Multiplex PCR to determine Streptococcus pneumoniae serotypes causing otitis media in the Republic of Ireland with further characterisation of antimicrobial susceptibilities and genotypes

The purpose of this study was to determine the serotypes, genotypes and antimicrobial susceptibilities of Streptococcus pneumoniae causing otitis media (OM) in children in Dublin, Ireland. S. pneumoniae isolates (n = 28) from spontaneously discharging OM were studied. Serotyping was performed using a previously undescribed multiplex polymerase chain reaction (PCR) scheme in combination with serological methods. Multilocus sequence typing (MLST) was performed using standard procedures. Antimicrobial susceptibility testing was performed using the Etest method. Fourteen different S. pneumoniae serotypes were identified. The five most common serotypes were 3, 19F, 19A, 14 and 6A, which accounted for 68% of all infections. The 7-valent pneumococcal conjugate vaccine (PCV7), 10-valent pneumococcal conjugate vaccine (PHiD-CV) and 13-valent pneumococcal conjugate vaccine (PCV13) provided potential coverages of 43%, 46% and 86%, respectively. Reduced susceptibility to penicillin was evident for 25% of isolates and was associated with serotypes 14, 19A, 19F and 9V. A total of 21 different sequence types (STs) were identified. Pneumococcal Molecular Epidemiology Network (PMEN) clones or their variants represented 54% (15/28) of all isolates. Continued monitoring and characterisation of S. pneumoniae causing OM in Ireland is warranted in order to guide future vaccine and treatment policies.     

Pneumococcal Conjugate Vaccine Rollout in India: Expectations and Challenges

India is one among the four Asian countries with the greatest number of deaths due to pneumococcal infection among children under 5 years. pneumococcal conjugate vaccine (PCV) has been introduced in a phased manner in five major Indian states. Ambiguity remains in choosing the appropriate type of PCV and optimum schedule with maximum effectiveness specific for each country. Here, we discuss the evidences with respect to serotype coverage, immunogenicity, reactogenicity and dosage schedule for introduction of PCV13 in India. In addition, the expected PCV impact and the challenges are detailed. PCV13 is expected to provide >75% serotype coverage for invasive pneumococcal disease (IPD) serotypes in Indian children combined with the replacement by nonvaccine serotypes which is unpredictable due to lack of complete data. Nasopharyngeal (NP) surveillance is easy, feasible and can replace IPD surveillance in resource-poor settings. Continuous IPD as well as NP surveillance in all the regions are necessary to assess the impact of PCV in India.     

Routine infant immunization with the 7- and 13-valent pneumococcal conjugate vaccines: current perspective on reduced-dosage regimens

The 7 and 13-valent pneumococcal conjugate vaccines are mostly used in routine infant immunizations to prevent the development of pneumococcal disease. Currently, the dosing schedule approved and recommended for PCV7 and PCV13 in infants is 3 primary doses followed by a booster dose in the second year of life. However, a number of countries use a 2-dose only primary series with a booster dose in the second year of life. This review is aimed at providing the reader with a broad perspective on the currently available evidence which supports the clinical use of such reduced dosing schedules for the PCV7 and PCV13 vaccines. Recent evidence has been able to promulgate the immunogenicity and in some cases the effectiveness of the reduced dosing schedule for these vaccines. These findings may reduce costs as well as minimize supply and administration problems relating to the provision of the pneumococcal conjugated vaccines (PCVs). However, some caution is warranted since some inferior data have emerged with regards to the antibody immune response to certain pneumococcal serotypes following the implementation of such reduced dosing regimens. In addition, it is proposed that prospective surveillance be undertaken in all countries which have adopted the reduced-dosage immunization programs. This review may go some way in educating healthcare practitioners and healthcare policy decision makers at large.     

Invasive pneumococcal pneumonia caused by 13-valent pneumococcal conjugate vaccine types in children with different schedules

Background

In Taiwan, the age group with the greatest incidence of invasive pneumococcal disease is 2–5 years of age, which is different from other countries. This study was conducted to identify risk factors and different 13-valent pneumococcal conjugate vaccine (PCV13) schedules associated with vaccine-type invasive pneumococcal pneumonia (IPP) despite prior vaccination.

