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Trends in antibiotic resistance of streptococcus pneumoniae and haemophilus influenzae isolated from nasopharyngeal flora in children with acute otitis media in france before and after 13 valent pneumococcal conjugate vaccine introduction

Angoulvant et al. BMC Infectious Diseases (2015) 15:236 DOI 10.1186/s12879-015-0978-9 Trends in antibiotic resistance of Streptococcuspneumoniae and Haemophilus influenzae isolatedfrom nasopharyngeal flora in children with acuteotitis media in France before and after 13 valentpneumococcal conjugate vaccine introduction François Angoulvant1*, Robert Cohen2,3,4,5, Catherine Doit6,7, Annie Elbez2, Andreas Werner5, Stéphane Béchet2,Stéphane Bonacorsi6,7, Emmanuelle Varon8 and Corinne Levy2,3,5 Background: After the implementation of pneumococcal conjugate vaccines (PCVs), the marked shift in Streptococcus pneumoniae (Pnc) serotype distribution led to a modification in pneumococcal antibiotic susceptibility. In 2011, thepattern of antibiotic prescription in France for acute otitis media in infants was greatly modified, with decreased use ofthird-generation cephalosporins and amoxicillin–clavulanate replaced by amoxicillin alone. To assess antibioticstrategies, here we measured the antibiotic susceptibility of Pnc and Haemophilus influenzae (Hi) isolated fromnasopharyngeal flora in infants with acute otitis media in the 13-valent PCV (PCV13) era in France.
Methods: From November 2006 to June 2013, 77 pediatricians obtained nasopharyngeal swabs from infants(6 to 24 months old) with acute otitis media. The swabs were sent for analysis to the national reference centre forpneumococci in France. Demographics, medical history, and physical examination findings were recorded.
Results: We examined data for 7200 children, 3498 in the pre-PCV13 period (2006–2009) and 3702 in the post-PCV13period (2010–2013). The Pnc carriage rate decreased from 57.9 % to 54.2 % between the 2 periods, and the proportionof pneumococcal strains with reduced susceptibility to penicillin or resistant to penicillin decreased from 47.1 % to39 % (P < 0.0001). The Hi carriage rate increased from 48.2 % to 52.4 %, with the proportion of ß-lactamase–producingstrains decreasing from 17.1 % to 11.9 % and the proportion of ß-lactamase–nonproducing, ampicillin-resistantstrains remaining stable, from 7.7 % to 8.2 %. We did not identify any risk factor associated withcarriage of ß-lactamase–producing Hi strains (such as daycare center attendance, otitis-prone condition orrecent antibiotic use).
Conclusion: In France, the nasopharyngeal carriage rate of reduced-susceptibility pneumococcal strains and ß-lactamase–producing Hi strains decreased in children with acute otitis media after 2010, the year the PCV13was introduced. Accordingly, amoxicillin as the first-line drug for acute otitis media requiring antibioticsremains a valid choice.
Keywords: Streptococcus pneumoniae, Conjugate vaccine, PCV, Otitis media, Antibiotic, Guideline, Blnar,Betalactamase, Haemophilus influenzae * Correspondence: 1Service d'Accueil des Urgences Pédiatriques, AP-HP, HôpitalNecker-Enfants-Malades, Université Paris Descartes Sorbonne Paris Cité, ECEVE- INSERM UMR1123, Paris, FranceFull list of author information is available at the end of the article 2015 Angoulvant et al. This is an Open Access article distributed under the terms of the Creative Commons AttributionLicense which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated.
Angoulvant et al. BMC Infectious Diseases (2015) 15:236 distribution has shifted, which has led to a modification in Acute otitis media (AOM) is the most frequent bacterial pneumococcal antibiotic susceptibility. The changes in anti- infection in childhood and one of the major indications biotic susceptibility could also result from other factors for antibiotics in many countries . Streptococcus pneu- such as variations in antibiotic consumption (volume and moniae (Pnc) and Haemophilus influenzae (Hi) are the type of compound used) or rate of children cared for out- leading bacterial species implicated in AOM, followed by Moraxella catarrhalis (Mc) and, to a lesser extent, group Since 2000, to follow the changes induced by PCV im- A β-hemolytic streptococci . For AOM, Pnc and Hi are plementation, our research group has analyzed several the main targets of antibiotics prescription . Detec- hundred NP samples from children with AOM all over tion of bacterial species in the middle ear fluid (MEF) by France each year The data obtained during the first culture is the "gold standard" for etiologic diagnosis of years of the study have served as the basis for the guide- lines published in 2011 for France which recom- Few medical centers in Europe or the United States con- mended amoxicillin, 80–90 mg/kg/d in 2 or 3 daily tinue to routinely perform tympanocentesis . The de- intakes, as first-line therapy for AOM in young children.
