Association Between Carriage of Streptococcus Pneumoniae and Staphylococcus Aureus in Children

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Association Between Carriage of Streptococcus pneumoniae and Staphylococcus aureus in Children

Gili Regev-Yochay, MD Context Widespread pneumococcal conjugate vaccination may bring about epidemio- Ron Dagan, MD logic changes in upper respiratory tract flora of children. Of particular significance may Meir Raz, MD be an interaction between Streptococcus pneumoniae and Staphylococcus aureus, in view of the recent emergence of community-acquired methicillin-resistant S aureus. Yehuda Carmeli, MD, MPH Objective To examine the prevalence and risk factors of carriage of S pneumoniae Bracha Shainberg, PhD and S aureus in the prevaccination era in young children. Estela Derazne, MSc Design, Setting, and Patients Cross-sectional surveillance study of nasopharyngeal carriage of S pneumoniae and nasal carriage of S aureus by 790 children aged 40 Galia Rahav, MD months or younger seen at primary care clinics in central Israel during February 2002. Ethan Rubinstein, MD Main Outcome Measures Carriage rates of S pneumoniae (by serotype) and S aureus; risk factors associated with carriage of each pathogen. TREPTOCOCCUS PNEUMONIAE AND Results Among 790 children screened, 43% carried S pneumoniae and 10% car- Staphylococcus aureus are com- ried S aureus. Staphylococcus aureus carriage among S pneumoniae carriers was 6.5% mon inhabitants of the upper vs 12.9% in S pneumoniae noncarriers. Streptococcus pneumoniae carriage among respiratory tract in children and S aureus carriers was 27.5% vs 44.8% in S aureus noncarriers. Only 2.8% carried both areS responsible for common infec- pathogens concomitantly vs 4.3% expected dual carriage (P=.03). Risk factors for tions. Carriage of S aureus and S pneu- S pneumoniae carriage (attending day care, having young siblings, and age older than moniae can result in bacterial spread and 3 months) were negatively associated with S aureus carriage. endogenous infections.1-3 Streptococ- Conclusions Streptococcus pneumoniae carriage, specifically of vaccine-type strains, cus pneumoniae is carried in the naso- is negatively associated with S aureus carriage in children. The implications of these pharynx by most children at least once findings in the pneumococcal vaccine era require further investigation. during early childhood1 but not fre- JAMA. 2004;292:716-720 www.jama.com quently by adults.4 Staphylococcus aureus is carried by 10% to 35% of chil- We investigated the possible asso- son in 53 participating primary care pe- dren5-7 and by approximately 35% of the ciation between the 2 pathogens by diatric clinics of a major health main- general adult population.3 Staphylococ- studying their prevalence and risk fac- tenance organization (Maccabi cus aureus is carried most consistently tors for carriage in young children in a Healthcare Services, Tel-Aviv) were en- in the nares. region where pneumococcal conju- rolled. The clinics were located in 4 Various studies have explored bac- gate vaccination is not practiced. large cities in the central district of Is- terial interference—the suppression of rael, inhabited by a middle-class Jew- one species by another.8-11 However, METHODS studies examining possible interfer- The study was approved by the Sheba Author Affiliations: Sheba Medical Center, Tel ence between S aureus and S pneumo- Medical Center Ethics Committee, Ra- Hashomer (Drs Regev-Yochay, Rahav, and Rubin- stein and Ms Derazne), and Sourasky Medical Center niae are noticeably absent. An associa- mat-Gan, Israel. Informed consent was (Dr Carmeli), Sackler School of Medicine, Tel-Aviv Uni- tion between these 2 pathogens may obtained from all parents. versity, and Tel-Aviv, Israel; and Soroka University Medical Center and Faculty of Health Science, Ben Gu- suggest epidemiologic changes that rion University of the Negev, Beer-Sheva, Israel could follow widespread vaccination Study Population (Dr Dagan). Corresponding Author: Gili Regev-Yochay, MD, In- with pneumococcal conjugate vac- During February 2002, children aged fectious Disease Unit, Sheba Medical Center, Ramat- cines. 40 months or younger seen for any rea- Gan, Israel 52621 ([email protected]).

