Dynamics of Pediatric Antibiotic Use Differ between High- and Low-Prescribing Clinics after Pneumococcal Conjugate Vaccines.

OBJECTIVE: To compare dispensed oral antibiotic prescription rates (DAPRs) after implementation of pneumococcal conjugate vaccine (PCV) in high antibiotic-prescribing clinics (HPC) with low antibiotic-prescribing clinics (LPC) in 2 distinct ethnic groups of children (Jewish and Bedouin children) <5 years of age. METHODS: Clinics with ≥50 insured children, active both pre-PCV (2005-2009) and post-PCV (2010-2018) implementation, were included. HPC and LPC were defined by DAPRs above or below the median in each age and ethnic group. Monthly dispensed antibiotic prescription rate (DAPR) trends (adjusted for age and ethnicity) were calculated using interrupted time series. Mean yearly incidence rate-ratios (late PCV13 vs pre-PCV) were calculated. RESULTS: Bedouin HPC had the highest pre-PCV overall-DAPR per 1000 child-years ± SD (2520.4 ± 121.2), followed by Jewish HPC (1885.5 ± 47.6), Bedouin LPC (1314.8 ± 81.6), and Jewish LPC (996.0 ± 19.6). Shortly after PCV implementation, all DAPRs and amoxicillin/amoxicillin-clavulanate DAPRs declined in all groups except Jewish LPC, stabilizing within 4-5 years post-PCV. The rates and magnitudes of declines were directly proportional to the pre-PCV DAPR magnitudes, achieving near-complete closure of the pre-PCV DAPR gaps between the 4 groups (rates during late-PCV13 ranging from 1649.4 ± 23.5 [Bedouin HPC] to 1200.3 ± 72.4 [Jewish LPC]). CONCLUSIONS: PCVs are a powerful tool in reducing outpatient antibiotic consumption among young children, especially in HPC, resulting in partial closure of DAPR gap between HPC and LPC. The higher impact on HPC suggests that PCV-associated declines of respiratory disease may strongly contribute to a judicious antibiotic approach in clinics with high antibiotic consumption.

The impact of pneumococcal conjugate vaccine on ceftriaxone consumption in the community among young children.

OBJECTIVES: Following pneumococcal conjugate vaccine (PCV) introduction, community pediatric dispensed prescription rates (DPR) of oral antibiotics declined, in parallel to respiratory tract infection (RTI). We assessed the dynamics of outpatient parenteral ceftriaxone DPR. METHODS: Computerized data for children <5 years were examined during 13 years (including 4 pre-PCV years). DPR from clinics with ≥50 insured children, active both before and after PCV implementation were included. Interrupted time series with segmented regression stratified by age and ethnicity, and adjusted for seasonality was applied to show monthly DPR trends. RESULTS: A total of 29,226 prescriptions were dispensed. No significant trends in ceftriaxone DPR were seen pre-PCV. Shortly after PCV implementation, DPR abruptly and significantly declined, stabilizing in late-PCV period (5 years postimplementation). The dynamics were compared between the two ethnic groups in the region, Jewish and Bedouin children (the latter with higher crowding and respiratory disease rates). Among Jewish children, ceftriaxone was mainly dispensed during winter vs no seasonality among Bedouin children. CONCLUSIONS: In southern Israel, outpatient ceftriaxone DPR declined post-PCV in young children, similar to the trends of RTIs and oral antibiotic prescriptions, suggesting a causative role of PCVs. The differences between the two ethnic groups suggest possible involvement of additional factors.

Dynamics of invasive pneumococcal disease in infants < 2 years old following PCV7/13 implementation using two infant and a booster dose schedule: evidence for indirect protection of young infants, Israel, 2004 to 2019.