Potential impact of conjugate vaccine on the incidence of invasive pneumococcal disease among children in Scotland

We sought to determine the potential impact of seven-valent pneumococcal conjugate vaccine on the incidence of invasive pneumococcal disease (IPD) among children in Scotland. Invasive pneumococci from blood and cerebrospinal fluid, isolated between 2000 and 2004 from all children aged less than 5 years in Scotland, were characterized by serotyping. Using reported efficacy data of the seven-valent pneumococcal conjugate vaccine (PCV7) along with likely coverage rates, we made an estimation of the potential impact on the incidence of IPD among children in Scotland. A total of 217 pneumococci were characterized into 22 different serogroups/types, the most common, in rank order, being 14, 19F, 6B, 18C, 23F, 9V, 4, 1, 19A, and 6A. Estimated serotype coverage for PCV7 was 76.5% in those aged less than 5 years of age but increased to 88.9% for those aged 1 year. By using serotype coverage and estimates of vaccine efficacy and uptake, the potential impact of the vaccine for those greater than 2 months of age, but less than 5 years, was estimated as 67.3%, leading to an average of 29 preventable cases per year. The introduction of PCV7 into the childhood immunization schedule would reduce the burden of pneumococcal disease in children, and the incidence would be particularly reduced in those children aged 1 year. Additional benefits may be gained in adults through herd protection. Continued surveillance of IPD is required before, during, and after the introduction of PCV7.     

Prevention of pneumococcal otitis media in chinchillas with human bacterial polysaccharide immune globulin.

Clinical and experimental observations suggest that immune globulin may prevent otitis media (OM) in children. We performed experiments in chinchillas to test the hypothesis that human bacterial polysaccharide immune globulin (BPIG) might prevent OM caused by Streptococcus pneumoniae. Animals were given BPIG or saline intraperitoneally on day 0. On day 3 the epitympanic bulla was inoculated with S. pneumoniae type 7F. All 12 saline-treated and none of 12 BPIG-treated animals developed pneumococcal OM by day 7 (P less than 0.0001). Bacteremia developed in 6 of 12 saline- and 0 of 12 BPIG-treated animals (P = 0.007). Death with pneumococcal OM occurred within 28 days in 5 of 12 saline- and 0 of 12 BPIG-injected animals (P = 0.02). A chinchilla-specific immunoassay was used to show that surviving saline-injected animals developed serum anticapsular antibody; BPIG-treated animals had no detectable response. At levels of anticapsular immunoglobulin G similar to those of human adults, BPIG given systemically prevented pneumococcal OM and disseminated infection in chinchillas. BPIG may be of value in preventing human bacterial infection and may also inhibit development of antibody if it affects local infection or colonization. Specific immunoglobulin G antibody may provide an important antibacterial defense of mucosal surfaces of the respiratory tract.     

Piliation of Invasive Streptococcus pneumoniae Isolates in the Era before Pneumococcal Conjugate Vaccine Introduction in Malawi

The pneumococcal pilus has been shown to be an important determinant of adhesion and virulence in mouse models of colonization, pneumonia, and bacteremia. A pilus is capable of inducing protective immunity, supporting its inclusion in next-generation pneumococcal protein vaccine formulations. Whether this vaccine target is common among pneumococci in sub-Saharan Africa is uncertain. To define the prevalence and genetic diversity of type I and II pili among invasive pneumococci in Malawi prior to the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into routine childhood immunization, we examined 188 Streptococcus pneumoniae isolates collected between 2002 and 2008 (17% serotype 1). In this region of high disease burden, we found a low frequency of invasive piliated pneumococci (14%) and pilus gene sequence diversity similar to that seen previously in multiple global pneumococcal lineages. All common serotypes with pilus were covered by PCV13 and so we predict that pilus prevalence will be reduced in the Malawian pneumococcal population after PCV13 introduction.     

Influenza-Induced Inflammation Drives Pneumococcal Otitis Media

Influenza A virus (IAV) predisposes individuals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis, or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV-induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes such as OM. Here, we used an infant mouse model, human middle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV promotes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication. This study thus provides the first evidence that inflammation drives pneumococcal replication in the middle ear cavity, which may have important implications for the treatment of pneumococcal OM.     