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ish population. Each child was in- coccus aureus was identified by mor- RESULTS cluded once; accompanying adults phology, ␤-hemolysis, catalase, DNA- A total of 790 children (90% of chil- (usually parents) were also screened. ase, and coagulase production. dren approached) aged 5 days to 40 None of the children or their contacts months (median, 1.3 years) were received pneumococcal vaccine. Statistical Analysis screened. Fifty-five percent were male. We expected 15% of children to carry A total of 6.1% came for healthy Study Design S aureus and 50% to carry S pneumo- check-up visits and 80% were diag- Nasopharyngeal and nasal swabs were niae. To detect a difference of at least nosed as having a respiratory tract in- obtained from children and their accom- 7% in S aureus carriage rates among S fection. Chronic or recurrent disease (ie, panying adults, who also responded to pneumoniae carriers and noncarriers asthma, recurrent otitis media, recur- an interviewer-administered question- with ␣=.05 and 80% power, a sample rent pneumonia, or skin disorders) was naire including demographic character- size of 353 children in each group was present in 27.8%. istics, number of young siblings (aged Ͻ6 needed. Staphylococcus aureus and S pneumo- years), day care attendance, prior anti- Odds ratios (ORs) and Fisher exact niae were isolated in 80 children biotic treatment, and smoking habits of tests were calculated to assess risk fac- (10.1%) and 340 children (43.0%), re- family members. The physician’s diag- tors for carriage of each organism in- spectively. The proportion of vaccine- nosis on the screening day and medical cluding age, sex, young siblings, dwell- type strains among S pneumoniae car- and immunization histories were ob- ing density, passive smoking, day care riers was 74.2%. Staphylococcus aureus tained from patients’ files. The diag- attendance, respiratory tract infection carriage among S pneumoniae carriers noses were categorized as respiratory in- diagnosis, chronic and recurrent dis- was 6.5% vs 12.9% in S pneumoniae fections, skin diseases (including eases, S pneumoniae or S aureus car- noncarriers. Streptococcus pneumoniae infections), other infections (including riage by the acccompanying adult, ste- carriage among S aureus carriers was urinary tract infections and enteric roid treatment, number of clinic visits 27.5% vs 44.8% in S aureus noncarri- infections), and noninfectious diag- and hospitalization in the last 6 months, ers. If carriage of the 2 organisms were noses. and antibiotic treatment in the last independent (ie, occurring at random), month. Mantel-Haenszel common ORs the expected dual carriage would be Laboratory Procedures and the Breslow-Day test for homoge- 4.3%. However, dual carriage was found Nasopharyngeal cultures were ob- neity were used to control for possible in only 22 children (2.8%) (OR, 0.47; tained with a rayon-tipped wire swab confounding variables (age and day care 95% confidence interval [CI], 0.28- and nasal cultures of both nares were attendance). 0.78; P=.03 by Fisher exact test). obtained with a sterile cotton polyes- A multivariate logistic regression Seven hundred four adults (621 ter swab. Swabs were placed in Amies model with stepwise backward elimi- mothers [88%], 77 fathers, and 6 other transport medium (Copan, Brescia, nation was performed separately for family members) aged 18 to 45 years Italy). All specimens were processed each pathogen. Variables with PϽ.10 (median, 30 years) were screened for within 6 hours. in the univariate analysis were in- S aureus nasal carriage and 693 for both Nasopharyngeal swabs for S pneumo- cluded. Interactions of S pneumoniae pathogens. Staphylococcus aureus and niae isolation were streaked onto tryp- with day care attendance, age, and hav- S pneumoniae were isolated from 182 tic soy agar plates with 5% sheep blood ing young siblings were also included (25.9%) of 704 and 35 (5.1%) of 693, and 5 µg/mL of gentamicin (HyLabs, in the model for S aureus carriage. The respectively. The proportion of vaccine- Rehovot, Israel) and incubated aerobi- criterion for entering into the model was type strains among S pneumoniae car- cally at 35°C in 5% CO2-enriched air. a score statistic of P=.05. A Wald sta- riers was 66.7%. Staphylococcus au- Suspect colonies were isolated and iden- tistic of P=.10 was used to remove a reus carriage among adults was similar tified according to National Commit- variable from the model. −2 Log like- in S pneumoniae carriers and noncarri- tee for Clinical Laboratory Standards lihood, the Nagelkerke R2, and the Hos- ers (25.7% and 25.3%, respectively), recommendations.12 Serotyping of mer-Lemeshow test were used to as- and S pneumoniae carriage was similar S pneumoniae was performed using an- sess goodness of fit. Risk factors were in S aureus carriers and noncarriers tisera (Statens Serum Institute, Copen- checked for confounding and collinear- (5.1% and 5.0%, respectively). Dual car- hagen, Denmark). Vaccine types were ity. Cross-validation was used to as- riage was found in 1.3%, the same as defined as serotypes included in the cur- sess overfitting. All tests used were the expected prevalence (OR, 1.02; 95% rent 7-valent conjugate vaccine as well 2-tailed, and PϽ.05 was considered sta- CI, 0.47-2.23; P=.96 by Fisher exact as the cross-reactive types (ie, sero- tistically significant. Computations were test). groups 4, 6, 9, 14, 18, 19, and 23). performed with SPSS software, ver- The highest S aureus carriage rate Nasal swabs for S aureus isolation sion 11.0 (SPSS Inc, Chicago, Ill) and (30%) was observed in children aged were streaked onto tryptic soy agar S-Plus, version 6.2 (Insightful Corp, Se- 3 months or younger, in whom S pneu- plates with 5% sheep blood. Staphylo- attle, Wash). moniae prevalence was lowest (9%)