BackgroundPneumococcal conjugated vaccine (PCV)7 and PCV13 programmes started in Israel from July 2009 and November 2010 respectively, with a 2+1 schedule (one dose at 2 months old, one at 4 months old, and a booster dose at 12 months old). Thereafter, invasive pneumococcal disease (IPD) rates substantially declined in children. Uptake of all three doses in < 2-year-olds since 2012 is > 90%. For still incompletely vaccinated infants (≤ 12 months old), how well the PCV 2+1 programme shields from IPD is not fully resolved.AimTo assess the adequacy of protection conferred by the 2+1 schedule PCV vaccination programme, particularly among incompletely-vaccinated infants.MethodsThis was a population-based, prospective, nationwide active IPD surveillance study in Israel, 2004-2019, in children < 24 months old. We estimated annual incidence rates (IR) of overall IPD, IPD caused by PCV13 serotypes (VT13), and non-PCV13 serotypes (NVT13). Annual IPD IRs were stratified by age: < 4 months (receiving ≤ 1 dose), 4-6 months (immediately post dose 2), 7-12 months (a few months post dose 2), and 13-23 months (post dose 3). Late-PCV (2004-2008) to pre-PCV13 (2016-2019) mean annual IR ratios (IRRs) were calculated.Results2,569 IPD episodes were recorded. VT13 decreased > 90% in all age groups, while NVT13 seemed to increase. All-IPD rates declined in all age groups by 56-70%. The 2+1 schedule impact on 7-12-month-old infants (pre-booster) was similar to that on 13-23-month-old children (post booster), with PCV13 IPD reductions of 97% and 98%, respectively.ConclusionsIndirect (herd) protection of infants, including < 4 month-olds with ≤ 1 PCV dose, was achieved by the 2+1 PCV schedule programme which thus seems adequate.

A Hypothesis-Generating Prospective Longitudinal Study to Assess the Relative Contribution of Common Respiratory Viruses to Severe Lower Respiratory Infections in Young Children.

BACKGROUND: Respiratory viruses such as respiratory syncytial virus (RSV), influenza, parainfluenza and human metapneumovirus are well-established etiologies of acute lower respiratory tract infections (ALRIs; LRI-viruses). In contrast, adenovirus (AdV), rhinovirus/enterovirus (RV/EV) and seasonal human coronaviruses (CoV), collectively termed AdV/RV/CoV, are detected both in healthy children and children with ALRI. METHODS: The methods include a prospective longitudinal case-control study, assessing the prevalence of LRI-viruses versus AdV/RV/CoV in ALRI [community-acquired alveolar pneumonia (CAAP) and bronchiolitis] during hospitalization (visit 1), 7-14 days (visit 2) and 28-35 days (visit 3) in 2-17-month-old children. Controls were 2-27-month-old children hospitalized for elective surgery during the same respiratory seasons. RESULTS: We enrolled 99 infants (37 CAAP, 38 bronchiolitis and 24 controls) and obtained 211 nasopharyngeal swabs. Overall, 163 (77%) had greater than or equal to 1 viruses detected; RV/EV (n = 94; 45%) and RSV (n = 71; 34%) were the most frequently detected viruses. In CAAP, the overall LRI-virus prevalence was 78.4%, 32.4% and 5.4% in visits 1, 2 and 3, respectively; the respective rates in bronchiolitis were 73.7%, 34.5% and 8.0%. In controls, no LRI-viruses were detected. In contrast, the overall AdV/RV/CoV prevalence was high among controls (70.8%) and similar among CAAP (48.6%, 40.5% and 40.5%) and bronchiolitis (47.4, 58.6% and 64.0%) across visits. CONCLUSIONS: Among ALRI cases, LRI-viruses dominated during the acute disease, with prevalence declining within 28-35 days, suggesting their causative role. In contrast, AdV/RV/CoV prevalence was similar during all 3 visits and in controls, suggesting that carriage of these viruses is common during the viral respiratory season. The current study is relatively small and of short duration; however, the findings are supported by other recent studies.

The COVID-19 pandemic as an opportunity for unravelling the causative association between respiratory viruses and pneumococcus-associated disease in young children: a prospective study.

