of the introduction of the 7- nd 10-vlentpneumococcl vccines in 2006 nd 2011, respectively in the Netherlnds, we ssessed respirtory ntibiotic use in one to nine yer-old children between 2002 nd Sesonl utoregressive integrted moving-verge models were pplied to estimte the percentge reduction in respirtory ntibiotic use. When compred with the pre-vccintion period, the proportion of respirtory ntibiotic prescriptions fell by 4.94% (95% CI: 4.63 to 5.26) nd 9.02% (95% CI: 2.83 to 14.82) fter the introduction of the 7-vlent vccine in children ged three nd four yers, respectively. After the introduction of the 10-vlent vccine, we observed reduction of 13.04% (95% CI: 2.76 to 22.23), 20.31% (95% CI: to 26.58), 16.92% (95% CI: 3.07 to 28.80), 22.34% (95% CI: 3.73 to 37.35), 23.75% (95% CI: 2.37 to 40.44) in two, three, four, six nd seven yer-old children, respectively. Thus, our results indicte reduction in respirtory ntibiotic prescriptions in young children fter introduction of the pneumococcl vccines. As only children in our study popultion ged one nd two yers born fter Mrch 2011 hd received the 10-vlent vccine, the effects of the 10-vlent vccine in children ged three to nine yers likely reflect the effects of the 7-vlent vccine nd herd immunity. Introduction In 2001 in the Netherlnds, 45% nd 20% of ll ntibiotics in children were prescribed for respirtory trct nd er infections, respectively, with cute otitis medi being the leding cuse [1]. One of the common pthogens responsible for these infections, especilly in young children, is Streptococcus pneumonie. In the United Sttes (US), it hs been found in 44% of children hospitlised in 1999 to 2000 with community-cquired lower respirtory trct infections [2]. Due to substntil use of ntibiotics for infections cused by S. pneumonie [1], preventing these infections should remin n importnt public helth gol. In June 2006, 7-vlent pneumococcl vccintion ws introduced in the Netherlnds s prt of the ntionl Dutch immunistion progrmme nd ws provided to ll infnts free of chrge [3]. Prescription rtes of orl ntibiotics for children seemed to decrese fter introduction of the vccine [4], but no decline in er, nose nd throt problems hs been observed [5]. The ltter finding might be explined by replcement of pneumococcl serotypes. Despite n overll decrese in invsive pneumococcl disese (IPD) fter the implementtion of the 7-vlent vccintion cmpign in the Netherlnds, decrese of vccine-serotype IPD ws followed by n increse in IPD cused by non-vccine serotypes [6,7]. There hs been no informtion, however, on ny chnges in use of ntibiotics tht re usully used for cute otitis medi nd pneumoni in young children (one to nine yer-olds) in the Netherlnds fter the 7-vlent pneumococcl vccine ws introduced. Moreover, in 2011, the 7-vlent pneumococcl vccine ws replced by 10-vlent vccine [8], whose effects hve not yet been ssessed in observtionl studies. Vccintions were provided t two, three, four months nd booster dose t 11 months of ge, with vccintion uptke rtes of 94 95% [3]. To ssess the ptterns of respirtory ntibiotic prescriptions in young children before nd fter the introduction of the pneumococcl vccines in the Netherlnds, we nlysed the use of moxicillin, zithromycin nd sulfmethoxzole nd trimethoprim from 2002 to In the Netherlnds, ntibiotics re vilble by prescription only. On the bsis of Dutch generl prctitioner guidelines, these ntibiotics re commonly prescribed for cute otitis medi nd pneumoni in children up to nine yers of ge in generl prctice [9,10]. We performed descriptive nd time-series nlyses to ssess whether the introduction of the pneumococcl vccines ntionlly reduced the proportion of respirtory ntibiotic prescriptions in children one to nine yers of ge. 1

