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1.  Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study 
PLoS Medicine  2011;8(4):e1001017.
A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.
Background
We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines.
Methods and Findings
Nasopharyngeal swabs were taken from children <5 y old and family members (n = 400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case∶carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76–1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence.
Conclusion
Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases—major causes of illness and death in children and adults worldwide—are caused by Streptococcus pneumoniae, a bacterium that often colonizes the nasopharynx (the area of the throat behind the nose). Carriage of S. pneumoniae bacteria does not necessarily cause disease. However, these bacteria can cause local, noninvasive diseases such as ear infections and sinusitis and, more rarely, they can spread into the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, and meningitis, respectively. Although these invasive pneumococcal diseases (IPDs) can be successfully treated if administered early, they can be fatal. Consequently, it is better to protect people against IPDs through vaccination than risk infection. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules (antigens) that it recognizes as foreign.
Why Was This Study Done?
There are more than 90 S. pneumoniae variants or “serotypes” characterized by different polysaccharide (complex sugar) coats, which trigger the immune response against S. pneumoniae and determine each serotype's propensity to cause IPD. The pneumococcal conjugate vaccine PCV7 contains polysaccharides (linked to a protein carrier) from the seven serotypes mainly responsible for IPD in the US in 2000 when routine childhood PCV7 vaccination was introduced in that country. PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes, which means that, after vaccination, previously uncommon, nonvaccine serotypes can colonize the nasopharynx. If these serotypes have a high invasiveness potential, then “serotype replacement” could reduce the benefits of vaccination. In this cross-sectional study (a study that investigates the relationship between a disease and an intervention in a population at one time point), the researchers investigate the effect of the UK PCV7 vaccination program (which began in 2006) on serotype-specific carriage and IPD in England to understand the role of PCV7 in serotype replacement and to predict the likely impact of vaccines containing additional serotypes (higher valency vaccines).
What Did the Researchers Do and Find?
The researchers examined nasopharyngeal swabs taken from PCV7-vaccinated children and their families for S. pneumoniae, determined the serotype of any bacteria they found, and compared the proportion of people carrying S. pneumoniae (carrier prevalence) and the distribution of serotypes in this study population and in a similar population that was studied in 2000/2001, before the PCV vaccination program began. Overall, there was no statistically significant change in carrier prevalence, but carriage of vaccine serotypes decreased in vaccinated children and their contacts whereas carriage of nonvaccine serotypes increased. The serotype-specific case-to-carrier ratios (CCRs; a measure of serotype invasiveness that was estimated using national IPD data) of the replacing serotypes were generally lower than those of the original serotypes, which resulted in a net reduction in IPD in children. Moreover, before PCV7 vaccination began, PCV7-included serotypes were responsible for similar proportions of pneumococcal carriage and disease; afterwards, the additional serotypes present in the higher valency vaccines PVC10 and PVC13 were responsible for a higher proportion of disease than carriage. Finally, three serotypes not present in the higher valency vaccines with outstandingly high CCRs (high invasiveness potential) are identified.
What Do These Findings Mean?
These findings document the serotype replacement of S. pneumoniae that has occurred in England since the introduction of PCV7 vaccination and highlight the importance of assessing the effects of pneumococcal vaccines on carriage as well as on IPDs. Because the additional serotypes included in PCV10 and PCV13 have high CCRs but low carriage prevalence and because most of the potential replacement serotypes have low CCRs, these findings suggest that the introduction of higher valency vaccines should further reduce the occurrence of invasive disease with limited risk of additional serotype replacement. However, the emergence of a few serotypes that have high CCRs but are not included in PCV10 and PCV13 might mitigate the benefits of higher valency vaccines. In other words, although the recent introduction of PCV13 into UK vaccination schedules is likely to have an incremental benefit on the reduction of IPD compared to PCV7, this benefit might be offset by increases in the carriage of some high CCR serotypes. These serotypes should be considered for inclusion in future vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001017.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal diseases
The UK Health Protection Agency provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
doi:10.1371/journal.pmed.1001017
PMCID: PMC3071372  PMID: 21483718
2.  Nasopharyngeal carriage, serotype distribution and antimicrobial resistance of Streptococcus pneumoniae among children from Brazil before the introduction of the 10-valent conjugate vaccine 
BMC Infectious Diseases  2013;13:318.
Background
Streptococcus pneumoniae remains a major cause of childhood morbidity and mortality worldwide. Nasopharyngeal colonization plays an important role in the development and transmission of pneumococcal diseases, and infants and young children are considered to be the main reservoir of this pathogen. The aim of this study was to evaluate the rates and characteristics associated with nasopharyngeal carriage, the distribution of serotypes and the antimicrobial resistance profiles of Streptococcus pneumoniae among children in a large metropolitan area in Brazil before the introduction of the 10-valent pneumococcal conjugate vaccine.
Methods
Between March and June 2010, nasopharyngeal swabs were collected from 242 children aged <6 years attending one day care center and the emergency room of a pediatric hospital. Pneumococcal isolates were identified by conventional methods and serotypes were determined by a sequential multiplex PCR assay and/or the Quellung reaction. The antimicrobial susceptibilities of the pneumococci were assessed by the disk diffusion method. MICs for erythromycin and penicillin were also performed. Erythromycin resistance genes were investigated by PCR.
Results
The overall colonization rate was 49.2% and it was considerably higher among children in the day care center. Pneumococcal carriage was more common among day care attenders and cohabitants with young siblings. The most prevalent serotypes were 6B, 19F, 6A, 14, 15C and 23F, which accounted for 61.2% of the isolates. All isolates were susceptible to clindamycin, levofloxacin, rifampicin and vancomycin. The highest rate of non-susceptibility was observed for sulphamethoxazole-trimethoprim (51.2%). Penicillin non-susceptible pneumococci (PNSP) accounted for 27.3% of the isolates (MICs of 0.12-4 μg/ml). Penicillin non-susceptibility was strongly associated with serotypes 14 and 23F. Hospital attendance and the presence of respiratory or general symptoms were frequently associated with PNSP carriage. The two erythromycin-resistant isolates (MICs of 2 and 4 μg/ml) belonged to serotype 6A, presented the M phenotype and harbored the mef(A/E) gene.
Conclusions
Correlations between serotypes, settings and penicillin non-susceptibility were observed. Serotypes coverage projected for the 10-valent pneumococcal conjugate vaccine was low (45.5%), but pointed out the potential reduction of PNSP nasopharyngeal colonization by nearly 20%.
doi:10.1186/1471-2334-13-318
PMCID: PMC3718621  PMID: 23849314
Streptococcus pneumoniae; Nasopharyngeal carriage; Serotypes; Antimicrobial resistance; Pneumococcal conjugate vaccines
3.  High carriage rate of high-level penicillin-resistant Streptococcus pneumoniae in a Taiwan kindergarten associated with a case of pneumococcal meningitis 
Background
The Taiwan19F-14 Streptococcus pneumoniae clone and its variants are being found with increasing frequency in the Asia-Pacific region. A 5-year old child with S. pneumoniae meningitis caused by a high-level penicillin resistant strain (MIC = 4 μg/ml) was admitted to a hospital in southern Taiwan. We carried out a study to determine the potential source of this strain.