BACKGROUND: In young children, rates of lower respiratory infections (LRI) and invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of these disease endpoints has not yet been elucidated. The COVID-19 pandemic provided a unique opportunity to examine the question. METHODS: This prospective study comprised all children <5 years, living in southern Israel, during 2016 through 2021. The data were previously collected in multiple ongoing prospective surveillance programs and include: hospital visits for community-acquired alveolar pneumonia (CAAP), non-CAAP LRI; nasopharyngeal pneumococcal carriage (<3 years of age); respiratory virus activity; and nationwide, all-ages COVID-19 episodes and IPD in children <5 years. A hierarchical statistical model was developed to estimate the proportion of the different clinical endpoints attributable to each virus from monthly time series data, stratified by age and ethnicity. A separate model was fit for each endpoint, with covariates that included a linear time trend, 12-month harmonic variables to capture unexplained seasonal variations, and the proportion of tests positive for each virus in that month. FINDINGS: During 2016 through 2021, 3,204, 26,695, 257, and 619 episodes of CAAP, non-CAAP LRI, pneumococcal bacteremic pneumonia and non-pneumonia IPD, respectively, were reported. Compared to 2016-2019, broad declines in the disease endpoints were observed shortly after the pandemic surge, coincident with a complete disappearance of all PDA-viruses and continued circulation of rhinovirus (RhV) and adenovirus (AdV). From April 2021, off-season and abrupt surges of all disease endpoints occurred, associated with similar dynamics among the PDA-viruses, which re-emerged sequentially. Using our model fit to the entire 2016-2021 period, 82% (95% CI, 75-88%) of CAAP episodes in 2021 were attributable to the common respiratory viruses, as were 22%-31% of the other disease endpoints. Virus-specific contributions to CAAP were: RSV, 49% (95% CI, 43-55%); hMPV, 13% (10-17%); PIV, 11% (7-15%); flu, 7% (1-13%). RhV and AdV did not contribute. RSV was the main contributor in all endpoints, especially in infants. Pneumococcal carriage prevalence remained largely stable throughout the study. INTERPRETATION: RSV and hMPV play a critical role in the burden of CAAP and pneumococcal disease in children. Interventions targeting these viruses could have a secondary effect on the burden of disease typically attributed to bacteria. FUNDING: There was no funding for this study.

Disproportionate reduction in respiratory vs. non-respiratory outpatient clinic visits and antibiotic use in children during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic led to improved hygiene and reduced social encounters. Near elimination of the activity of respiratory syncytial virus and influenza viruses were observed, worldwide. Therefore, we assessed the rates of pediatric outpatient clinic visits and medications prescribed at those visits during the coronavirus disease 2019 (COVID-19) pandemic and pre-COVID-19 period (2016-2019). METHODS: Monthly and annual incidence rates for respiratory and non-respiratory diagnoses and dispensed prescription rates were calculated. Acute gastroenteritis (AGE) visits were analyzed separately since the mode of transmission is influenced by hygiene and social distancing. RESULTS: Overall, 5,588,702 visits were recorded. Respiratory and AGE visits declined by 49.9% and 47.3% comparing the COVID-19 and pre-COVID-19 periods. The respective rate reductions for urinary tract infections, trauma, and skin and soft tissue infections were 18.2%, 19.9%, and 21.8%. Epilepsy visits increased by 8.2%. Overall visits rates declined by 21.6%. Dispensed prescription rates of antibiotics and non-antibiotics respiratory medications declined by 49.3% and 44.4%, respectively. The respective declines for non-respiratory antibiotics and non-antibiotics were 15.1% and 0.2%. Clinic visits and prescription rates reductions were highest in April-May, following the first lockdown in Israel. CONCLUSIONS: COVID-19 pandemic resulted in a substantial reduction in respiratory outpatient clinic visits and dispensed respiratory drugs, with only a mild reduction seen for non-respiratory visits. These trends were probably driven by COVID-19 mitigation measures and by the profound disruption to non-SARS COV-2 respiratory virus activity.

The impact of the pneumococcal conjugate vaccines on the incidence of community-acquired alveolar pneumonia in premature compared with in term-born infants.