crease in centers performing tympanocentesis probably Indeed, the guidelines stated that amoxicillin was the reflects no new antibiotics introduced for AOM [. Tym- most active agent for pneumococci with decreased sus- panocentesis or myringotomy (both considered painful) ceptibility to penicillin and was active for more than are performed mainly for special circumstances: antibi- 85 % of nontypable Hi according to microbiologic data otics non-response, recurrent cases and chronic OM.
at the time Since 2011, 2 major changes have oc- Therefore, the profile of antibiotics resistance among oto- curred: the implementation of 13-valent PCV (PCV13) pathogens isolated from MEF could be biased and we have and the shift in antibiotic prescription for AOM, with no current MEF microbiology data on which to base treat- decreased use of third-generation cephalosporins and ment decisions for the most frequent situations: first-line amoxicillin–clavulanate replaced by amoxicillin AOM seen by pediatricians or general practitioners. Be- A rapid change in resistance of Pnc and Hi to the cause the microbiology of AOM is linked to nasopharyn- commonly used antimicrobials prompts a reevaluation geal (NP) flora, many studies have assessed the possibility of the treatment strategies To assess this question, of using NP culture, a painless procedure, to predict the we measured NP carriage and antibiotic susceptibility of bacterial etiology of AOM . These studies have these 2 otopathogens in young children with AOM in shown that if Pnc or Hi is not found in the nasopharynx, the PCV13 era in France.
the isolates will not likely be found in the MEF in case ofAOM. However, because the causative bacteria of AOM are often isolated from NP cultures in addition to other From November 2006 to June 2013, 77 French pediatri- organisms, the positive predictive value of this type of cians throughout France took part in a cross-sectional sample for the causative agent is poor [.
study. An NP swab was obtained from children aged 6 For these reasons, NP culture has not been considered to 24 months with a diagnosis of purulent AOM a useful predictor of AOM etiology in clinical practice.
We excluded children who had received antibiotics However, if NP cultures are not useful for treatment for within 7 days before enrolment, had a severe underlying specific patients with AOM, they may be useful on a health disorder, or had been included in the study during population basis for formulating recommendations in the previous 12 months. Demographic data, medical his- one country or in different regions [ tory and physical findings were recorded. To monitor In France, 7 valent pneumococcal conjugate vaccine the impact of the introduction of PCV13 on this eco- (PCV7) was introduced for high risk children < 2 years logical niche, 2 periods were defined: pre-PCV13 (2006– old in 2002, then for all children < 2 years old in 2006.
2009) and post-PCV13 (2010–2013).
PCV7 coverage reached 86 % in 2008. In June 2010, the The study was approved by the Saint Germain en Laye French authorities recommended routine vaccination Ethics Committee (CPP île de France XI, 20 rue Arma- with PCV13 of infants at 2, 4 and 12 months old to re- gis, 78105 Saint Germain en Laye Cedex, France), and place PCV7. During a one-year transition period, switch- written informed consent was obtained from parents or ing from PCV7 to PCV13 was recommended at any point in the schedule to complete the immunizationseries. The PCV vaccination coverage for children youn- ger than 2 years after changing from PCV7 to PCV13 is NP specimens were obtained with use of cotton-tipped greater than 92 % wire swabs. The swabs were inserted into the anterior Since the implementation of PCV7 and PCV13, two nares, gently rubbed on the NP wall and immediately major and related changes have occurred: the Pnc serotype placed in transport medium (Copan Venturi Transystem, Angoulvant et al. BMC Infectious Diseases (2015) 15:236 Brescia, Italy). The samples were transferred within 48 h dichotomized as <1 and ≥ 1 year. The cut-off of 1 year to Robert Debré Hospital and to the national reference was chosen because the vaccination schedules differ center for pneumococci in France.