Methods
Nasopharyngeal cultures were obtained from all children attending the same kindergarten as the index case. To determine their relatedness all isolates were compared by serotype, antimicrobial susceptibility profile and pulsed field gel electrophoresis (PFGE).
Results
A high proportion of the children including the index case (32/78, 41.0%) carried S. pneumoniae in their nasopharynx (NP). The most common serotype was 19F (13/32, 40.6%). The PFGE types of the 19F serotype isolates obtained from the patient's blood, CSF and NP were identical and were related to 11 other serotype 19F NP isolates including 10 that were indistinguishable from the Taiwan19F-14 clone. All 14 isolates had similar high-level penicillin and multi-drug resistance. The serotypes of the other 19 NP isolates included 6A (2), 6B (10), 23F (5), 9V (1) and 3 (1). The overall rate of penicillin resistance in these S. pneumoniae from these children was 87.5% (28/32), with an MIC50 of 2 and MIC90 of 4 ug/ml. In addition, multi-drug resistant-isolates (isolates resistant to 3 different classes of antimicrobials) accounted for 87.5% (28/32) of all isolates.
Conclusion
The high carriage rate of high-level penicillin- and multi-drug- resistant S. pneumoniae in a kindergarten associated with a case of pneumococcal meningitis emphasizes the need for restraint in antibiotic use and consideration of childhood immunization with conjugate pneumococcal vaccine to prevent the further spread of resistant S. pneumoniae in Taiwan.
doi:10.1186/1471-2334-5-96
PMCID: PMC1289284  PMID: 16259643
4.  Pneumococcal Capsular Polysaccharide Structure Predicts Serotype Prevalence 
PLoS Pathogens  2009;5(6):e1000476.
There are 91 known capsular serotypes of Streptococcus pneumoniae. The nasopharyngeal carriage prevalence of particular serotypes is relatively stable worldwide, but the host and bacterial factors that maintain these patterns are poorly understood. Given the possibility of serotype replacement following vaccination against seven clinically important serotypes, it is increasingly important to understand these factors. We hypothesized that the biochemical structure of the capsular polysaccharides could influence the degree of encapsulation of different serotypes, their susceptibility to killing by neutrophils, and ultimately their success during nasopharyngeal carriage. We sought to measure biological differences among capsular serotypes that may account for epidemiological patterns. Using an in vitro assay with both isogenic capsule-switch variants and clinical carriage isolates, we found an association between increased carriage prevalence and resistance to non-opsonic neutrophil-mediated killing, and serotypes that were resistant to neutrophil-mediated killing tended to be more heavily encapsulated, as determined by FITC-dextran exclusion. Next, we identified a link between polysaccharide structure and carriage prevalence. Significantly, non-vaccine serotypes that have become common in vaccinated populations tend to be those with fewer carbons per repeat unit and low energy expended per repeat unit, suggesting a novel biological principle to explain patterns of serotype replacement. More prevalent serotypes are more heavily encapsulated and more resistant to neutrophil-mediated killing, and these phenotypes are associated with the structure of the capsular polysaccharide, suggesting a direct relationship between polysaccharide biochemistry and the success of a serotype during nasopharyngeal carriage and potentially providing a method for predicting serotype replacement.
Author Summary
Streptococcus pneumoniae, or pneumococcus, is an important pathogen worldwide and causes a wide range of diseases, mostly in young children and the elderly. There are 91 serotypes of pneumococcus, each of which produces a unique polysaccharide, called the capsule, that attaches to the bacterial surface and prevents it from being cleared by the host. The serotypes differ greatly in their prevalence in the human population. There is currently a vaccine, effective in infancy, which targets seven clinically important serotypes, but several types not covered by the vaccine are beginning to increase in carriage frequency. As a result, it is critical to understand why some serotypes are frequently carried in the human population while others are not. In this study, we find that the high-prevalence serotypes tend to be more heavily encapsulated and more resistant to killing by neutrophils. Significantly, we find that the biochemical properties of the different polysaccharides can be used to predict their carriage frequency both before and after introduction of the vaccine. These results provide a biologically plausible explanation for differences in prevalence between serotypes.
doi:10.1371/journal.ppat.1000476
PMCID: PMC2689349  PMID: 19521509
5.  Serotypes, Clones, and Mechanisms of Resistance of Erythromycin-Resistant Streptococcus pneumoniae Isolates Collected in Spain▿  
The aim of this study was to analyze the distributions of antibiotic susceptibility patterns, serotypes, phenotypes, genotypes, and macrolide resistance genes among 125 nonduplicated erythromycin-resistant Streptococcus pneumoniae clinical isolates collected in a Spanish point prevalence study. The prevalence of resistance to macrolides in this study was 34.7%. Multiresistance (to three or more antimicrobials) was observed in 81.6% of these strains. Among 15 antimicrobials studied, cefotaxime, moxifloxacin, telithromycin, and quinupristin-dalfopristin were the most active drugs. The most frequent serotypes of erythromycin-resistant isolates were 19F (25%), 19A (17%), 6B (12%), 14 (10%), and 23F (10%). Of the 125 strains, 109 (87.2%) showed the MLSB phenotype [103 had the erm(B) gene and 6 had both erm(B) and mef(E) genes]. Sixteen (12.8%) strains showed the M phenotype [14 with mef(E) and 2 with mef(A)]. All isolates were tested by PCR for the presence of the int, xis, tnpR, and tnpA genes associated with conjugative transposons (Tn916 family and Tn917). Positive detection of erm(B), tet(M), int, and xis genes related to the Tn916 family was found in 77.1% of MLSB phenotype strains. In 16 strains, only the tndX, erm(B), and tet(M) genes were detected, suggesting the presence of Tn1116, a transposon recently described for Streptococcus pyogenes. Five clones, namely, Sweden15A-25, clone19F ST87, Spain23F-1, Spain6B-2, and clone19A ST276, accounted for half of the MLSB strains. In conclusion, the majority of erythromycin-resistant pneumococci isolated in Spain had the MLSB phenotype, belonged to multiresistant international clones, and carried the erm(B), tet(M), xis, and int genes, suggesting the spread of transposons of the Tn916 family.
doi:10.1128/AAC.00157-07
PMCID: PMC2043242  PMID: 17606677
6.  Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial 
PLoS Medicine  2010;7(12):e1000377.
Jeremy Keenan and colleagues report that during a cluster-randomized clinical trial in Ethiopia, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to receive azithromycin compared with untreated control communities.
Background
It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.
Methods and Findings
In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.
Conclusions
This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.
Trial registration
www.ClinicalTrials.gov NCT00322972
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 1928, Alexander Fleming discovered penicillin, the first antibiotic (a drug that kills bacteria). By the early 1940s, scientists were able to make large quantities of penicillin and, in the following decades, several other classes of powerful antibiotics were discovered. For example, erythromycin—the first macrolide antibiotic—was developed in the early 1950s. For a time, it looked like bacteria and the diseases that they cause had been defeated. But bacteria rapidly become resistant to antibiotics. Under the “selective pressure” of an antibiotic, bacteria that have acquired a random change in their DNA that allows them to survive in the antibiotic's presence outgrow nonresistant bacteria. What's more, bacteria can transfer antibiotic resistance genes between themselves. Nowadays, antibiotic resistance is a major public health concern. Almost every type of disease-causing bacteria has developed resistance to one or more antibiotic in clinical use and multi-drug resistant bacteria are causing outbreaks of potentially fatal diseases in hospitals and in the community.