2 Methods The study popultion consisted of one to nine yer-old children identified from the IADB.nl dtbse, which contins phrmcy-dispensing dt from community phrmcies in the Netherlnds. A detiled description of this dtbse is vilble elsewhere [11]). The min outcome of our study ws the proportion of monthly respirtory ntibiotic prescriptions in prticulr ge group (the number of monthly prescriptions in the ge group per month divided by the number of children in tht ge group in tht month). The ggregted mesure of respirtory ntibiotic prescriptions per yer (the number of monthly prescriptions in the ge group per yer divided by the number of children in tht ge group in tht yer) ws clculted s well. The outcome mesure ws bsed on prescriptions for moxicillin (Antomicl Therpeuticl Chemicl (ATC) code J01CA04), zithromycin (J01FA10) nd/or sulfmethoxzole nd trimethoprim (ATC code J01EE01), s described bove. The nme of the ntibiotic dispensed, ATC code [12], dte of prescription nd birthdte of the children included in the study were extrcted from the IADB.nl dtbse. The first intervention studied ws the introduction of the 7-vlent pneumococcl vccine in the Netherlnds in June 2006 for ll infnts born fter 1 April 2006 [3]. We lso ssessed the effects of the introduction of 10-vlent pneumococcl vccine for infnts born fter 1 Mrch 2011 [8]. The study period ws chosen bsed on some preliminry nlyses: we excluded dt before 2002 s we observed decrese in respirtory ntibiotic use between 1995 nd 2002, which might hve been due to policies nd interventions trgeted t decresing ntibiotic use, nd it ws not our im to ssess these interventions in this study. Given tht, the pre-vccintion period ws defined s 1 Jnury 2002 to 31 Mrch 2007, i.e. the time before the 7-vlent introduction of the pneumococcl vccine ws ssumed to strt hving n effect. We considered tht n effect of the introduction of the 7-vlent pneumococcl vccine could first be seen from 1 April 2007, s we nticipted tht ll four doses of the vccine, including the booster dose, would hve been dministered nd hd n effect within yer fter birth. The end of the period to ssess the effect of the 7-vlent vccine ws 30 April 2011, i.e. before the 10-vlent vccine replced the 7-vlent vccine. To study ny dditionl effect of the introduction of the 10-vlent pneumococcl vccine, the end of the study period ws set to 31 December We considered tht n effect of the introduction of the 10-vlent vccine could first be seen from 1 Mrch 2012, ssuming tht the full vccintion schedule would hve been dministered within yer fter birth. The end of the study ws 31 December We ssessed the effect of the 10-vlent vccine in two wys. We first rn the model including the introduction of both vccines. Secondly, we ssessed the effectiveness of the introduction of the 10-vlent vccintion cmpign s compred to pre-vccintion period, when dt points following introduction of the 7-vlent vccine (1 June 2006 to 29 Februry 2012) were excluded. Children born between 1 April 2006 nd 28 Februry 2011 were ssumed to hve received the 7-vlent vccine; children born before 1 April 2006 were ssumed to hve not been vccinted, but potentilly indirectly protected by vccintion of younger ge groups. Children born fter 1 Mrch 2011 were ssumed to hve received the 10-vlent pneumococcl vccine. Sttisticl nlysis We first ssessed the ggregted yerly respirtory ntibiotic prescription proportions from 2002 to 2013 for ech ge group seprtely by plotting the dt. We then ssessed monthly ntibiotic prescription proportions dt using multiplictive decomposition [13] tht shows the observed trend of the outcome s well s sesonl nd rndom ptterns, nd the trend fter removing the sesonl nd rndom components. To ssess the effectiveness of the introduction of the pneumococcl vccines, we used sesonl utoregressive integrted moving verge (SARIMA(p,d,q)(P,D,Q) s ) time series models [14] with intervention nlysis [15], where p nd P is the number of uto-regressive components, d nd D stnds for differencing pplied in the series, q nd Q indictes the number of moving verge components, nd s is equl to the number of units of sesonl periods tht re used in the model to remove dditive sesonl effects. SARIMA llows us to estimte the effect of n intervention of interest by tking into ccount sesonl ptterns. As pneumococcl illness tends to occur during the winter months, we ssumed sesonl ptterns occurring every 12 months, nd therefore s ws set to 12. We estimted the level (the brupt chnge) of respirtory ntibiotic prescription proportions nd the chnge in trend (the