Pediatric osteoarticular infections caused by Streptococcus pneumoniae before and after the introduction of the heptavalent pneumococcal conjugate vaccine

Streptococcus pneumoniae is an uncommon cause of osteoarticular infections (OAI) in children. The objective of this study was to investigate the clinical and laboratory characteristics of pneumococcal OAI before and after the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7). Data were retrospectively collected from children aged?<16?years who were hospitalized for pneumococcal OAI between 1997 and 2007 in four Parisian teaching hospitals. Forty-three children were included (32 with arthritis and 11 with osteomyelitis) and the median age of these children was 12.5?months (range 3?months to 14?years). Serotypes were available for 19/43 strains (44?%) from 1997 onwards and for 12/13 strains (92?%) from 2005 onwards. Seven unvaccinated children were infected with vaccine serotypes and we observed only one vaccine failure. After the introduction of PCV7, we noted an increase in short-term complications and the emergence of serotype 19A, which was penicillin-intermediate in 86?% of cases. After PCV7 introduction, serotype 19A was the most frequent serotype implicated in pediatric pneumococcal OAI. The 13-valent pneumococcal conjugate vaccine introduced in France in June 2010 should cover the emerging serotype.     

Pneumococcal vaccination among adults with chronic respiratory diseases: a historical overview

Streptococcus pneumoniae, the most common cause of community-acquired pneumonia, remains a major cause of morbidity and mortality worldwide. The presence of chronic respiratory illness is a major risk factor for pneumonia, and smoking (the most common cause of chronic obstructive pulmonary disease) is also an important risk factor for pneumonia and invasive pneumococcal disease. There are currently three established approaches to antipneumococcal vaccination: capsular polysaccharide pneumococcal vaccines (recommended for adults and some children at risk), protein-polysaccharide conjugate pneumococcal vaccines (classically recommended for infants and young children and currently under evaluation for adults aged 50 years or older for the prevention of invasive disease) and experimental protein-based pneumococcal vaccines (under investigation in animal models). Although patients with chronic respiratory diseases are commonly described as an at-risk population for pneumococcal infections, studies on pneumococcal vaccination efficacy in such patients are very limited and vaccination effectiveness remains controversial. This paper reviews available data on the efficacy and effectiveness of polysaccharide pneumococcal vaccination among adults with chronic respiratory diseases.     

Age-stratified prevalences of pneumococcal-serotype-specific immunoglobulin G in England and their relationship to the serotype-specific incidence of invasive pneumococcal disease prior to the introduction of the pneumococcal 7-valent conjugate vaccine

Recent changes to the childhood immunization schedule in the United Kingdom have resulted in the inclusion of the 7-valent pneumococcal conjugate vaccine. However, the seroprevalence of pneumococcal antibodies in the population was unknown. To address this, we measured pneumococcal, age-specific immunoglobulin G (IgG) concentrations specific for nine serotypes by an assay run on the Bioplex platform, using 2,664 serum samples collected in England from 2000 to 2004. The lowest concentrations of IgG specific to all serotypes and the proportions of serotype-specific IgG concentrations of ≥0.35 μg/ml were observed in children aged <1 year. From 1 year on, there was a general increase in antibody levels with increasing age, and they remained high in adults. Maternal antibody was detected in young children aged <36 days but waned rapidly. Comparison of the age-specific seroprevalence of serotype-specific IgG to the serotype-specific incidence of invasive pneumococcal disease demonstrated a general inverse relationship for all age groups except the elderly. These data provide a baseline for natural immunity to the pneumococcal serotypes analyzed prior to the introduction of pneumococcal conjugate vaccine in the United Kingdom.     

High invasiveness of pneumococcal serotypes included in the new generation of conjugate vaccines