BACKGROUND: Preterm-born children are prone to respiratory infections and complications during infancy and early childhood. In Israel, pneumococcal conjugated vaccines (PCVs) were introduced in 2009-2010, with high vaccination coverage. We assessed the impact of PCV implementation on community-acquired alveolar pneumonia (CAAP) in children < 2 years old born prematurely, in comparison with term born infants. METHODS: We conducted a prospective, active, population-based surveillance of children < 2 years old with radiologically-proven CAAP, visiting the only regional medical center. CAAP incidence in the pre-PCV and post-PCV eras were compared in early premature (29-32 weeks gestational age [WGA]), late premature (33-36 WGA) and term-born infants (>36 WGA). RESULTS: Of 214,947 births during the study period, 6'791 CAAP episodes were diagnosed; 211, 653 and 5,806 were in early premature, late premature and term infants, respectively. After PCV implementation, overall CAAP visits were reduced by 44% (95% CI 36-51): 60%, 21% and 45% among those born early preterm, late preterm and at term, respectively (statistically significant for children born early preterm and at term). For outpatients, the respective rate reductions were 79%, 40% and 65% (statistically significant for the children born at term). Importantly, the mean annual rates in the post-PCV period became similar in all 3 groups. The rate reductions among the hospitalized children were lower those that among the non-hospitalized children, with reductions of 56%, 16% and 33% for the three groups, respectively (statistically significant for early preterm and at term children). CONCLUSIONS: CAAP reduction trends after PCV implementation for preterm-born infants were similar to those for term-born infants. Whether this was because of similar direct PCV- protection, because of indirect (herd) protection or both, is unclear. Post-PCV implementation, the gaps in CAAP rates between infants born prematurely and at term were reduced.

Decline in Pneumococcal Disease in Young Children During the Coronavirus Disease 2019 (COVID-19) Pandemic in Israel Associated With Suppression of Seasonal Respiratory Viruses, Despite Persistent Pneumococcal Carriage: A Prospective Cohort Study.

BACKGROUND: The incidence of invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from nonpharmaceutical interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis. METHODS: The first SARS-CoV-2 cases were detected in February 2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory infections necessitating chest X-rays (NA-LRIs), nasopharyngeal pneumococcal carriage in nonrespiratory visits, nasopharyngeal respiratory virus detection (by polymerase chain reaction), and nationwide IPD. Monthly rates (January 2020 through February 2021 vs mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity were compared. RESULTS: CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios [IRRs]: .07 and .19, respectively); NA-LRIs and nonpneumonia IPD were also reduced by a lesser magnitude (IRRs: .46 and .42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced, and density of colonization and pneumococcal serotype distributions were similar to previous years. The decline in pneumococcus-associated disease was temporally associated with a full suppression of respiratory syncytial virus, influenza viruses, and human metapneumovirus, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. CONCLUSIONS: Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic in Israel were not predominantly related to reduced pneumococcal carriage and density but were strongly associated with the disappearance of specific respiratory viruses.

Dynamics of Invasive Pneumococcal Disease in Israel in Children and Adults in the 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Era: A Nationwide Prospective Surveillance.

BACKGROUND: Following 13-valent pneumococcal conjugate vaccine (PCV13) implementation in infants worldwide, overall and vaccine-type invasive pneumococcal disease (IPD) rates declined in children, with variable indirect impact on adults. METHODS: A population-based, prospective, nationwide active surveillance of IPD in Israel, 2004-2019 (for adults ≥18 years, 2009-2019). The 7-valent PCV (PCV7)/PCV13 were implemented in Israel in July 2009/November 2010, respectively, with >90% uptake in children <2 years. The 23-valent pneumococcal polysaccharide vaccine (PPV-23) uptake among those >65 years was ~75%. For pre-PCV episodes with missing serotype, extrapolations were applied. Overall, PCV13 serotypes (VT13) and non-VT13 (NVT) incidence rate ratios (IRRs) comparing pre-PCV (2004-2008), early-PCV (2009-2011), and late-PCV13 (2016-2019) periods were calculated for different age groups. RESULTS: Overall, 8614 IPD cases were recorded. IPD rates declined by 67% in children <5 and 5-17 years, comparing late-PCV13 versus pre-PCV periods (IRR [95% CI]: .33 [.27-.40] and .33 [.21-.50], respectively). For adults, comparing late-PCV13 with early-PCV periods, rates significantly declined by 53% in those aged 18-44, while rates did not decline significantly in other age groups. VT13 rates significantly declined in all ages, with decline rates ranging between 94% in children <5 years and 60% in adults ≥85 years. NVT rates significantly increased in <5-, 50-64-, and ≥65-year age groups. In the late-PCV13 period, serotypes 3, 14, and 19A remained the predominant VT13, while serotypes 8 and 12F emerged as predominant NVTs. CONCLUSIONS: Continuous monitoring of circulating serotypes in all ages demonstrated direct and indirect PCV effects, which are essential for the development of new vaccination strategies.