slope) fter, s compred with before, the introduction of the pneumococcl vccines. The intervention vribles were coded s 0 before the intervention nd1 fter the intervention. To ssess the chnge in trends fter the interventions were introduced, slope chnge vribles denoting time were introduced. It ws coded s 0 before the interventions, nd fterwrds counted the number of months fter the introduction of the intervention of interest [16,17]. The best SARIMA models were identified bsed on the Akike Informtion Criterion (AIC) during the pre-vccintion period for ech ge group seprtely [18]. They were then pplied to estimte the effects of the introduction of the7- nd 10-vlent vccines throughout ech prt of the study period, s described bove. When both interventions were included in the sme model, the best model (the model with only the first intervention 2

3 Figure Proportion of yerly respirtory ntibiotic prescriptions in children ged one to nine yers, the Netherlnds, Proportion of respirtry ntibiotic use PCV PCV10 Age in yers Number of users per yer/number of children in the prticulr ge group in tht yer. The children s ges shown re the ge t which the ntibiotic ws prescribed. (introduction of the 7-vlent vccine) versus the model with both interventions) were selected bsed on likelihood rtio test. The coefficients nd their stndrd errors were estimted using mximum likelihood estimtion. The percentge of chnge nd its confidence intervls were clculted s (exp(coefficient) 1) 100% nd (exp(coefficient+/ 1.96 stndrd error) 1) 100%. The dequcy of ech model ws verified by visully ssessing the correlogrms (there should be negligible residul utocorreltion) nd the plots of the residuls (the residuls of the model should be rndomly scttered). The nlysis ws performed with RStudio sttisticl softwre [19]. Results Aggregted yerly estimtes reveled tht very young children hd the most prescriptions of respirtory ntibiotics: this decresed with ge (Figure). We observed slight decrese in respirtory ntibiotic prescriptions fter the introduction of the pneumococcl vccines in 2006 nd 2011 (Figure).We observed similr ptterns when we inspected decomposed monthly trends of ntibiotic prescriptions (dt not shown). To revel the effects of the introduction of the pneumococcl vccines on respirtory ntibiotic prescriptions, we performed time series nlysis from 2002 to The best time series SARIMA models were identified bsed on AIC during the pre-vccintion period (see Tble 1for the best model for ech ge group) nd the likelihood rtio test when the dditionl effect of the introduction of the 10-vlent vccine ws ssessed in the model, including both interventions t the sme time. The finl models did not show evidence of utocorreltion nd we could not detect cler ptterns in the residul utocorreltion for most of the ge groups. Only the models for the eight nd nine yer-old children showed significnt utocorreltion t lg 12, indicting remining sesonl effect. However, due to low levels of utocorreltion, it is unlikely tht this would hve hd strong effect on the overll results. The level of respirtory ntibiotic prescription proportions decresed fter the introduction of the 7-vlent vccine in most of the ge groups (Tble 1). The reduction ws, however, only sttisticlly significnt in three nd four yer-old children, 4.94% (95% CI: 5.26 to 4.63) nd 9.02% (95% CI: to 2.83), respectively. When we performed likelihood rtio test, the model including both interventions ws better thn the model including the 7-vlent vccine intervention lone for few ge groups, nmely in one, five nd six yer-olds. 3