Why Was This Study Done?
Although epidemiological studies (investigations of the causes, distribution, and control of disease in population) show a correlation between antibiotic use and antibiotic resistance in populations, such studies cannot prove that antibiotic use actually causes antibiotic resistance. It could be that the people who use more antibiotics share other characteristics that increase their chance of developing antibiotic resistance (so-called “confounding”). A causal link between antibiotic use and the development of antibiotic resistance can only be established by doing a randomized controlled trial. In such trials, groups of individuals are chosen at random to avoid confounding, given different treatments, and outcomes in the different groups compared. Here, the researchers undertake a randomized clinical trial to assess whether macrolide resistance is higher in communities treated with azithromycin for trachoma than in untreated communities. Azithromycin—an erythromycin derivative—is used to treat common bacterial infections such as middle ear infections caused by Streptococcus pneumoniae. Trachoma—the world's leading infectious cause of blindness—is caused by Chlamydia trachomatis. The World Health Organization's trachoma elimination strategy includes annual azithromycin treatment of at-risk communities.
What Did the Researchers Do and Find?
In this cluster-randomized trial (a study that randomly assigns groups of people rather than individuals to different treatments), 12 Ethiopian communities received mass azithromycin treatment of children aged 1–10 years old at 0, 3, 6, and 9 months, and 12 control communities received the antibiotic only at 12 months. The researchers took nasopharyngeal (nose and throat) swabs from randomly selected treated children at 0 and 12 months and from randomly selected control children at 12 months. They isolated S. pneumoniae from the swabs and tested the isolates for antibiotic susceptibility. 70%–80% of the children tested had S. pneumoniae in their nose or throat. In the treated group, 3.6% of monitored children were carrying azithromycin-resistant S. pneumoniae at 0 months, whereas 46.9% were doing so at 12 months—a statistically significant increase. Only 9.2% of the monitored children in the untreated group were carrying azithromycin-resistant S. pneumoniae at 12 months, a significantly lower prevalence than in the treated group. Importantly, there was no resistance to penicillin in any S. pneumoniae isolates obtained from the treated children at 0 or 12 months; one penicillin-resistant isolate was obtained from the control children.
What Do These Findings Mean?
These findings indicate that macrolide resistance is higher in nasopharyngeal S. pneumoniae in communities receiving intensive azithromycin treatment than in untreated communities. Thus, they support the idea that frequent antibiotic use selects for antibiotic resistance in populations. Although the study was undertaken in Ethiopian communities with high rates of nasopharyngeal S. pneumoniae carriage, this finding is likely to be generalizable to other settings. Importantly, these findings have no bearing on current trachoma control activities, which use less frequent antibiotic treatments and are less likely to select for azithromycin resistance. The lack of any increase in penicillin resistance, which is usually the first-line therapy for S. pneumoniae infections, is also reassuring. However, although these findings suggest that the benefits of mass azithromycin treatment for trachoma outweigh any potential adverse affects, they nonetheless highlight the importance of continued monitoring for the secondary effects of mass antibiotic distributions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000377.
The Bugs and Drugs website provides information about antibiotic resistance and links to other resources
The US National Institute of Allergy and Infectious Diseases provides information on antimicrobial drug resistance and on diseases caused by S. pneumoniae (pneumococcal diseases)
The US Centers for Disease Control and Prevention also have information on antibiotic resistance (in English and Spanish)
The World Health Organization has information about the global threat of antimicrobial resistance and about trachoma (in several languages)
More information about the trial described in this paper is available on ClinicalTrials.gov
doi:10.1371/journal.pmed.1000377
PMCID: PMC3001893  PMID: 21179434
7.  Distribution of Serotypes, Genotypes, and Resistance Determinants among Macrolide-Resistant Streptococcus pneumoniae Isolates ▿  
Macrolide resistance in Streptococcus pneumoniae has emerged as an important clinical problem worldwide over the past decade. The aim of this study was to analyze the phenotypes (serotype and antibiotic susceptibility), genotypes (multilocus sequence type [MLST] and antibiotic resistance gene/transposon profiles) among the 31% (102/328) of invasive isolates from children in New South Wales, Australia, in 2005 that were resistant to erythromycin. Three serotypes—19F (47 isolates [46%]), 14 (27 isolates [26%]), and 6B (12 isolates [12%])—accounted for 86 (84%) of these 102 isolates. Seventy four (73%) isolates had the macrolide-lincosamide-streptogramin B (MLSB) resistance phenotype and carried Tn916 transposons (most commonly Tn6002); of these, 73 (99%) contained the erythromycin ribosomal methylase gene [erm(B)], 34 (47%) also carried the macrolide efflux gene [mef(E)], and 41 (55%) belonged to serotype 19F. Of 28 (27%) isolates with the M phenotype, 22 (79%) carried mef(A), including 16 (57%) belonging to serotype 14, and only six (19%) carried Tn916 transposons. Most (84%) isolates which contained mef also contained one of the msr(A) homologues, mel or msr(D); 38 of 40 (95%) isolates with mef(E) (on mega) carried mel, and of 28 (39%) isolates with mef(A), 10 (39%) carried mel and another 11(39%) carried msr(D), on Tn1207.1. Two predominant macrolide-resistant S. pneumoniae clonal clusters (CCs) were identified in this population. CC-271 contained 44% of isolates, most of which belonged to serotype 19F, had the MLSB phenotype, were multidrug resistant, and carried transposons of the Tn916 family; CC-15 contained 23% of isolates, most of which were serotype 14, had the M phenotype, and carried mef(A) on Tn1207.1. Erythromycin resistance among S. pneumoniae isolates in New South Wales is mainly due to the dissemination of multidrug-resistant S. pneumoniae strains or horizontal spread of the Tn916 family of transposons.
doi:10.1128/AAC.01268-09
PMCID: PMC2825966  PMID: 20065057
8.  Nasopharyngeal Carriage Rate and Serotypes of Streptococcus pneumoniae and Antimicrobial Susceptibility in Healthy Korean Children Younger than 5 Years Old: Focus on Influence of Pneumococcal Conjugate Vaccination 
Infection & Chemotherapy  2013;45(1):76-84.
Background
Even after pneumococcal vaccination introduction, Streptococcus pneumoniae (pneumoccocus) is still an important cause of respiratory and invasive severe infection. Pneumococcus is resided in nasal mucosa and local or systemic infection begins with the nasal mucosa damage. We studied the indirect effect of pneumococcal conjugate vaccine (PCV) on pneumococcal nasopharyngeal carriage rates, serotypes and antimicrobial susceptibility between vaccinate and non-vaccinated children.
Materials and Methods
From January 2010 to October 2010, 379 healthy children under 5 years old from three university hospitals were recruited. Fully vaccinated children over 3 time doses of PCV and children with no vaccination history of PCV were enrolled, and nasopharyngeal aspirations were obtained from these children. Serotypes using multibead serotyping assay with multiplex PCR and antimicrobial susceptibility was analyzed. Antimicrobial susceptibilities were determined by the CLIS guideline.