Decline in pneumococcal nasopharyngeal carriage in children 6-23 months with respiratory illnesses following pneumococcal conjugate vaccine implementation.

BACKGROUND: Following pneumococcal conjugate vaccines (PCVs) implementation, worldwide, pneumococcal carriage rates remained stable, indicating full replacement of vaccine-serotypes (VT) with non-VT. However, data are scarce regarding PCV impact on pneumococcal carriage rates in healthy vs. sick children. We assessed pneumococcal carriage rates dynamics in healthy and sick children 6-23 months, following PCV introduction. METHODS: This is a prospective, population-based surveillance conducted during the years 2009-2017, in southern Israel. Three groups were defined as follows: Children without respiratory infection signs (the healthy/non-respiratory group); Children who had a chest radiography at the hospital (the Hosp-CXR group); and children with community-acquired alveolar pneumonia (CAAP). Rate ratios (RRs; 95% CI) were calculated, comparing between late-13-valent PCV (PCV13) period (2016-2017) and early-PCV period (2009-2010). Rate ratios were adjusted for antibiotic administration, seasonality and ethnicity, and separate calculations were performed for 6-11 and 12-23 month old children. RESULTS: Overall, 51% of 8627 nasopharyngeal cultures were positive. In 2009-2010 (early-PCV period), the overall carriage rate was 55%; serotypes included in the PCV13 carriage rates were 28%, 31% and 38% in the healthy/non-respiratory, Hosp-CXR, and CAAP groups, respectively. Overall carriage rates in healthy/non-respiratory episodes were stable (~54%) when comparing between 2016 and 17 and 2009-10 (RR = 0.98; 0.84-1.15). In contrast, rates significantly declined for Hosp-CXR (RR = 0.78; 0.63-0.98) and CAAP (RR = 0.65; 0.47-0.89). These trends were driven by ~ 80% VT reductions, coupled with non-VT increase. CONCLUSIONS: Following 7-valent PCV/ PCV13 introduction, pneumococcal carriage rates declined in respiratory diseases, but not in healthy children and children without respiratory infections. These trends suggest that a reduction in pneumococcal carriage rates during respiratory infections indicates a decline in respiratory infections caused by VT, while carriage rates in non-respiratory cases reflect non-VT predominance, that have low disease potential for respiratory disease.

Unraveling the Impact of Pneumococcal Conjugate Vaccines on Ambulatory Antibiotic Drug Consumption in Young Children: An Interrupted Time-Series Analysis.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) reduce respiratory infections in young children, the main antibiotic consumers. Following PCV implementation, dispensed antibiotic prescription (DAP) rates in young children were expected to decline. METHODS: Computerized data on DAP for children <5 years were examined during a 13-year period (including 4 pre-PCV years). All DAPs from clinics with ≥50 insured children, active both pre- and post-PCV implementation were included. Interrupted time-series with segmented regression was applied to analyze monthly DAP rate trends, adjusted for age, ethnicity, and season. Incidence rate ratios (IRRs) of DAPs during the late PCV13 period versus 4 years pre-PCV were calculated both as absolute rate ratios (aIRRs) and relative to expected rates (rIRRs). RESULTS: Of 1 090 870 DAPs, 57% were in children <2 years. All-DAP rates peaked in the cold season. Post-PCV7/PCV13 implementation, all DAP rates abruptly and significantly declined, reaching a plateau within 5 years. This was largely driven by amoxicillin/amoxicillin-clavulanate (75% of DAPs). Age <2 years and Bedouin ethnicity were significantly associated with higher pre-PCV DAP rates but with faster and greater decline post-PCV, achieving near elimination of gaps between ages and ethnic groups. Overall reduction (95% CIs) in DAP rates per 1000 was estimated between aIRR (344.7 [370.9-358.4]) and rIRR (110.4 [96.9-123.7]) values. CONCLUSIONS: Shortly following PCV implementation, overall DAP rates showed an abrupt, steep decline, stabilizing within 5 years, in parallel to post-PCV respiratory infection trends previously described in this population, suggesting causality. The variable patterns of certain drug categories suggest additional influences beyond PCV.

Effectiveness of the 7- and 13-Valent Pneumococcal Conjugate Vaccines Against Vaccine-Serotype Otitis Media.