before and after this age (reflecting the immunity Pnc culture, identification, serotyping and antibiotic maturation); in many studies, the NP carriage is susceptibility testing were performed as previously de- higher after 1 year; and in one of our studies, young scribed [Susceptibility of Pnc isolates to penicillin age (<1 year) predicted penicillin non-susceptible G and erythromycin was determined from minimal in- pneumococci carriage hibitory concentrations (MICs) by the agar-dilutionmethod. Isolates were classified as penicillin-susceptible (MIC ≤ 0.06 μg/ml), penicillin–non-susceptible (MIC ≥ During the 7 years, we assessed samples for 7200 pa- μg/ml), penicillin–intermediate-resistant (MIC tients (3498 in the pre-PCV13 period and 3702 in the 0.12–2.0 μg/ml), or penicillin-resistant (MIC > 2 μg/ml) post-PCV13 period). Table shows demographic charac- according to the European Committee on Antimicro- teristics and NP carriage of the children enrolled. Me- bial Susceptibility Testing ( dian age was 13 months (Q1–Q3 9–17 months) and more than 99 % were PCV-vaccinated, including 3399 Isolates of Hi were identified by colony morphology (47.2 %) with PCV13. Among the children, 44.8 % assay and conventional methods of determination. Hi attended a daycare center and 45.1 % had received anti- isolates underwent capsular serotyping by the slide ag- biotics within 3 months before inclusion.
glutination method with specific antisera (Phadebact; The Pnc carriage rate decreased from 57.9 % to 54.2 % Boule Diagnostics, Huddinge, Sweden). The production between the pre- and post-PCV13 period, and the pro- of ß-lactamase was assessed by a chromogenic cephalo- portion of Pnc strains with reduced susceptibility to sporin test (Nitrocefin; Cefinase; Biomerieux, Marcy penicillin or resistant to penicillin decreased from l'Etoile, France). H. influenzae strains were further classi- 47.1 % to 39 % (P < 0.0001) (Table and Fig. In the fied as ampicillin susceptible (MIC ≤ 1 mg/L), or resist- pre-PCV13 period, pneumococcal penicillin–non-sus- ant (MIC > 1 mg/L). ß-lactamase negative ampicillin ceptible strains were represented by serotypes 19A, 15A, resistance (BLNAR) was determined according to the 35B and 19 F. Among the Pnc carriers, between the two CLSI break points ]. If the 2 μg ampicillin diffusion periods, the proportion of PCV7 serotype and 6 add- test (Becton Dickinson) gave a zone of inhibition <20 mm itional PCV13 serotypes decreased from 9.5 % to 3.2 % and if the cefalotin disk diffusion test gave a zone of in- (P < 0.001) and from 32.0 % to 11.1 % (P < 0.001), re- hibition <17 mm, strains were considered BLNAR ].
spectively. Serotype 19A, the most frequently serotypeidentified during the whole study, decreased from 22.6 % Statistical analysis to 8.4 % between the 2 periods. By contrast, non-PCV13 Data were double-entered by using 4D software 6.4 and serotypes increased from 58.5 % to 85.7 % (P < 0.001).
analyzed by using Stata SE 13.1 (Stata Corp., College The most frequently carried non-PCV13 serotypes in Station, TX, USA) for univariate analysis and multivari- post PCV13 period were serotype 15B/C (12.2 %), 15A ate logistic regression (odds ratios [ORs] and 95 % confi- (9.3 %), 11A (9.1 %), 35B (7.5 %), 23A (5.9 %), and 6C dence intervals [95 % CI]). Chi-square test was used to (5.0 %), 33 other serotypes accounted for 34.9 %. In this compare NP carriage of pneumococci and Hi before and period, pneumococcal penicillin–non-susceptible strains after PCV13 implementation. Factors related to NP car- were predominantly represented by serotypes 11A, 15A, riage were identified on univariate analysis (p < 0.20, chi- 15B/C, 19A and 35B. Non-typeable Pnc remained stable square test). Multivariate logistic regression analysis was (2.1 % to 1.8 %) between the 2 periods.