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(FIGURE 1). The highest S pneumoniae (TABLE). These same factors were in- ated with S pneumoniae carriage. To as- carriage rate (approximately 50%) was versely associated with S aureus car- sess for confounding effects, the in- in children aged 7 to 40 months, in riage. Being an S pneumoniae carrier was verse relation of carriage was analyzed whom S aureus prevalence was the low- inversely associated with S aureus car- while controlling for age and day care est (5%-9%). riage and vice versa (P=.003). Antibi- attendance. In children, the preva- In a univariate analysis, age older otic treatment during the prior month lence of S aureus was lower among than 3 months, having young siblings, reduced carriage of both pathogens. S pneumoniae carriers compared with day care attendance, respiratory tract Having a parent who was an S aureus S pneumoniae noncarriers in all age infection at screening, and prior ste- carrier was a risk factor for carrying S groups (Mantel-Haenszel OR, 0.51; 95% roid treatment were risk factors for S aureus, but having a parent who was an CI, 0.29-0.89; P=.02) (FIGURE 2). There pneumoniae carriage in children S pneumoniae carrier was not associ- was no evidence that this association was modified by age (Breslow-Day ␹2=1.716; P=.63). Figure 1. Staphylococcus aureus and Streptococcus pneumoniae Prevalence by Age Group The association between S pneumo-

S aureus Carriage S pneumoniae Carriage niae and S aureus carriage was strati- 60 fied by day care attendance. Among day

50 care attendees, S aureus carriage was sig- Dual Carriage nificantly lower among S pneumoniae 40 carriers compared with S pneumoniae noncarriers (3.0% vs 9.8%; OR, 0.28; 30 95% CI, 0.11-0.73; P=.005). Among

Carriage, % 20 non–day care attendees, S aureus carriage rates were 11.3% and 11.7% in 10 S pneumoniae carriers and noncarri-

0 ers, respectively (OR, 0.96; 95% CI, ≤3 4-6 7-12 13-24 25-40 ≤3 4-6 7-12 13-24 25-40 0.48-1.94; P=.54; conditional indepen- (n = 57) (n = 83) (n = 154) (n = 274) (n = 222) (n = 57) (n = 83) (n = 154) (n = 274) (n = 222) ␹2 Age, mo Age, mo dence Mantel-Haenszel =2.858, P =.09; homogeneity Breslow-Day The association between age and the proportion of carriers was examined by trend test for linear association. ␹2=4.313; P=.04). A significant descending trend in S aureus carriage between age 3 months or younger and age 13 to 24 months (PϽ.001) and an ascending trend thereafter (P=.04) was found. For S pneumoniae, a significant increase was Risk factors for S pneumoniae car- found among children older than 3 months vs younger children (PϽ.001). riage in a multivariate logistic analysis

Table. Risk Factors for Staphylococcus aureus and Streptococcus pneumoniae Carriage by Children (Univariate Analysis) S pneumoniae Carriers S aureus Carriers