Results
Two hundred seventy six children were received pneumococcal vaccination while 103 were not. 137 pneumococci were isolated from nasopharyngeal aspiration specimens. Nasal carriage rate was significantly low in vaccinated group (P-value; 0.001). Nasopharyngeal carriage rate was 28.6% (79/276) in vaccinate group and 56.3% (58/103) in non-vaccinated group. Among those vaccinated group, 13.0% (36/276) of the serotypes were vaccine or vaccine related type with the most common type 19F. In contrast, 31.1% (32/103) of the serotypes in non vaccinated group were vaccine or vaccine related type with the most common type 6A. The resistant rate of penicillin was 90.5%. For antimicrobial susceptibility, amoxicillin and amoxicillin/clavulanate showed high susceptibility (73.0%), but 19F and 19A serotypes were all resistant against amoxicillin.
Conclusions
High nasopharyngeal carriage rate in non vaccinated group corresponded to the result of past study. However, 19F and 19A still came up as problematic serotypes with a high carriage rate and antimicrobial resistance in both vaccinated and non vaccinated groups. Also, this study showed that the resistance rate of primary oral antimicrobial agents was increased in compared to past. For solving these problems, the selective antimicrobial use with establishment of high dose amoxicillin/clavulanate regimen and active PCV immunization should be needed. Furthermore, pneumococcal carriage and serotype study concerning with antimicrobial susceptibility should be conducted in the future in 10 or 13-valent PCV received children.
doi:10.3947/ic.2013.45.1.76
PMCID: PMC3780942  PMID: 24265953
Streptococcus pneumoniae; Serotype; Pneumococcal conjugate vaccine; Oral antimicrobial; Antimicrobial resistance
9.  Nasopharyngeal carriage, antibiogram & serotype distribution of Streptococcus pneumoniae among healthy under five children 
Background & objectives:
Information related to nasopharyngeal carriage of Streptococcus pneumoniae among healthy children is scanty in India. This prospective study was undertaken to determine the presence of asymptomatic nasopharyngeal colonization, assess serogroups/types (SGT) and drug resistance of S. pneumoniae in children below five years of age.
Methods:
A total of 109 male and 81 female children in the age group of three months to five years belonging to different socio-economic classes were enrolled. They were recruited across all age groups from those attending paediatric OPD of a tertiary care and research centre for immunization program. Fifty three isolates identified as pneumococci were tested for their antimicrobial susceptibility pattern by Kirby-Bauer's disc diffusion and E-Test methods. Serotyping was performed by detection of the quelling reaction with specific antiserum.
Result:
The pneumococcal carriage rate in the study population was 27.9 per cent. The isolation rate was associated with age being higher (49.2%) in smaller children (3-12 months) and among male (62.2%). The most prevalent SGTs were 19 followed by 10, 14 and 7; 21 per cent of isolates belonging to serotype 10 (n=7) were 11 (n=4) were not covered in any of the conjugate vaccines currently available in Indian market. Resistance to co-trimoxazole, tetracycline, penicillin and erythromycin was observed in 91 per cent (n=48), 36 per cent (n=19), 17 per cent (n=9) and 9 per cent (n=5) isolates, respectively. All the penicillin resistant isolates were found to be intermediately resistant by E-Test. Multidrug resistance was observed in 19 per cent (n=10) isolates.
Interpretation & conclusions:
High level of antibiotic resistance was present in S. pneumoniae isolated from healthy children below age five. A pneumococcal conjugate vaccine with the prevailing SGTs would help to reduce the pool of antibiotic resistant pneumococci. Continued surveillance of serotypes and tracking susceptibility pattern of S. pneumoniae will help to introduce appropriate vaccination protocols.
PMCID: PMC4216494  PMID: 25297353
Antibiotic resistance; nasopharyngeal carriage; serotypes; Streptococcus pneumoniae
10.  Molecular characteristics of erythromycin-resistant Streptococcus pneumoniae from pediatric patients younger than five years in Beijing, 2010 
BMC Microbiology  2012;12:228.
Background
Streptococcus pneumoniae is the main pathogen that causes respiratory infections in children younger than five years. The increasing incidence of macrolide- and tetracycline-resistant pneumococci among children has been a serious problem in China for many years. The molecular characteristics of erythromycin-resistant pneumococcal isolates that were collected from pediatric patients younger than five years in Beijing in 2010 were analyzed in this study.
Results
A total of 140 pneumococcal isolates were collected. The resistance rates of all isolates to erythromycin and tetracycline were 96.4% and 79.3%, respectively. Of the 135 erythromycin-resistant pneumococci, 91.1% were non-susceptible to tetracycline. In addition, 30.4% of the erythromycin-resistant isolates expressed both the ermB and mef genes, whereas 69.6% expressed the ermB gene but not the mef gene. Up to 98.5% of the resistant isolates exhibited the cMLSB phenotype, and Tn6002 was the most common transposon present in approximately 56.3% of the resistant isolates, followed by Tn2010, with a proportion of 28.9%. The dominant sequence types (STs) in all erythromycin-resistant S. pneumoniae were ST271 (11.9%), ST81 (8.9%), ST876 (8.9%), and ST320 (6.7%), whereas the prevailing serotypes were 19F (19.3%), 23F (9.6%), 14 (9.6%), 15 (8.9%), and 6A (7.4%). The 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) coverage of the erythromycin-resistant pneumococci among the children younger than five years were 45.2% and 62.2%, respectively. ST320 and serotype 19A pneumococci were common in children aged 0 to 2 years. CC271 was the most frequent clonal complex (CC), which accounts for 24.4% of all erythromycin-resistant isolates.
Conclusions
The non-invasive S. pneumoniae in children younger than five years in Beijing presented high and significant resistance rates to erythromycin and tetracycline. The expressions of ermB and tetM genes were the main factors that influence pneumococcal resistance to erythromycin and tetracycline, respectively. Majority of the erythromycin-resistant non-invasive isolates exhibited the cMLSB phenotype and carried the ermB, tetM, xis, and int genes, suggesting the spread of the transposons of the Tn916 family. PCV13 provided higher serotype coverage in the childhood pneumococcal diseases caused by the erythromycin-resistant isolates better than PCV7. Further long-term surveys are required to monitor the molecular characteristics of the erythromycin-resistant S. pneumoniae in children.
doi:10.1186/1471-2180-12-228
PMCID: PMC3534231  PMID: 23043378
11.  Macrolide resistance determinants among Streptococcus pneumoniae isolates from carriers in Central Greece 
BMC Infectious Diseases  2012;12:255.
Background
We sought to characterize the temporal trends in nasopharyngeal carriage of macrolide-resistant pneumococci during a period with increased heptavalent pneumococcal conjugate vaccine (PCV7) coverage in Central Greece.
Methods
Streptococcus pneumoniae isolates were recovered from 2649 nasopharyngeal samples obtained from day-care center attendees in Central Greece during 2005–2009. A phenotypic and genotypic analysis of the isolates was performed, including the identification of macrolide resistance genes mef(A), subclasses mef(A) and mef(E), as well as erm(B).