4 Tble 1 Effectiveness of introduction of 7-vlent pneumococcl vccine by ge: chnge in level of respirtory ntibiotic prescriptions nd in trend of respirtory ntibiotic prescription proportions, the Netherlnds, Children s ge in yers Chnge in level Best SARIMA (p,d,q)(p,d,q)12 model ( 3.51 to 6.13) 0.01 ( 0.13 to 0.15) (6,0,5)(8,1,9) ( 1.85 to 7.15) 0.26 ( 0.42 to 0.10) (8,0,8)(5,0,5) ( 5.26 to 4.63) 0.16 (NA) (8,0,3)(7,0,7) ( to 2.83) 0.11 ( 0.33 to 0.11) (8,0,4)(4,1,3) ( 7.39 to 1.07) 0.28 ( 0.47 to 0.08) (5,0,0)(9,0,9) ( to 3.14) 0.11 ( 0.56 to 0.34) (2,0,3)(6,1,8) ( to 13.91) 0.15 ( 0.75 to 1.06) (0,0,1)(8,1,8) ( to 11.79) 0.23 ( 0.85 to 0.40) (2,0,5)(3,1,0) ( to 11.17) 0.20 ( 1.11 to 0.72) (0,0,0)(8,1,9)12 CI: confidence intervl; NA: not pplicble; SARIMA(p,d,q)(P,D,Q)s: sesonl utoregressive integrted moving verge model with intervention nlysis, where p nd P is the number of uto-regressive components, d nd D stnds for differencing pplied in the series, q nd Q indictes the number of moving verge components nd s is equl to the number of units of sesonl period tht re used in the model. The stndrd error could not be pproximted using the mximum likelihood lgorithm. However, estimtes of the effect of the introduction of the 10-vlent vccine were inconsistent: the proportions of ntibiotic prescriptions decresed nd/or incresed fter the introduction of 7- nd/or 10-vlent vccintion nd the results were not sttisticlly significnt (Tble 2). When we ssessed the effectiveness of the introduction of the 10-vlent vccine s compred with the pre-vccintion period, we observed reduction in respirtory ntibiotic prescriptions of 13.04% (95% CI: to 2.76), 20.31% (95% CI: to 13.50), 16.92% (95% CI: to 3.07), 22.34% (95% CI: to 3.73), 23.75% (95% CI: to 2.37) in two, three, four, six nd seven yer-olds, respectively (Tble 3). The trends of ntibiotic prescription proportions were similr before nd fter the interventions in most ge groups (Tbles 1 3). Discussion We found decrese in ntibiotic prescriptions for respirtory infections in three nd four yer-old children fter the introduction of the 7-vlent pneumococcl vccine. Furthermore, we demonstrted tht the introduction of the 10-vlent pneumococcl vccine continued to dd benefit in terms of fewer respirtory ntibiotic prescriptions. It is importnt to note, however, tht the effect estimtes of the ltter intervention most likely include the effects of the 7-vlent vccintions s well s herd immunity, s in our study, only children ged one nd two yers born fter 1 Mrch 2011 received the 10-vlent vccine. Our results re in line with the results from recently conducted study on the effect of 13-vlent pneumococcl conjugte vccine on dmissions to hospitl in the US: in children up to five yers-old, introduction of the vccine led to the reduction of ll-cuse, invsive pneumococcl nd non-invsive pneumococcl or lobr pneumoni hospitlistion [20]. Such decrese in outcomes, mesured only couple of yers fter Tble 2 Added effectiveness of introduction of 10-vlent pneumococcl vccine for different ges : chnge in level nd trend of ntibiotic prescription proportions, the Netherlnds, Children s ge in yers Chnge in level 7-vlent vccine Chnge in level 10-vlent vccine (2.74 to 8.41) 0.13 ( 0.21 to 0.05) 6.27 ( to 6.56) 0.63 ( 1.52 to 0.27) ( 3.92 to 9.82) 0.29 ( 0.50 to 0.07) 1.35 ( to 22.33) 0.32 ( 0.87 to 1.53) ( to 1.85) 0.08 ( 0.41 to 0.25) 0.08 ( 0.41 to 0.25) 9.72 ( to 13.44) CI: confidence intervl. Included re only the ges for which n dded effect of the introduction of the 10-vlent vccine ws demonstrted, bsed on likelihood rtio test. 4

5 Tble 3 Effectiveness of introduction of 10-vlent pneumococcl vccine for children ged one to nine yers: chnge in level nd trend of ntibiotic prescription proportions s compred with the pre-vccintion period, the Netherlnds Children s ge in yers Chnge in level ( 8.92 to 10.28) 1.43 ( 2.16 to 0.69) ( to 2.76) 0.80 ( 1.69 to 0.10) ( to 13.50) 0.04 ( 0.94 to 0.87) ( to 3.07) 0.66 ( 1.70 to 0.40) ( to 2.38) 0.47 ( 1.73 to 0.81) ( to 3.73) 0.56 ( 2.14 to 1.05) ( to 2.37) 0.51 ( 2.29 to 1.30) ( to 22.57) 1.75 ( 3.81 to 0.35) ( to 3.14) 0.63 ( 2.94 to 1.74) CI: confidence intervl. Pre-vccintion period: 1 Jnury 2002 to 31 My introduction of the new vccine covering more serotypes nd with vccintion coverge in children up to five yers-old of 54%in the US study indictes not only direct, but lso indirect protection. We lso found tht, lthough it ws not sttisticlly significnt, there ws n indiction of decrese in prescriptions of respirtory ntibiotics in unvccinted children ged eight nd nine yers born before the introduction of pneumococcl vccintion. Our point estimtes of the effect of the introduction of the pneumococcl vccines showed decrese, but