Variables No. No. (%) OR (95% CI) P Value No. (%) OR (95% CI) P Value Ͼ Age 3 mo 733 335 (45.7) Ͻ 63 (8.6) Ͻ Reference: age Յ3 mo 57 5 (8.8)8.75 (3.46-22.17) .001 17 (29.8) 0.22 (0.12-0.41) .001 Day care attendance 377 203 (53.8) Ͻ 23 (6.1) Ͻ Reference: no day care attendance 386 129 (33.4)2.32 (1.73-3.11) .001 55 (14.2) 0.39 (0.24-0.65) .001 Ͻ Have siblings aged 6 y 381 191 (50.1) Ͻ 28 (7.3) Reference: no sibling aged Ͻ6 y 409 149 (36.4)1.75 (1.32-2.33) .001 52 (12.7) 0.55 (0.34-0.88) .01 RTI at screening 620 281 (45.3) 57 (9.2) Reference: no RTI at screening 145 53 (36.6)1.44 (0.99-2.09) .06 21 (14.5) 0.60 (0.35-1.02) .07 Antibiotic treatment in last month 236 90 (38.1) 16 (6.8) Reference: no antibiotic treatment in last month 520 239 (46.0)0.73 (0.53-0.99) .048 61 (11.7) 0.55 (0.31-0.97) .04 Steroid treatment in last month 114 62 (54.4) 6 (5.3) Reference: no steroid treatment in last month 593 251 (42.3)1.63 (1.09-2.43) .02 69 (11.6) 0.42 (0.18-1.00) .046 Male 434 195 (44.9) 52 (12.0) Reference: Female 356 145 (40.7)1.19 (0.89-1.58) .25 28 (7.9) 1.60 (0.98-2.58) .06 S pneumoniae carrier 340 NA 22 (6.5) Reference: noncarrier of S pneumoniae 450 NANA NA 58 (12.9) 0.47 (0.28-0.78) .003 S aureus carrier 80 22 (27.5) NA Reference: noncarrier of S aureus 710 318 (44.8)0.47 (0.28-0.78) .003 NA NA NA Have S pneumoniae−carrying guardian 35 17 (48.6) 3 (8.6) Reference: guardian not S pneumoniae carrier 658 294 (44.7)1.17 (0.59-2.31) .73 62 (9.4) 0.90 (0.27-3.03) .99 Have S aureus−carrying guardian 182 78 (42.9) 30 (16.5) Ͻ Reference: guardian not S aureus carrier 522 239 (45.8)0.89 (0.63-1.25) .55 35 (6.7) 2.75 (1.63-4.62) .001 Abbreviations: CI, confidence interval; NA, data not applicable; OR, odds ratio; RTI, respiratory tract infection.

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were day care attendance (OR, 2.18; ported in older children.13 In addition, Ͻ Figure 2. Association Between 95% CI, 1.56-3.06; P .001); having concurrent carriage of S pneumoniae and Streptococcus pneumoniae and young siblings (Ͻ6 years) (OR, 1.86; S aureus in children was significantly Staphylococcus aureus Stratified by Age 95% CI, 1.34-2.56; PϽ.001); and age lower than expected. Group older than 3 months (OR, 5.93; 95% CI, This apparent inverse relationship 30 2.28-15.42; PϽ.001); antibiotic treat- could be due to bacterial interference S pneumoniae Carriers (Dual Carriers) ment during the previous month was or could be a consequence of confound- 25 S pneumoniae Noncarriers inversely related (OR, 0.60; 95% CI, ing effects. Age was considered a pos- 0.43-0.85; P=.004). Sex, S pneumo- sible confounder because the associa- 20 niae carriage by parents, respiratory tion between the 2 pathogens was not 15 tract infection at screening, and S au- demonstrated in the adult group and the Carriage, % reus carriage did not significantly affect tendency to carry different pathogens 10