Results
Of the 1105 typeable S. pneumoniae isolates, 265 (24%) were macrolide-resistant; 22% in 2005, 33.3% in 2006, 23.7% in 2007, and 20.5% in 2009 (P=0.398). Among these macrolide-resistant pneumococci, 28.5% possessed erm(B), 24.3% erm(B)+mef(E), 41.8% mef(E), and 5.3% mef(A). A mef gene as the sole resistance determinant was carried by 31% of macrolide-resistant isolates belonging to PCV7 serotypes and 75.8% of the non-PCV7 serotypes. Across the 4 annual surveillances, pneumococci carrying mef(A) gradually disappeared, whereas serotype 19F isolates carrying both erm(B) and mef(E) persisted without significant yearly fluctuations. Among isolates belonging to non-PCV7 serotypes, macrolide-resistance was observed in those of serotypes 6A, 19A, 10A, 15A, 15B/C, 35F, 35A, and 24F. In 2009, ie 5 years after the introduction of PCV7 in our country, 59% of macrolide-resistant pneumococci belonged to non-PCV7 serotypes.
Conclusions
Across the study period, the annual frequency of macrolide-resistant isolates did not change significantly, but in 2009 a marked shift to non-PCV7 serotypes occurred. Overall, more than half of the macrolide-resistant isolates possessed erm(B) either alone or in combination with mef(E). erm(B) dominated among isolates belonging to PCV7 serotypes, but not among those of non-PCV7 serotypes.
doi:10.1186/1471-2334-12-255
PMCID: PMC3484024  PMID: 23057516
12.  High Nasopharyngeal Carriage of Non-Vaccine Serotypes in Western Australian Aboriginal People Following 10 Years of Pneumococcal Conjugate Vaccination 
PLoS ONE  2013;8(12):e82280.
Background
Invasive pneumococcal disease (IPD) continues to occur at high rates among Australian Aboriginal people. The seven-valent pneumococcal conjugate vaccine (7vPCV) was given in a 2-4-6-month schedule from 2001, with a 23-valent pneumococcal polysaccharide vaccine (23vPPV) booster at 18 months, and replaced with 13vPCV in July 2011. Since carriage surveillance can supplement IPD surveillance, we have monitored pneumococcal carriage in western Australia (WA) since 2008 to assess the impact of the 10-year 7vPCV program.
Methods
We collected 1,500 nasopharyngeal specimens from Aboriginal people living in varied regions of WA from August 2008 until June 2011. Specimens were cultured on selective media. Pneumococcal isolates were serotyped by the quellung reaction.
Results
Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were carried by 71.9%, 63.2% and 63.3% respectively of children <5 years of age, and 34.6%, 22.4% and 27.2% of people ≥5 years. Of 43 pneumococcal serotypes identified, the most common were 19A, 16F and 6C in children <5 years, and 15B, 34 and 22F in older people. 7vPCV serotypes accounted for 14.5% of all serotypeable isolates, 13vPCV for 32.4% and 23vPPV for 49.9%, with little variation across all age groups. Serotypes 1 and 12F were rarely identified, despite causing recent IPD outbreaks in WA. Complete penicillin resistance (MIC ≥2µg/ml) was found in 1.6% of serotype 19A (5.2%), 19F (4.9%) and 16F (3.2%) isolates and reduced penicillin susceptibility (MIC ≥0.125µg/ml) in 24.9% of isolates, particularly 19F (92.7%), 19A (41.3%), 16F (29.0%). Multi-resistance to cotrimoxazole, tetracycline and erythromycin was found in 83.0% of 23F isolates. Among non-serotypeable isolates 76.0% had reduced susceptibility and 4.0% showed complete resistance to penicillin.
Conclusions
Ten years after introduction of 7vPCV for Aboriginal Australian children, 7vPCV serotypes account for a small proportion of carried pneumococci. A large proportion of circulating serotypes are not covered by any currently licensed vaccine.
doi:10.1371/journal.pone.0082280
PMCID: PMC3857785  PMID: 24349245
13.  Identifying an appropriate PCV for use in Senegal, recent insights concerning Streptococcus pneumoniae NP carriage and IPD in Dakar 
BMC Infectious Diseases  2014;14(1):627.
Background
Since 2000, the Global Alliance for Vaccines and Immunization (GAVI) and WHO have supported the introduction of the Pneumococcal Conjugate Vaccine (PCV) in the immunization programs of developing countries. The highest pneumococcal nasopharyngeal carriage rates have been reported (40-60%) in these countries, and the highest incidence and case fatality rates of pneumococcal infections have been demonstrated in Africa.
Methods
Studies concerning nasopharyngeal pneumococcal carriage and pneumococcal infection in children less than 5 years old were conducted in Dakar from 2007 to 2008. Serotype, antibiotic susceptibility and minimum inhibitory concentrations were determined. In addition, among 17 overall publications, 6 manuscripts of the Senegalese literature published from 1972 to 2013 were selected for data comparisons.
Results
Among the 264 children observed, 132 (50%) children generated a nasopharyngeal (NP) positive culture with Streptococcus pneumoniae. The five most prevalent serotypes, were 6B (9%), 19 F (9%), 23 F (7.6%), 14 (7.6%) and 6A (6.8%). Fifteen percent of the strains (20/132) showed reduced susceptibility to penicillin and 3% (4/132) showed reduced susceptibility to anti-pneumococcal fluoroquinolones. Among the 196 suspected pneumococcal infections, 62 (31.6%) Streptococcus pneumoniae were isolated. Serogroup 1 was the most prevalent serotype (21.3%), followed by 6B (14.9%), 23 F (14.9%) and 5 (8.5%). Vaccine coverage for PCV-7, PCV-10 and PCV-13, were 36.2% (17/47), 66% (31/47) and 70.2% (33/47) respectively. Reduced susceptibility to penicillin and anti-pneumococcal fluoroquinolones was 6.4% and 4.3%, respectively, and the overall lethality was 42.4% (14/33).
Conclusions
This study confirms a high rate of carriage and disease caused by Streptococcus pneumoniae serotypes contained within the current generation of pneumococcal conjugate vaccines and consistent with reports from other countries in sub-Saharan Africa prior to PCV introduction. Antimicrobial resistance in this small unselected sample confirms a low rate of antibiotic resistance. Case-fatality is high. Introduction of a high valency pneumococcal vaccine should be a priority for health planners with the establishment of an effective surveillance system to monitor post vaccine changes.
doi:10.1186/s12879-014-0627-8
PMCID: PMC4258793  PMID: 25471219
Streptococcus pneumoniae; Nasopharyngeal carriage; Invasive pneumococcal disease; Serotypes; Antibiotic resistance; Children; Sub-Saharan Africa; Senegal
14.  Serotype Distribution and Antimicrobial Resistance of Streptococcus pneumoniae Isolates Causing Invasive Diseases from Shenzhen Children’s Hospital 
PLoS ONE  2013;8(6):e67507.
Objective
To provide guidance for clinical disease prevention and treatment, this study examined the epidemiology, antibiotic susceptibility, and serotype distribution of Streptococcus pneumoniae (S. pneumoniae) associated with invasive pneumococcal diseases (IPDs) among children less than 14 years of age in Shenzhen, China.
Materials and Methods
All the clinical strains were isolated from children less than 14 years old from January 2009 to August 2012. The serotypes and antibiotic resistance of strains of S. pneumoniae were determined using the capsular swelling method and the E-test.