it ws not lwys sttisticlly significnt. Even though overll ntibiotic prescription trends hd decresing pttern, fter the introduction of the vccines, there were some fluctutions. The effects of the pneumococcl vccines might therefore hve been not significnt due to quite low overll use of ntibiotics in the Netherlnds [1,21], thus mking the dt more sensitive to fluctutions. Moreover, it hs been documented tht fter the introduction of the 7-vlent pneumococcl vccine in the Netherlnds, invsive pneumococcl disese rtes cused by non-vccine serotypes incresed [6,7]. This might lso prtly explin the observed fluctutions, even fter the introduction of the vccines. However, in our study, we were unble to explore the effect of serotype replcement, since serotype-specific clinicl outcome dt were not prt of the dtset. We my not hve been ble to show the benefits of the 10-vlent pneumococcl vccintion in ddition to the 7-vlent cmpign due to severl resons. First, the 10-vlent vccine covers dditionl three serotypes, mening tht the reltive benefit of this cmpign might be too smll to detect when compred with the 7-vlent vccine. Additionlly, s mentioned bove, we observed some fluctution (smll increses nd decreses) in the dt following the introduction of the vccines. These fctors might explin why there ws no sttisticlly significnt dded benefit of the 10-vlent vccine nd tht for severl ges, the model including the 7-vlent vccine lone ppered to be better thn the model including both cmpigns. These explntions seem plusible becuse when we ssessed the effect of the 10-vlent vccine s compred with the pre-vccintion period, the observed reduction in respirtory ntibiotic prescription proportions ws lrge, reching for some ges bove 20%. Becuse the pneumococcl vccines trgeted welldefined popultion groups t the ntionl level t well-defined time points nd vccintion uptke rtes were high (94 95%) [3,8], we were ble to study the effects of the interventions t the popultion rther thn individul level. This is dvntgeous s lrge popultion-bsed dtbses, such s IADB.nl, which do not include individul vccintion informtion, cn still be used to ssess the impct of popultion-bsed interventions. By using SARIMA time-series models, we were ble to estimte direct (mong children ge done to seven yers) nd indirect (mong eight to nine yer-olds) effects of the introduction of the pneumococcl vccines. We were ble to tke sesonl effects into ccount s well s ssess the introduction of both the 7-vlent nd 10-vlent pneumococcl vccintions by using different pproches. Although we did not hve informtion bout the reson for the ntibiotic prescriptions, the ntibiotics tht we looked t re specificlly recommended to tret cute otitis medi nd pneumoni in young children in the Netherlnds [9,10]. As S. pneumonie is one of the leding cuses of mucosl infections [22], our results re likely to indicte n effect of the introduction of the pneumococcl vccines on helth problems cused by S. pneumonie. 5

6 In conclusion, our study provides evidence tht introduction of the 7- nd 10-vlent pneumococcl vccines were effective in reducing respirtory ntibiotic prescriptions in young children, with reduction of bout 5 24% in ntibiotic prescriptions for mucosl infections likely due to the introduction of the pneumococcl vccines. Nevertheless, it is importnt to keep in mind tht due to its recent introduction, the effect of the introduction of the 10-vlent vccine is likely in prt due to the continuing effects of the 7-vlent vccine nd herd immunity. Future studies re needed to further ssess the effects of the pneumococcl vccines on different helth outcomes s well on popultions other thn children. Conflict of interest None declred. Authors contributions Designed the study: GG. Prepred nd nlysed dt: GG, MJB, JB. Interpreted the results: GG, MJB. Wrote the first drft: GG. Revised the rticle: GG, MJB, JB, EH. All uthors red nd pproved the finl mnuscript. References 1. Otters HB, vn der Wouden JC, Schellevis FG, vn Suijlekom- Smit LW, Koes BW. Trends in prescribing ntibiotics for children in Dutch generl prctice. J Antimicrob Chemother. 