S pneumoniae carriage (−2 log likeli- at different age groups is well known S aureus 2 hood=868.59; Nagelkerke R =0.131; (eg, pharyngeal Streptococcus pyo- 5 ␹2 14 Hosmer-Lemeshow 5=1.199; P=.95). genes at age 6-14 years ; nasopharyn- 15 The only significant risk factor for geal meningococcus in adolescents ). 0 4-6 7-12 13-24 25-40 S aureus carriage in a multivariate logis- Nevertheless, when controlling for age, Age, mo tic analysis model was having an S au- the negative association between S pneu- No. 33 50 80 74 113 161 109 113 reus carrier parent (OR, 2.60; 95% CI, moniae and S aureus carriage among 1.48-4.55; P=.001), while several fac- children persisted. Children aged 3 months or younger were not in- tors were inversely related: carrying S Although close contacts and poor hy- cluded in this analysis, since only 5 children in that group were S pneumoniae carriers. Mantel-Haenszel pneumoniae while attending day care gienic conditions (eg, in day care cen- odds ratio, 0.51 (95% confidence interval, 0.29-0.89). (OR, 0.27; 95% CI, 0.10-0.72; P=.009); ters and among young siblings) are having young siblings (OR, 0.52; 95% considered to increase S aureus trans- CI, 0.30-0.91; P=.02); and age older than mission,16 in our study day care atten- also toward higher S aureus carriage rates 3 months (OR, 0.51; 95% CI, 0.21- dance was surprisingly inversely in children. This would be particularly 1.26; P=.15 for age 4-6 months; OR, related to S aureus carriage (when com- disturbing in light of the emergence of 0.31; 95% CI, 0.13-0.74, P=.009 for 7-12 bined with S pneumoniae carriage). A community-associated methicillin- 5,6,18 months; OR, 0.14; 95% CI, 0.05-0.36; possible explanation is that day care at- resistant S aureus. This possibility is PϽ.001 for 13-24 months; and OR, 0.35; tendance may indicate prolonged S supported by a recent report of an in- 95% CI, 0.15-0.35, P=.02 for 25-40 pneumoniae carriage (the inhibitory fac- creased rate of S aureus culture- months). Sex and skin disease did not tor against S aureus), while this study positive draining ears in vaccinated chil- 19 have a significant influence (−2 log like- measured point prevalence solely. Al- dren compared with controls. lihood=367.63; Nagelkirk R2=0.178; ternatively, day care attendance could Limitations of this study include ␹ 2 Hosmer=Lemeshow 8=9.448; P=.31). be an indicator of the presence of an- being a point prevalence study of chil- When the analysis was repeated but re- other bacterial or viral pathogen that in- dren visiting primary care clinics that stricted to vaccine-type S pneumoniae terferes with S aureus. may underrepresent healthy pediatric carriage, the results were almost iden- Bacterial interference could explain populations; other pathogens poten- tical (OR, 0.22; 95% CI, 0.07-0.74; the inverse relation between S aureus tially involved in bacterial interfer- P=.02 for being a vaccine-type S pneu- and S pneumoniae. This phenomenon ence were not studied and antibiotic use moniae carrier and attending day care). has been reported between S aureus and was examined only for the prior month. Analysis of non–vaccine-type S pneu- coagulase-negative staphylococci,9 Co- Longitudinal studies including older moniae did not yield any associations rynebacterium,8 and viridans group children and additional pathogens with S aureus carriage. streptococci.10 Hydrogen peroxide has could further refine this association. been suggested to be the inhibitory fac- Our study suggests a protective role COMMENT tor of viridans streptococci on S au- of S pneumoniae carriage against S au- We have shown an inverse relation be- reus10 and of S pneumoniae on other res- reus carriage. Studies measuring the tween S aureus and S pneumoniae car- piratory tract bacteria.11 effect of vaccination on S pneumoniae riage (specifically of vaccine-type strains) Pneumococcal conjugate vaccines epidemiology should also examine con- in children. Factors positively associ- reduce nasopharyngeal carriage of vac- current changes in S aureus. ated with S pneumoniae carriage were cine-type S pneumoniae. Our finding of Author Contributions: Dr Regev-Yochay had full ac- negatively associated with S aureus car- an inverse relationship between vaccine- cess to all of the data in the study and takes respon- riage. The distribution of S aureus car- type S pneumoniae and S aureus may im- sibility for the integrity of the data and the accuracy of the data analysis. riage by age was a mirror image of that ply an upcoming shift, not only toward Study concept and design: Regev-Yochay, Dagan, Raz, of S pneumoniae, an observation also re- nonvaccine S pneumoniae serotypes17 but Carmeli, Shainberg, Derazne, Rahav, Rubinstein.