Results
A total of 89 strains were isolated and 87 isolates were included. The five prevailing serotypes were 19F (28.7%), 14 (16.1%), 23F (11.5%), 19A (9.2%) and 6B (6.9%). The most common sequence types (ST) were ST271 (21.8%), ST876 (18.4%), ST320 (8.0%) and ST81 (6.9%) which were mainly related to 19F, 14, 19A and 23F, respectively. The potential coverage by 7-, 10-, and 13-valent pneumococcal conjugate vaccine were 77.0%, 77.0%, and 89.7%, respectively. Among the 87 isolates investigated, 11.5% were resistant to penicillin, and for meningitis isolates, the resistance rate was 100%. Multi-drug resistance (MDR) was exhibited by 49 (56.3%) isolates. Eighty-four isolates were resistance to erythromycin, among which, 56 (66.7%) carried the ermB gene alone and 28 (33.3%) expressed both the ermB and mefA/E genes.
Conclusions
The potential coverage of PCV13 is higher than PCV7 and PCV10 because high rates of serotypes 19A and 6A in Shenzhen. The clinical treatment of IPD needs a higher drug concentration of antibiotics. Continued surveillance of the antimicrobial susceptibility and serotypes distribution of IPD isolates may be necessary.
doi:10.1371/journal.pone.0067507
PMCID: PMC3696094  PMID: 23840728
15.  Improved Detection of Nasopharyngeal Cocolonization by Multiple Pneumococcal Serotypes by Use of Latex Agglutination or Molecular Serotyping by Microarray▿† 
Journal of Clinical Microbiology  2011;49(5):1784-1789.
Identification of Streptococcus pneumoniae in the nasopharynx is critical for an understanding of transmission, estimates of vaccine efficacy, and possible replacement disease. Conventional nasopharyngeal swab (NPS) culture and serotyping (the WHO protocol) is likely to underestimate multiple-serotype carriage. We compared the WHO protocol with methods aimed at improving cocolonization detection. One hundred twenty-five NPSs from an infant pneumococcal-carriage study, containing ≥1 serotype by WHO culture, were recultured in duplicate. A sweep of colonies from one plate culture was serotyped by latex agglutination. DNA extracted from the second plate was analyzed by S. pneumoniae molecular-serotyping microarray. Multiple serotypes were detected in 11.2% of the swabs by WHO culture, 43.2% by sweep serotyping, and 48.8% by microarray. Sweep and microarray were more likely to detect multiple serotypes than WHO culture (P < 0.0001). Cocolonization detection rates were similar between microarray and sweep, but the microarray identified the greatest number of serotypes. A common serogroup type was identified in 95.2% of swabs by all methods. WHO methodology significantly underestimates multiple-serotype carriage compared to these alternate methods. Sweep serotyping is cost-effective and field deployable but may fail to detect serotypes at low abundance, whereas microarray serotyping is more costly and technology dependent but may detect these additional minor carried serotypes.
doi:10.1128/JCM.00157-11
PMCID: PMC3122683  PMID: 21411589
16.  Molecular Epidemiology of Penicillin-Resistant Streptococcus pneumoniae Isolates Recovered in Italy from 1993 to 1996 
Journal of Clinical Microbiology  1998;36(10):2944-2949.
Thirty-nine penicillin-resistant Streptococcus pneumoniae isolates recovered among the approximately 700 pneumococcal strains collected from 1993 to 1996 in central and northern Italy were analyzed for several characteristics, including serotype, antibiotic susceptibility profile, chromosomal relatedness (by using pulsed-field gel electrophoresis [PFGE]), restriction fragment length polymorphism (RFLP) of the penicillin-binding protein (PBP) genes 1A, 2X, and 2B, and the presence of a variety of antibiotic resistance genes (determined by hybridization with appropriate DNA probes). The MICs of penicillin for most of the isolates (30 of 39) were high, in the range of 1 μg/ml or higher, and these 30 isolates carried additional resistance traits to two or more drugs (erythromycin, chloramphenicol, co-trimoxazole, and tetracycline) and expressed serotypes 9, 19, and 23 and three distinct PFGE patterns. More than half (22 of 30) of the isolates for which MICs were high were identified as representatives of two widespread international epidemic clones of S. pneumoniae. The first one of these clones (seven isolates) expressed serotype 23F and possessed all properties characteristic of the widespread Spanish/USA international clone. Seven additional strains with serotype 19 also had the same PFGE pattern, PBP gene, and RFLP polymorphisms, and other properties typical of the serotype 23 Spanish/USA clone, suggesting that these strains were the products of a capsular transformation event (from serotype 23F to serotype 19) in which the Spanish/USA clone was the recipient. The second international clone was represented by eight serotype 9 isolates which were resistant to penicillin and trimethoprim-sulfamethoxazole and had the molecular properties of the French/Spanish epidemic clone. The remaining eight isolates for which penicillin MICs were high appeared to represent a hitherto-undescribed “Italian” clone; they had a novel PFGE type, unique RFLPs for the PBP genes, and resistance to tetracycline, trimethoprim-sulfamethoxazole, and erythromycin, and the penicillin MICs for these isolates were 2 to 4 μg/ml.
PMCID: PMC105092  PMID: 9738048
17.  Clonal Diversity and Resistance Mechanisms in Tetracycline-Nonsusceptible Streptococcus pneumoniae Isolates in Poland▿  
The frequency of tetracycline resistance in Streptococcus pneumoniae isolates in Poland is one of the highest in Europe. The aim of this study was to analyze the clonal diversity and resistance determinants of tetracycline-nonsusceptible S. pneumoniae isolates identified in Poland and to investigate the effect of tetracycline resistance on their susceptibilities to tigecycline, doxycycline, and minocycline. We have analyzed 866 pneumococcal isolates collected from 1998 to 2003 from patients with respiratory tract diseases, and 242 of these (27.9%) were found to be resistant to tetracycline. All of the resistant isolates were characterized by testing of their susceptibilities to other antimicrobials, serotyping, pulsed-field gel electrophoresis (PFGE), and identification of tetracycline resistance genes and transposons. Selected isolates representing the main PFGE types were analyzed by multilocus sequence typing. Among the isolates investigated, 27 serotypes and 146 various PFGE patterns, grouped into 90 types, were discerned. The most common PFGE type, corresponding to serotype 19F and sequence type 423, was represented by 22.3% of all of the tetracycline-resistant isolates. The tet(M) gene was the sole resistance gene in the group of isolates studied, and in over 96% of the isolates, the Tn916 family of tet(M)-containing conjugative transposons was detected. Several isolates contained specific variants of the transposons, the Tn1545-like, Tn3872-like, or Tn2009-like element. The correlation between the MICs of tetracycline, doxycycline, and minocycline was revealed, whereas no cross-resistance to tetracycline and tigecycline was observed.
doi:10.1128/AAC.01384-06
PMCID: PMC1855514  PMID: 17210772
18.  Continued Impact of Pneumococcal Conjugate Vaccine on Carriage in Young Children 
Pediatrics  2009;124(1):e1-11.
OBJECTIVES
The goals were to assess serial changes in Streptococcus pneumoniae serotypes and antibiotic resistance in young children and to evaluate whether risk factors for carriage have been altered by heptavalent pneumococcal conjugate vaccine (PCV7).