The implementation of the seven-valent pneumococcal conjugate vaccine, PCV7, has resulted in significant changes in the pneumococcal population being carried and causing disease. We aimed to determine the invasive disease potential of serotypes causing invasive paediatric disease in the era of conjugate vaccines in Catalonia, Spain, and their potential coverage by the 13-valent pneumococcal conjugate vaccine, PCV13. As a secondary objective, we evaluated whether implementation of PCV7 had resulted in significant changes in the invasive disease potential of the most frequent serotypes circulating in the area. Two pneumococcal collections obtained from children admitted to the University Hospital Sant Joan de Déu (Barcelona, Spain) between 2007 and 2011 were compared: a first set of 159 invasive disease isolates, and a second set of 209 nasopharyngeal isolates recovered from healthy children admitted for minor surgery. The most common invasive serotypes were 1 (24.5%, n = 39), 19A (21.2%, n = 34), 5 (8.8%, n = 14), 7F (8.8%, n = 14) and 3 (5%, n = 8). The most common serotypes in carriage were 19A (10%, n = 21), 6C (9%, n = 19), 23B (8.1%, n = 17), 6A (7.6%, n = 16) and 19F (6.2%, n = 13). A significantly higher propensity to cause invasive disease was observed for serotypes 1, 3, 5, 7F and 19A, all of which are included in PCV13. After false-discovery-rate correction, the results were robust for serotypes 1, 5, 7F and 19A. Non-PCV13 serotypes had a low invasive disease potential. Our data reinforce the need for continuous surveillance and should encourage efforts to introduce universal vaccination with PCV13 in children in our region.     

Impact of a Pneumococcal Conjugate Vaccination Program on Carriage among Children in Norway

In July 2006, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in Norway with a reduced (2 doses + 1 boost) dose schedule. Post-PCV7 shifts in pneumococcal reservoirs were assessed by two point prevalence studies of nasopharyngeal colonization among children in day care centers, before (2006) and after (2008) widespread use of PCV7. Nasopharyngeal swabs were obtained from 1,213 children, 611 in 2006 and 602 in 2008. A total of 1,102 pneumococcal isolates were recovered. Serotyping, multilocus sequence typing, and antimicrobial drug susceptibility testing were performed on all isolates. Although carriage of PCV7 serotypes decreased among both vaccinated and unvaccinated children, the overall prevalence of pneumococcal carriage remained high (80.4%) after vaccine introduction. The pneumococcal populations were diverse, and in the shift toward non-PCV7 serotypes, expansion of a limited number of established clonal complexes was observed. While non-antimicrobial-susceptible clones persisted among PCV7 serotypes, antimicrobial resistance did not increase among non-PCV7 serotypes. Direct and indirect protection of PCV7 against nasopharyngeal colonization was inferred from an overall decrease in carriage of PCV7 serotypes. No preference was found for nonsusceptible clones among the replacing non-PCV7 serotypes.Streptococcus pneumoniae is a leading cause of otitis media, sinusitis, pneumonia, and meningitis worldwide (35). S. pneumoniae colonizes the nasopharynx and is considered a part of the normal flora in early childhood (1). Following the implementation of childhood vaccination with the seven-valent conjugated pneumococcal vaccine (PCV7), reports from several locations have described declines in carriage of the seven serotypes included in the vaccine, i.e., serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (4, 6, 13, 19, 24). Due to reduced transmission of PCV7 serotypes, the incidence of invasive pneumococcal disease (IPD) declines also among the unvaccinated, which is an indirect effect of conjugate pneumococcal vaccination. However, the effect of PCV7 may in part be eroded over time as non-PCV7 serotypes emerge as a more frequent cause of IPD (11). In the United States, non-antimicrobial-susceptible clones seem to have an advantage among the emerging and expanding non-PCV7 serotypes, both in asymptomatic colonization and IPD (10, 20). This is primarily demonstrated by increasing incidence rates of drug-resistant clones of serotype 19A (23).PCV7 was introduced into the Norwegian childhood vaccination program in a dose schedule of two doses and one boost (2 + 1 dose schedule) in July 2006 and has been offered free of charge to all children born in 2006 and since. A high level of effectiveness of the vaccination program among children was demonstrated quickly after vaccine introduction, and the effect included a decline in IPD caused by erythromycin-resistant S. pneumoniae (34).As part of the Norwegian surveillance of PCV7 introduction, a cross-sectional study of nasopharyngeal carriage of Streptococcus pneumoniae among children attending day care centers (DCC) was performed in the early autumn of 2006. Data from this study, with exception of data regarding 38 vaccinated participants, have been reported previously (33). To assess the impact of the 2 + 1 dose schedule PCV7 vaccination program on carriage of S. pneumoniae, a follow-up was performed in 2008. Serotyping, antimicrobial susceptibility testing, and genotyping of the isolates from 2008 were performed, and the results were compared to those from analyses of the previous collection. Shifts in clonal compositions of the pneumococcal populations were analyzed and are reported here.Limited outpatient use of antimicrobial agents is recommended in Norway, and the levels of nonsusceptibility to antimicrobials among S. pneumoniae isolates from both local infections and IPD are low (25). Hence, emphasis has been put on post-PCV7 changes in nonsusceptibility to antimicrobials and nonsusceptible clones in a setting with limited antimicrobial use and resistance.     