performed to identify the main factors associated with The Hi carriage rate increased from 48.2 % to 52.4 % carriage of Pnc, Pnc strains with reduced susceptibility between the pre- and post-PCV13 period. During the to penicillin (RSP), Hi carriage, and ß-lactamase–produ- whole study, 18/3624 (0.5 %) Hi isolates were serotype b.
cing Hi strains. For these models, factors had to be de- The proportion of ß-lactamase–producing Hi strains de- termined by the physician during the visits. When creased from 17.1 % (n = 289) to 11.9 % (n = 230) and different factors were highly correlated, such as recent that of ß-lactamase–nonproducing, ampicillin-resistant antibiotic use, history of AOM and otitis-prone children, (BLNAR) strains remained stable, < 10 %, with 7.7 % we retained the most relevant factor. The following and 8.2 % in the pre- and post-PCV13 periods (Table variables were included in multivariate logistic regres- On multivariate logistic regression analysis (Table sion models: daycare attendance, siblings, recent anti- the main factors associated with RSP-Pnc carriage were biotic treatment (within 3 months before enrolment), daycare center attendance (adjusted OR [aOR] = 1.55, otalgia + fever ≥38.5 °C, conjunctivitis, and bilateral 95 % CI [1.36;1.77]), age < 1 year old (aOR = 1.19, 95 % AOM. All models were adjusted for age. Age was CI [1.04;1.35]), and antibiotic use within 3 months Angoulvant et al. BMC Infectious Diseases (2015) 15:236 Table 1 Characteristics of children with acute otitis media before/after 13-valent pneumococcal conjugate vaccine implementationin France Child characteristics Age (months), mean ± SD Antibiotics 3 months before enrolment Only 1 antibiotic At least 2 antibiotics Others antibiotic Last antibiotic in the previous month Fever (≥38.5 °C) Otalgia + fever ≥38.5 °C Otitis-prone childrenb adata not available in 2006/2008, bdata not available in 2006/2007AOM: Acute Otitis Media; PCV13: 13-valent pneumococcal conjugate vaccine; Q1-Q3, quartiles 1 to 3; Pnc: pneumococcus; Hi: H. influenzae (aOR = 1.78, 95 % CI [1.56;2.03]. In contrast, de- creased RSP-Pnc carriage was associated with pres- The levels of resistance to antibiotic for S. pneumoniae ence of siblings and post-PCV13 period (aOR = 0.75, and H. influenzae are the cornerstones of the rationale 95 % CI [0.65;0.85]) and (aOR = 0.71, 95 % CI [0.62;0.81]).
for antimicrobial recommendations for AOM In Factors associated with Hi carriage were conjunctivitis 2011, guidelines in France designated amoxicillin as the (aOR = 4.10, 95 % CI [3.54;4.76]), bilateral AOM (aOR = first-line drug for AOM requiring antibiotics, with 1.33, 95 % CI [1.17;1.51]), daycare center attendance amoxicillin-clavulanate and cefpodoxime proxetil limited (aOR = 1.93, 95 % CI [1.70;2.19]), age < 1 year old (aOR = to rare and specific situations These guidelines were 1.49, 95 % CI [1.31;1.69]), presence of siblings aOR = 1.82, based on a decreased proportion of ß-lactamase–produ- 95 % CI [1.60;2.07]), and post-PCV13 period (aOR = 1.23, cing Hi strains in France Complying with these 95 % CI [1.05;1.44]). Post-PCV13 period was the only fac- 2011 recommendations, in 2012, the most frequently tor retained in the ß-lactamase–producing Hi carriage (66 %) prescribed antibiotic for AOM in France was model and was associated with decreased carriage amoxicillin, as was recently shown Conversely, (aOR = 0.65, 95 % CI [0.54;0.79]).