METHODS
Nasopharyngeal specimens and questionnaire/medical record data were obtained from children 3 months to <7 years of age in primary care practices in 16 Massachusetts communities during the winter seasons of 2000–2001 and 2003–2004 and in 8 communities in 2006–2007. Antimicrobial susceptibility testing and serotyping were performed with S pneumoniae isolates.
RESULTS
We collected 678, 988, and 972 specimens during the sampling periods in 2000–2001, 2003–2004, and 2006–2007, respectively. Carriage of non-PCV7 serotypes increased from 15% to 19% and 29% (P < .001), with vaccine serotypes decreasing to 3% of carried serotypes in 2006–2007. The relative contribution of several non-PCV7 serotypes, including 19A, 35B, and 23A, increased across sampling periods. By 2007, commonly carried serotypes included 19A (16%), 6A (12%), 15B/C (11%), 35B (9%), and 11A (8%), and high-prevalence serotypes seemed to have greater proportions of penicillin nonsusceptibility. In multivariate models, common predictors of pneumococcal carriage, such as child care attendance, upper respiratory tract infection, and the presence of young siblings, persisted.
CONCLUSIONS
The virtual disappearance of vaccine serotypes in S pneumoniae carriage has occurred in young children, with rapid replacement with penicillin-nonsusceptible nonvaccine serotypes, particularly 19A and 35B. Except for the age group at highest risk, previous predictors of carriage, such as child care attendance and the presence of young siblings, have not been changed by the vaccine.
doi:10.1542/peds.2008-3099
PMCID: PMC2782668  PMID: 19564254
Streptococcus pneumoniae; pneumococcal conjugate vaccine; antibiotic resistance; serotype; colonization
19.  Genome evolution driven by host adaptations results in a more virulent and antimicrobial-resistant Streptococcus pneumoniae serotype 14 
BMC Genomics  2009;10:158.
Background
Streptococcus pneumoniae serotype 14 is one of the most common pneumococcal serotypes that cause invasive pneumococcal diseases worldwide. Serotype 14 often expresses resistance to a variety of antimicrobial agents, resulting in difficulties in treatment. To gain insight into the evolution of virulence and antimicrobial resistance traits in S. pneumoniae from the genome level, we sequenced the entire genome of a serotype 14 isolate (CGSP14), and carried out comprehensive comparison with other pneumococcal genomes. Multiple serotype 14 clinical isolates were also genotyped by multilocus sequence typing (MLST).
Results
Comparative genomic analysis revealed that the CGSP14 acquired a number of new genes by horizontal gene transfer (HGT), most of which were associated with virulence and antimicrobial resistance and clustered in mobile genetic elements. The most remarkable feature is the acquisition of two conjugative transposons and one resistance island encoding eight resistance genes. Results of MLST suggested that the major driving force for the genome evolution is the environmental drug pressure.
Conclusion
The genome sequence of S. pneumoniae serotype 14 shows a bacterium with rapid adaptations to its lifecycle in human community. These include a versatile genome content, with a wide range of mobile elements, and chromosomal rearrangement; the latter re-balanced the genome after events of HGT.
doi:10.1186/1471-2164-10-158
PMCID: PMC2678160  PMID: 19361343
20.  Pneumococcal Carriage and Antibiotic Resistance in Young Children before 13-Valent Conjugate Vaccine 
Background
We sought to measure trends in Streptococcus pneumoniae (SP) carriage and antibiotic resistance in young children in Massachusetts communities after widespread adoption of heptavalent pneumococcal conjugate vaccine (PCV7) and before the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13).
Methods
We conducted a cross-sectional study including collection of questionnaire data and nasopharyngeal specimens among children <7 years in primary care practices from 8 Massachusetts communities during the winter season of 2008–9 and compared with to similar studies performed in 2001, 2003–4, and 2006–7. Antimicrobial susceptibility testing and serotyping were performed on pneumococcal isolates, and risk factors for colonization in recent seasons (2006–07 and 2008–09) were evaluated.
Results
We collected nasopharyngeal specimens from 1,011 children, 290 (29%) of whom were colonized with pneumococcus. Non-PCV7 serotypes accounted for 98% of pneumococcal isolates, most commonly 19A (14%), 6C (11%), and 15B/C (11%). In 2008–09, newly-targeted PCV13 serotypes accounted for 20% of carriage isolates and 41% of penicillin non-susceptible S. pneumoniae (PNSP). In multivariate models, younger age, child care, young siblings, and upper respiratory illness remained predictors of pneumococcal carriage, despite near-complete serotype replacement. Only young age and child care were significantly associated with PNSP carriage.
Conclusions
Serotype replacement post-PCV7 is essentially complete and has been sustained in young children, with the relatively virulent 19A being the most common serotype. Predictors of carriage remained similar despite serotype replacement. PCV13 may reduce 19A and decrease antibiotic-resistant strains, but monitoring for new serotype replacement is warranted.
doi:10.1097/INF.0b013e31824214ac
PMCID: PMC3288953  PMID: 22173142
Streptococcus pneumoniae; pneumococcal conjugate vaccine; antibiotic resistance; serotype; colonization
21.  Penicillin resistance and serotype distribution of Streptococcus pneumoniae in Ghanaian children less than six years of age 
BMC Infectious Diseases  2013;13:490.
Background
The objective of this study was to determine the prevalence of nasopharyngeal carriage, serotype distribution, and penicillin resistance of Streptococcus pneumoniae in children ≤6 years of age in Ghana.
Methods
A cross-sectional study was carried out on a cluster-randomized sample of children ≤6 years of age attending nurseries and kindergartens in Accra and Tamale, Ghana. Basic data on age, sex and exposure to antimicrobials in the previous month were collected on all study subjects. Nasopharyngeal swabs were obtained from participants and all pneumococcal isolates were characterized by serotyping and their penicillin resistance determined.
Results
The overall prevalence of pneumococcal carriage among the children was 34% in Accra and 31% in Tamale. The predominant serotypes were 19F, 6B, 23F, and 6A with 23% of the isolates being non-typable in Accra and 12% in Tamale. Only two isolates (serotypes 19F and 6B) from Tamale had a MIC >2 μg/ml and were classified as fully penicillin resistant with 45% of the isolates having intermediate resistance.
Conclusions
These findings indicate that the 13-valent pneumococcal conjugate vaccine (PCV-13) recently introduced in Ghana will cover 48% and 51% of the serotypes identified in Accra and Tamale, respectively. The 23-valent pneumococcal polysaccharide vaccine (PPV-23) will cover 54% of all serotypes detected. The two penicillin resistant isolates (MIC 32 μg/ml) were serotypes included in both PCV-13 and PPV-23. A nationwide monitoring system of penicillin susceptibility patterns and pneumococcal serotypes is recommended.
doi:10.1186/1471-2334-13-490
PMCID: PMC4015758  PMID: 24148091
22.  Genotypes and serotype distribution of macrolide resistant invasive and non- invasive Streptococcus pneumoniae isolates from Lebanon 
Background
This study determined macrolide resistance genotypes in clinical isolates of Streptococcus pneumoniae from multiple medical centers in Lebanon and assessed the serotype distribution in relation to these mechanism(s) of resistance and the source of isolate recovery.