2004;53(2): Michelow IC, Olsen K, Lozno J, Rollins NK, Duffy LB, Ziegler T, et l. Epidemiology nd clinicl chrcteristics of communitycquired pneumoni in hospitlized children. Peditrics. 2004;113(4): vn Lier EA, Oomen PJ, Giesbers H, Drijfhout IH, de Hoogh PA, de Melker HE. Vccintiegrd Rijksvccintieprogrmm Nederlnd.Verslgjr [Immuniztion coverge Ntionl Immuniztion Progrmme in the Netherlnds: Yer of report 2011]. Bilthoven: Ntionl Institute for Public Helth nd the Environment (RIVM); Report /2011. Dutch. Avilble from: rpporten/ pdf 4. de Bont EG, vn Loo IH, Dukers-Muijrers NH, Hoebe CJ, Bruggemn CA, Dinnt GJ, et l. Orl nd topicl ntibiotic prescriptions for children in generl prctice. Arch Dis Child. 2013;98(3): rchdischild Uijen JH, Bindels PJ, Schellevis FG, vn der Wouden JC. ENT problems in Dutch children: trends in incidence rtes, ntibiotic prescribing nd referrls Scnd J Prim Helth Cre. 2011; 29(2): Rodenburg GD, de Greeff SC, Jnsen AG, de Melker HE, Schouls LM, Hk E, et l. Effects of pneumococcl conjugte vccine 2 yers fter its introduction, the Netherlnds. Emerg Infect Dis. 2010;16(5): Elberse KE, vn der Heide HG, Witteveen S, vn de Pol I, Schot CS, vn der Ende A, et l. Chnges in the composition of the pneumococcl popultion nd in IPD incidence in The Netherlnds fter the implementtion of the 7-vlent pneumococcl conjugte vccine.vccine. 2012;30(52): vn t Klooster T, de Melker H. The Ntionl Immunistion Progrmme in the Netherlnds: Developments in Bilthoven: Ntionl Institute for Public Helth nd the Environment (RIVM); Report /2011 Avilble from: ype=org&disposition=inline&ns_nc=1 9. Dutch College of Generl Prctitioners (NHG). NHG-Stndrd, Otitis medi cut bij kinderenm09 (Actulisering 2013: herzient.o.v. de versie vn 2006). [The Dutch College of Generl Prctitioners Guidelines, Otitis medi cut in children M09 (Updted in 2013: bsed on the version of 2006)]. Utrecht: NHG; 2006 (in revision). [Accessed 19 Mr 2013]. Dutch. Avilble from: richtlijnen/k_nhgstndrden/smenvttingskrtje- NHGStndrd/M09_svk.htm 10. Dutch College of Generl Prctitioners (NHG).NHG- Stndrden, Acuut hoesten M78 (Actulisering 2013: herzien t.o.v. de versie vn 2011). [The Dutch College of Generl Prctitioners Guidelines, Acute cough M78 (Updted in 2013: bsed on the version of 2011)]. Utrecht: NHG; [Accessed 19 Mr 2013]. Dutch. Avilble from: rtsennet.nl/kenniscentrum/k_richtlijnen/k_nhgstndrden/ Smenvttingskrtje-NHGStndrd/M78_svk.htm 11. Visser ST, Schuiling-Vening CC, Bos JH, de Jong-vn den Berg LT, Postm MJ. The popultion-bsed prescription dtbse IADB. nl: its development, usefulness in outcomes reserch nd chllenges. Expert Rev Phrmcoecon Outcomes Res. 2013;13(3): World Helth Orgniztion (WHO) Collborting Centre for Drug Sttistics Methodology. ATC/DDD Index Oslo: WHO Collborting Centre for Drug Sttistics Methodology. [Accessed 19 Mr 2013]. 13. Cowpertwit PS, Metclfe AV. Introductory time series with R. Berlin: Springer; Box GE, Jenkins GM, Reinsel GC. Time series nlysis, forecsting nd control. 3rd ed. Englewood Cliff, NJ: Prentice Hll; Box GE, Tio GC. Intervention nlysis with pplictions to economic nd environmentl problems. J Am SttAssoc. 1975;70(349): HuitemBE, Mcken JW. Design specifiction issues in time-series intervention models. Educ Psychol Mes. 2000; 60(1): Wgner AK, Soumeri SB, Zhng F, Ross-Degnn D. Segmented regression nlysis of interrupted time series studies in mediction use reserch. J Clin Phrm Ther. 2002;27(4): Time-series nlysis. In: Tbchnick B, Fidell L. Using multivrite sttistics. 5th ed. Chpter 18. Needhm Heights, MA: Allyn & Bcon; Ihk R, Gentlemn R. R: lnguge for dt nlysis nd grphics. J Comput Grph Stt. 1996;5(3): Simonsen L, Tylor RJ, Schuck-Pim C, Lustig R, Hber M, Klugmn KP. Effect of 13-vlent pneumococcl conjugte vccine on dmissions to hospitl 2 yers fter its introduction in the USA: time series nlysis. Lncet Respir Med. 2014;2(5): S (14) Goossens H, Ferech M, Vnder Stichele R, Elseviers M; ESAC Project Group. Outptient ntibiotic use in Europe nd ssocition with resistnce: cross-ntionl dtbse study. Lncet. 2005;365(9459): S (05) Weil Olivier C. Ten yers of experience with the pneumococcl conjugte 7-vlent vccine in children. Med Ml Infect. 2013;43(8): medml