Pneumococcal conjugate vaccines: emerging clinical information and its implications

Since 2000, when the first pneumococcal conjugate vaccine was introduced into routine use in the USA, it has had a substantial impact on invasive pneumococcal disease both in the immunized and nonimmunized population. It has also been shown to reduce pneumonia and otitis in young children and has reduced antibiotic nonsusceptible pneumococcal infections. In the USA, three primary doses and a booster dose are recommended (a so-called '3 + 1 schedule'). Some countries have or will soon introduce routine immunization with fewer doses, with either two primary doses and a booster dose ('2 + 1 schedule') or no booster dose ('3 + 0 schedule'). Some serotypes produce less antibody in a two-dose compared with a three-dose primary series. The booster dose may also be important in reducing nasopharyngeal carriage, hence absence of a booster dose may reduce indirect protection. It remains to be seen whether these schedule changes will reduce vaccine effectiveness within the population. Important future developments include extending the number of serotypes included in the vaccine and the possible extension of use into adults in whom indirect protection has been useful, but not as extensive as might be possible with direct immunization.     

Detection of Streptococcus pneumoniae and identification of pneumococcal serotypes by real-time polymerase chain reaction using blood samples from Italian children ≤ 5 years of age with community-acquired pneumonia

Streptococcus pneumoniae is a leading cause of severe life-threatening infections. Laboratory identification and serotyping of this pathogens is desirable to monitor vaccine impact and coverage; however, especially in pediatric patients, the yield of traditional microbiological diagnostic procedures can be very low. The aim of this study was to develop real-time polymerase chain reaction (PCR)-based assays to be performed directly on blood samples to identify the most common capsular serotypes causing pneumonia in Italian children (≤ 5 years of ages) after the introduction of the 7-valent conjugate vaccine. Our real-time PCR-based assays showed high sensitivity (at least 35 fg of pneumococcal DNA), and they were validated with 49 well-characterized pneumococcal isolates, 8 nonpneumococcal isolates, 13 simulated blood clinical samples loaded with S. pneumoniae of known serotypes, and 46 blood clinical samples. All the strains tested and the simulated blood clinical samples were correctly typed by the technique. Real-time PCR allowed serotyping in 37/46 children ≤ 5 years of age (80.4%) in whom pneumonia was diagnosed in four Italian hospitals. Non-PCV7 serotypes accounted for at least 47.8% (22/46) of cases, serotype 19A being the most common (34.7%, 16/46). Although, it is not known at present whether the incidence of 19A serotype is attributable to the use of PCV7 only, expanding pneumococcal serotype coverage has clearly the potential to prevent a larger number of pneumonias in Italian children less than ≤ 5 years of age. Molecular methods are of increasing importance in the diagnosis of pneumococcal pneumonia and in monitoring serotype distribution and replacement.     

Early Changes in the Serotype Distribution of Invasive Pneumococcal Isolates from Children after the Introduction of Extended-valent Pneumococcal Conjugate Vaccines in Korea, 2011-2013