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Acquisition of data: Regev-Yochay, Raz, Derazne. 2. Von Eiff C, Becker K, Machka K, Stammer H, reus colonization of oral cavities in newborns. Clin In- Analysis and interpretation of data: Regev-Yochay, Peters G. Nasal carriage as a source of Staphylococ- fect Dis. 2001;32:1408-1413. Dagan, Raz, Derazne. cus aureus bacteremia. N Engl J Med. 2001;344:11- 11. Pericone CD, Overweg K, Hermans PWM, Wei- Drafting of the manuscript: Regev-Yochay, Raz, 16. ser JN. Inhibitory and bactericidal effects of hydro- Carmeli, Rahav, Rubinstein. 3. Kluytmans J, van Belkum A, Verbrugh H. Nasal car- gen peroxide production by Streptococcus pneumo- Critical revision of the manuscript for important in- riage of Staphylococcus aureus: epidemiology, un- niae on other inhabitants of the upper respiratory tract. tellectual content: Regev-Yochay, Dagan, Shainberg, derlying mechanisms, and associated risks. Clin Mi- Infect Immun. 2000;68:3990-3997. Derazne, Rahav, Rubinstein. crobiol Rev. 1997;10:505-520. 12. Performance Standards for Antimicrobial Sus- Statistical analysis: Carmeli, Derazne. 4. Regev-Yochay G, Raz M, Dagan R, et al. Naso- ceptibility Testing. Wayne, Pa; National Committee Obtained funding: Regev-Yochay, Raz. pharyngeal carriage of Streptococcus pneumoniae by for Clinical Laboratory Standards; 2001. Publication Administrative, technical, or material support: adults and children in community and family set- M100-S11. Regev-Yochay, Raz, Shainberg, Rahav. tings. Clin Infect Dis. 2004;38:632-639. 13. Bogaert D, van Belkum A, Sluijter M, et al. Colo- Study supervision: Regev-Yochay, Dagan, Raz, 5. Nakamura MM, Rohling KL, Shashaty M, Lu H, Yi- nisation by Streptococcus pneumoniae and Staphy- Derazne, Rahav, Rubinstein. Wei T, Edwards K. Prevalence of methicillin-resistant lococcus aureus in healthy children. Lancet. 2004; Funding/Support: This study was financially sup- Staphylococcus aureus nasal carriage in the commu- 363:1871-1872. ported by the Israeli National Institute for Health Policy ity pediatric population. Pediatr Infect Dis J. 2002; 14. Bergovac J, Bobinac E, Benic B, et al. Asympto- and by Maccabi Healthcare Services. 21:917-921. matic pharyngeal carriage of beta-haemolytic strep- Role of the Sponsors: The study sponsors played no role 6. Shopsin B, Methema B, Martinez J, et al. Preva- tococci and streptococcal pharyngitis among pa- in the design and conduct of the study, in the collec- lence of methicillin-resistant and methicillin- tients at an urban hospital in Croatia. Eur J Epidemiol. tion, analysis, and interpretation of the data, or in the susceptible Staphylococcus aureus in the commu- 1993;9:405-410. preparation, review, or approval of the manuscript. nity. J Infect Dis. 2000;182:359-362. 15. Balmer P, Borrow R, Miller E. Impact of menin- Previous Presentation: This study was partially pre- 7. Peacock SJ, Justice A, Griffiths D, et al. Determi- gococcal C conjugate vaccine in the UK. J Med Mi- sented at the 43rd Interscience Conference on Anti- nants of acquisition and carriage of Staphylococcus crobiol. 2002;51:717-722. microbial Agents and Chemotherapy meeting, Sep- aureus in infancy. J Clin Microbiol. 2003;41:5718- 16. Rao GG. Risk factors for the spread of antibiotic- tember 14-17, 2003, Chicago, Ill (abstract G-2048). 5725. resistant bacteria. Drugs. 1998;55:323-330. Acknowledgment: We thank Erica Pinco, MSc, for 8. Uehara Y, Nakama H, Agematsu K, et al. Bacterial 17. Givon-Lavi N, Fraser D, Dagan R. Vaccination of laboratory assistance and Nurit Porat, PhD, and Ronit interference among nasal inhabitants: eradication of day-care center attendees reduces carriage of Strep- Trefler, BSc, for serotyping. 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