prescriptions of broad-spectrum antibiotics such as Angoulvant et al. BMC Infectious Diseases (2015) 15:236 Table 2 Nasopharyngeal carriage and resistance of Pnc and Hi amoxicillin-clavulanate and cefpodoxime proxetil sharply in children with AOM before/after PCV13 implementation Before PCV13 After PCV13 Since 2011 (Fig. the NP carriage of RSP-Pnc de- n = 3,498 (%) n = 3,702 (%) creased 18 % in the post-PCV13 period. Moreover, thisreduction was associated with a decrease ( carriage of ß-lactamase–producing Hi strains. Accord- Penicillin susceptible ingly, amoxicillin as the first-line drug for AOM requir- ing antibiotics remains an adapted recommendation in Penicillin resistant France. In addition, we did not identify any risk factor Erythromycin susceptible associated with carriage of ß-lactamase–producing Hi strains (such as daycare center attendance, otitis-pronecondition or recent antibiotic use). Taking into account Erythromycin resistant the low proportion of ß-lactamase–producing Hi strains PCV7 vaccine types and the lack of risk factors associated with their carriage, Additional PCV13 vaccine types 648 (32.0) the prescription of amoxicillin-clavulanate as the first- Non-vaccine types line drug for AOM in this situation seems to have no benefit or justification.
The decrease in antibiotic resistance to S. pneumoniae was expected As in other studies, the reduction islinked to the 66 % decrease in the 6 additional PCV13 ß-lactamase + BLNAR- serotypes in our study Despite a dramatically ß-lactamase + BLNAR+ decrease of vaccine serotypes, 19A known in France to ß-lactamase- BLNAR+ harbor a high proportion of RSP remained frequently ß-lactamase- BLNAR- isolated in post PCV13 period (8.4 %) Several non- vaccine serotypes such as 15B/C (12.2 %), 15A (9.3 %),11A (9.1 %), 35B (7.5 %), 23A (5.9 %), and 6C (5.0 %) Hi or Pnc carriage seem to emerge in the post PCV13 period.
Hi and Pnc carriage In contrast, the decrease in ß-lactamase–producing Hi Pnc: pneumococcus; Hi: H. influenzae; BLNAR:ß-lactamase strains was not expected. Two explanations could be raised. The first is the reduced antibiotic use for childrenin France. Since 2001, following a national campaign Fig. 1 Antibiotic resistance of Streptococcus pneumoniae and Haemophilus influenzae isolated from nasopharyngeal flora in 7200 infants with acuteotitis media between 2006 and 2013. Pnc: pneumococcus; Hi: H. influenzae; BL+: ß-lactamase–producing strains; BLNAR: ß-lactamase–nonproducingampicillin-resistant strains Angoulvant et al. BMC Infectious Diseases (2015) 15:236 Table 3 Risk factors of nasopharyngeal carriage of Pnc, strains with reduced susceptibility to penicillin (RSP) Pnc, Hi and ß-lactamase+ Hi strains by univariate and multivariate analysis Univariate analysis Multivariate analysis Otalgia + fever ≥38.5 °C Recent use of cephalosporin Otitis-prone childrenb Periods (post-PCV13) Recent use of antibiotics Carriage of RSP Pnc** Recent use of antibiotics Recent use of cephalosporin Otitis-prone childrenb Otalgia + fever ≥38.5 °C Periods (post-PCV13) Carriage of Hi*** Otitis-prone childrenb Recent use of antibiotics Recent use of cephalosporin Periods (post-PCV13) Otalgia + fever ≥38.5 °C Carriage of ß-lactamase producing Hi**** Otitis-prone childrenb Recent use of cephalosporin Angoulvant et al. BMC Infectious Diseases (2015) 15:236 Table 3 Risk factors of nasopharyngeal carriage of Pnc, strains with reduced susceptibility to penicillin (RSP) Pnc, Hi and ß-lactamase+ Hi strains by univariate and multivariate analysis (Continued) Recent use of antibiotics Otalgia + fever ≥38.5 °C Periods (post-PCV13) aOR, adjusted odds ratio; 95 % CI, 95 % confidence interval; Pnc: pneumococcus; Hi: H. influenzae; AOM: Acute otitis medi; a adata not available in 2006/2008, bdatanot available in 2006/2007*univariate and multivariate analysis of overall population (n = 7,200), with 4,033 Pnc carriers; **univariate and multivariate analysis of Pnc carriers (n = 4,033), with1,735 RSP Pnc carriers; ***univariate and multivariate analysis of overall population (n = 7,200), with 3,624 Hi carriers; ****univariate analysis of Hi carriers (n =3,624), with 519 ß-lactamase+ promoting a judicious use of antibiotics in France, anti- Competing interests biotic use in children has been sharply reduced, par- Grants for ACTIV from Pfizer, Novartis, Sanofi and GSK during the conduct ofthe study.