This study was performed to measure early changes in the serotype distribution of pneumococci isolated from children with invasive disease during the 3-year period following the introduction of 10- and 13-valent pneumococcal conjugate vaccines (PCVs) in Korea. From January 2011 to December 2013 at 25 hospitals located throughout Korea, pneumococci were isolated among children who had invasive pneumococcal disease (IPD). Serotypes were determined using the Quellung reaction, and the change in serotype distribution was analyzed. Seventy-five cases of IPD were included. Eighty percent of patients were aged 3-59 months, and 32% had a comorbidity that increased the risk of pneumococcal infection. The most common serotypes were 19A (32.0%), 10A (8.0%), and 15C (6.7%). The PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, and 6A) accounted for 14.7% of the total isolates and the PCV13 minus PCV7 types (1, 3, 5, 7F and 19A) accounted for 32.0% of the total isolates. Serotype 19A was the only serotype in the PCV13 minus PCV7 group. The proportion of serotype 19A showed decreasing tendency from 37.5% in 2011 to 22.2% in 2013 (P = 0.309), while the proportion of non-PCV13 types showed increasing tendency from 45.8% in 2011 to 72.2% in 2013 (P = 0.108). Shortly after the introduction of extended-valent PCVs in Korea, serotype 19A continued to be the most common serotype causing IPD in children. Subsequently, the proportion of 19A decreased, and non-vaccine serotypes emerged as an important cause of IPD. The impact of extended-valent vaccines must be continuously monitored.     

Pediatric invasive pneumococcal disease in the United States in the era of pneumococcal conjugate vaccines

Invasive infections caused by Streptococcus pneumoniae continue to be a major cause of morbidity and mortality worldwide, especially in children under 5 years of age. In the United States, 90% of invasive pneumococcal infections in children are caused by 13 serotypes of S. pneumoniae. The licensure (in 2000) and subsequent widespread use of a heptavalent pneumococcal conjugate vaccine (PCV7) have had a significant impact on decreasing the incidence of serious invasive pneumococcal disease (IPD) in all age groups, especially in children under 2 years of age. However, the emergence of replacement non-PCV7 serotypes, especially serotype 19A, has resulted in an increase in the incidence of serious and invasive infections. In 2010, a 13-valent PCV was licensed in the United States. However, the impact that this vaccine will have on IPD remains to be seen. The objectives of this review are to discuss the epidemiology of serious and invasive pneumococcal infections in the United States in the PCV era and to review some of the pneumococcal vaccines that are in development.     

Global prevailing and emerging pediatric pneumococcal serotypes

Streptococcus pneumoniae is the leading cause of vaccine-preventable deaths among children younger than 5 years of age worldwide. The 7-valent pneumococcal conjugate vaccine (PCV7) is currently licensed in more than 90 countries and has contributed to significant declines in the incidence of invasive pneumococcal disease (IPD). Recent studies report an increased incidence of IPD caused by non-PCV7 vaccine serotypes (NVTs). Seroepidemiology of IPD caused by NVTs following the introduction of PCV7 is of interest, and this article provides a comprehensive global summary of the prevailing and emerging serotypes causing IPD in children. Currently, globally emerging or persistent NVTs include serotypes 1, 3, 5, 6A, 7F and 19A. Serotypes included in the recently licensed 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13) account for pneumococcal disease burdens in most developed countries of 65-85% and 80-90%, respectively. The seroprevalence of NVTs after widespread use of PCV10 and PCV13 requires ongoing monitoring.     

Nationwide study of recurrent invasive pneumococcal infections in a population with a low prevalence of human immunodeficiency virus infection

Recurrent invasive infections caused by Streptococcus pneumoniae are rare, and often considered to be indicative of serious underlying illness. However, the prevalence of this problem, and the relevance of specific predisposing conditions, can be hard to assess, since many of the studies are based on specific risk groups. A population-based study of recurrent invasive pneumococcal disease in Iceland during the 30-year period 1975-2004 was performed. Clinical information, including mortality and vaccine use, was analysed retrospectively. Invasive pneumococcal isolates were serotyped and susceptibility testing was performed. During this period, 36 (4.4%) of 819 patients who survived an initial infection experienced recurrence, with a median time between episodes of 9.7 months. Pneumonia with bacteraemia was the most common clinical diagnosis (48% of cases), followed by bacteraemia without a clear focus (21%) and meningitis (13%). Most (94%) of the patients had identifiable predisposing conditions, most commonly, multiple myeloma in adults, and antibody deficiencies in children. Compared with children, adults were more likely to present with pneumonia (65% vs. 18%; p 0.0001). No significant change in the 30-day mortality rate was observed during the three decades of the study. Only 26% of eligible patients received pneumococcal vaccination. Patients with recurrent invasive pneumococcal disease should be investigated thoroughly for underlying diseases. Greater use of pneumococcal vaccines should be encouraged among high-risk patients. More effective preventive and therapeutic measures are needed to improve outcomes.