BACKGROUND: Despite the demonstrated impact of pneumococcal vaccine (PCV) implementation on otitis media (OM), demonstration of real-life serotype-specific effectiveness of the 7-valent and 13-valent PCVs (PCV7 and PCV13) is lacking owing to the paucity of culture-positive cases. Furthermore, prelicensure PCV13 efficacy against OM was not studied. METHODS: The study was conducted from October 2009 to July 2013. Case patients were children aged 5-35 months with OM (mostly complex OM [recurrent/nonresponsive, spontaneously draining, chronic with effusion]) from whom middle-ear fluid culture was obtained; controls were contemporary children with rotavirus-negative gastroenteritis in a prospective population-based rotavirus surveillance, from the same age group with similar ethnic distribution and geographic location. Vaccine effectiveness (VE) was estimated as 1 minus the odds ratio using unconditional logistic regression, adjusting for time since PCV implementation, age, and ethnicity. RESULTS: A total of 223 case patients and 1370 controls were studied. Serotypes 19F and 19A together caused 56.1% of all vaccine-type (VT) OM. VE of ≥2 PCV doses in children aged 5-35 months was demonstrated as follows: PCV7 against OM due to PCV7 serotypes, 57.2% (95% confidence interval, 6.0%-80.5%); PCV13 against OM due to PCV13 serotypes, 77.4% (53.3%-92.1%); PCV13 against OM due to the 6 additional non-PCV7 serotypes 67.4% (17.6%-87.1%); PCV13 against OM due to serotype 19F, 91.3% (1.4%-99.2%); and PCV13 against OM due to serotype 3, 85.2% (23.9%-98.4%). PCV7 and PCV13 VE against OM due to serotype 19A in children aged 12-35 months was 72.4% (95% confidence interval, 6.2%-91.9%) and 94.6% (33.9%-99.6%), respectively. CONCLUSIONS: PCV7 and PCV13 were effective against complex OM caused by the targeted serotypes.

Substantial reduction of antibiotic-non-susceptible pneumococcal otitis media following PCV7/PCV13 sequential introduction.

BACKGROUND: In the pre-pneumococcal conjugated vaccines (PCVs) era, serotypes included in the 7/13-valent PCVs (PCV7/PCV13) caused most pneumococcal otitis media (OM) and antibiotic-non-susceptible pneumococcal OM (ANSP-OM) episodes. In southern Israel, sequential PCV7/PCV13 introduction resulted in >90% reduction of vaccine-serotype OM. OBJECTIVES: We assessed the dynamics of ANSP-OM necessitating middle ear fluid culture following PCV7/PCV13 sequential introduction in young children. METHODS: This was a prospective, population-based, active surveillance. All episodes in children <3 years old, during 2004-16, were included. Two subperiods were defined: (i) pre-PCV: 2004-08; and (ii) PCV13: 2014-16. ANSP was defined for the following antibiotics: penicillin (MIC ≥0.1 mg/L and ≥1.0 mg/L), macrolide, tetracycline, clindamycin, ceftriaxone, trimethoprim/sulfamethoxazole and chloramphenicol. MDR was defined as ANSP for ≥3 classes. RESULTS: Overall, 2270 pneumococcal OM episodes were identified. Annual overall pneumococcal, PCV13 and non-PCV13 serotype OM incidence declined by 86%, 97% and 33%, respectively, comparing pre-PCV with the PCV13 period. During 2004-08, 95% of ANSP was observed in vaccine serotypes. Incidence of penicillin (MIC ≥0.1 mg/L and ≥1.0 mg/L), macrolide, tetracycline, clindamycin, ceftriaxone and multidrug ANSP-OM declined by >90% in the PCV13 period. Rates of trimethoprim/sulfamethoxazole and chloramphenicol ANSP-OM declined by 85% and 79%, respectively. The proportions of ANSP of all pneumococcal isolates declined by ∼70% for penicillin, ceftriaxone and erythromycin; 53% for tetracycline; and 55% for MDR, versus no significant reductions observed for chloramphenicol, trimethoprim/sulfamethoxazole and clindamycin. CONCLUSIONS: PCV7/PCV13 sequential introduction resulted in rapid and substantial ANSP-OM reduction, in parallel with the near disappearance of PCV13-serotype OM and no increase in replacement disease.