ticularly for children < 2 years Furthermore, PCV Dr François Angoulvant reports personal fees from Pfizer outside the implementation may have led to an additional reduc- submitted work.
tion in prescriptions The second hypothesis is Dr Robert Cohen reports personal fees from Pfizer, GSK, Sanofi and Novartisoutside the submitted work.
more speculative: in our population, most Hi strains Dr Emmanuelle Varon reports personal fees and non-financial support from now produce biofilms which allows for resistance Pfizer, personal fees from GSK, outside the submitted work.
to antibiotic treatments without another mechanism of Dr Corinne Levy reports personal fees from Pfizer and Novartis outside thesubmitted work.
resistance required PCV13 impact in our population was expected since we have already showed the impact of PCV7 on carriage Authors' contributionsThe followings authors contributed as follows: RC, SBE, SBO, EV, CL and antibiotic resistance We have previously conceived and design the study. FA RC CD AE AW SBO EV performed the showed in pre PCV13 period that Pnc carriage was less data acquisition. FA RC CD AE AW SBE SBO EV CL analyzed the study. FA RC frequently associated with AOM treatment failure than CD AE AW SBE SBO EV CL contributed to the writing of the manuscript. Allauthors read and approved the final manuscript.
Hi However, in this current study, we have not ana-lyzed the evolution of risk of AOM antibiotic failure be- tween pre and post PCV13 periods.
We thank all pediatricians who participated in the study: C Abt-Nord, M-J This situation of infection and antibiotic resistance is Aim-Mille, D Allain, M Amzallag, I Aubier, P Bakhache, J Baron, B Baszanger, G very dynamic and the few non-vaccine strains of S. pneu- Beley, M Benani, C Bensoussan-Ambacher, E Billard, L Billet, J-P Blanc, M-J Bodin, E Boez, B Bohe, J Bouglé, F Bouillot, J-L Cabos, P Camier, F Ceccato, D , which are resistant to penicillin, may, similar to Clavel, C Claverie, R Cohen, L Coicadan, F Corrard, L Cret, B de Brito, F De serotype 19A, become more prevalent. This possibility Grenier, P Deberdt, I Defives, A Delatour, V Derkx, V Desvignes, M Dogneton, underscores the importance of the continuous availabil- I Donikian-Pujol, M Dubosc, C Dumont, A Elbez, J Elbhar, N Elkhoury, C Ferte-Devin, J-M Fiorini, D Garel, J-L Gasnier, A Gasser, B Gaudin, N Gelbert- ity of current data that reflects local and national micro- Baudino, C Georgeot, M Gerardin, M Giorno, R Gorge, J-L Guillon, J-F Hassan, biologic trends.
A Hayat, P Huguet, M Hunin, A Kalindjian, K Kassmann, Z Klink, M Koskas, CLastman-Lahmi, M-C Lemarchand, J-C Lévêque, J Levy, D Livon, N Maamri,M-O Mercier-Oger, C Messica, A-S Michot, J Miclot, P Migault, I Nave, M Navel,J-F Nicolas, A Pappo, J Peguet, C Perrin, C Petit, O Pinard, A Piollet, J-F Pujol, M-T Pujol, Y Regnard, M Robert, C Turberg-Romain, O Romain, M-C Rondeau, The NP carriage rate of RSP-Pnc strains and ß-lactamase– C Schlemmer, G Sivelle, D Somerville, N Temam-Basse, J-M Thiron, F Thollot,J Vaugeois, F Vie Le Sage, J-L Vuillemin, A Werner, R Wisnewsky, A Wollner, C producing Hi strains has decreased in children with AOM Wollner, C Ythier.
in France since 2010, the year of PCV13 implementation We thank M Boucherat, M Fernandes, I Ramay, D Menguy, C Prieur, and Elsa in France. Accordingly, amoxicillin as the first-line drug Sobral for technical assistance.
for AOM requiring antibiotics remains a valid recommen-dation. However, the AOM microbiology is evolving and FundingFinancial support was given by Pfizer Pharmaceuticals France.
requires continuous monitoring and adjustments of policy The sponsor helped design the study but had no role in data collection, for antibiotics.
data analysis, data interpretation, or writing of the report.
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