Methods
Forty four macrolide resistant and 21 macrolide susceptible S. pneumoniae clinical isolates were tested for antimicrobial susceptibility according to CLSI guidelines (2008) and underwent molecular characterization. Serotyping of these isolates was performed by Multiplex PCR-based serotype deduction using CDC protocols. PCR amplification of macrolide resistant erm (encoding methylase) and mef (encoding macrolide efflux pump protein) genes was carried out.
Results
Among 44 isolates resistant to erythromycin, 35 were resistant to penicillin and 18 to ceftriaxone. Examination of 44 macrolide resistant isolates by PCR showed that 16 isolates harbored the erm(B) gene, 8 isolates harbored the mef gene, and 14 isolates harbored both the erm(B) and mef genes. There was no amplification by PCR of the erm(B) or mef genes in 6 isolates. Seven different capsular serotypes 2, 9V/9A,12F, 14,19A, 19F, and 23, were detected by multiplex PCR serotype deduction in 35 of 44 macrolide resistant isolates, with 19F being the most prevalent serotype. With the exception of serotype 2, all serotypes were invasive. Isolates belonging to the invasive serotypes 14 and 19F harbored both erm(B) and mef genes. Nine of the 44 macrolide resistant isolates were non-serotypable by our protocols.
Conclusion
Macrolide resistance in S. pneumoniae in Lebanon is mainly through target site modification but is also mediated through efflux pumps, with serotype 19F having dual resistance and being the most prevalent and invasive.
doi:10.1186/1476-0711-11-2
PMCID: PMC3371826  PMID: 22248318
Antimicrobials; Macrolides; Resistance; Genes; Serotyping
23.  Occurrence, Distribution, and Origins of Streptococcus pneumoniae Serotype 6C, a Recently Recognized Serotype▿  
The prevalence of Streptococcus pneumoniae serotype 6C, a recently recognized serotype that cross-reacts serologically with serotype 6A, was investigated. Isolates of serotype 6A in various collections were recovered, and serotype 6C was differentiated from 6A by multiplex PCR of DNA extracts by using appropriate primers. Antimicrobial susceptibility was performed by Clinical and Laboratory Standards Institute broth microdilution, and selected isolates were typed by pulsed-field gel electrophoresis, repetitive sequence-based PCR typing, and rapid multilocus sequence typing (MLST) by electrospray ionization mass spectrometry of PCR products. A total of 60 serotype 6C isolates were found: 30 of 122 Cleveland isolates collected from 1979 to 2007, 19 of 39 pediatric isolates collected nationwide in 2005 and 2006, and 11 pediatric isolates from Massachusetts collected in 2006 and 2007. Only four isolates were recovered prior to introduction of the conjugate pneumococcal vaccine in 2000; the earliest isolate was recovered in 1989. The sources of the isolates included blood (n = 5), the lower respiratory tract (n = 27), the sinus (n = 5), the ear (n = 2), and the nasopharynx (n = 18); isolates were recovered from 49 children and 11 adults. Pediatric isolates were found in all six major U.S. geographic regions. Antimicrobial susceptibility showed that 22 isolates were nonsusceptible to penicillin, macrolides, and trimethoprim-sulfamethoxazole, 8 had other resistance patterns, and 30 were fully susceptible. The three typing methods used showed similar clusters of up to eight isolates per cluster. MLST showed five clusters related to serotype 6A, two clusters related to serotype 6B, one cluster related to serotype 3, and one cluster related to serotype 34. This study documents the occurrence, nationwide distribution, diversity, likely origins, and increasing incidence after 2001 of this recently recognized serotype. Serotype 6C warrants consideration for addition to future conjugate pneumococcal vaccines.
doi:10.1128/JCM.01524-08
PMCID: PMC2620864  PMID: 18971356
24.  Increase in serotype 19A prevalence and amoxicillin non-susceptibility among paediatric Streptococcus pneumoniae isolates from middle ear fluid in a passive laboratory-based surveillance in Spain, 1997-2009 
BMC Infectious Diseases  2011;11:239.
Background
Conjugate vaccines, such as the 7-valent conjugate vaccine (PCV7), alter serotype nasopharyngeal carriage, potentially increasing cases of otitis media by non-vaccine serotypes.
Methods
All paediatric middle ear fluid (MEF) isolates received in the Spanish Reference Laboratory for Pneumococci through a passive, laboratory-based surveillance system from January 1997 to June 2009 were analysed. Data from 1997 to 2000 were pooled as pre-vaccination period. Trends over time were explored by linear regression analysis.
Results
A total of 2,077 isolates were analysed: 855 belonging to PCV7 serotypes, 466 to serotype 19A, 215 to serotype 3, 89 to serotype 6A and 452 to other serotypes (< 40 isolates each). Over time, there has been a decreasing trend for PCV7 serotypes (R2 = 0.944; p < 0.001, with significant decreasing trends for serotypes 19F, 14, 23F and 9V), and increasing trends for serotype 19A (R2 = 0.901; p < 0.001), serotype 3 (R2 = 0.463; p = 0.030) and other non-PCV7 serotypes (R2 = 0.877; p < 0.001), but not for serotype 6A (R2 = 0.311; p = 0.094). Considering all isolates, amoxicillin non-susceptibility showed an increasing trend (R2 = 0.528; p = 0.017). Regarding serotype 19A, increasing trends in non-susceptibility to penicillin (R2 = 0.726; p = 0.001), amoxicillin (R2 = 0.804; p < 0.001), cefotaxime (R2 = 0.546; p = 0.005) and erythromycin (R2 = 0.546; p = 0.009) were found, with amoxicillin non-susceptibility firstly detected in 2003 (7.4%) and increasing up to 38.0% in 2009. In PCV7 serotypes (which prevalence decreased from 70.7% during 1997-2000 to 10.6% in 2009) amoxicillin non-susceptibility rates showed an increasing trend (R2 = 0.702; p = 0.002). However, overall, amoxicillin non-susceptibility (≈25% in 2008-9) could be mainly attributed to serotype 19A (> 35% isolates) since PCV7 strains represented < 11% of total clinical isolates.
Conclusions
In contrast to reports on invasive pneumococcal strains, in MEF isolates the reduction in the prevalence of PCV7 serotypes was not associated with decreases in penicillin/erythromycin non-susceptibility. The high prevalence of serotype 19A among paediatric MEF isolates and the amoxicillin non-susceptibility found in this serotype are worrisome since amoxicillin is the most common antibiotic used in the treatment of acute otitis media. These data suggest that non-PCV7 serotypes (mainly serotype 19A followed by serotypes 3 and 6A) are important etiological agents of acute otitis media and support the added value of the broader coverage of the new 13-valent conjugate vaccine.
doi:10.1186/1471-2334-11-239
PMCID: PMC3180674  PMID: 21910891
Susceptibility; serotype 19A; middle ear isolates; non-susceptibility time trends; surveillance
25.  Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model 
Epidemiology (Cambridge, Mass.)  2012;23(4):510-519.
BACKGROUND
There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a non-serotype-specific fashion.
METHODS
We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children aged 3-59 months, following up positive swabs at days 2, 4, 8, 16, and 32, and then monthly thereafter until two swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance and competition parameters for 27 serotypes using a Markov transition model .
RESULTS
Point estimates of type-specific acquisition rates ranged from 0.00025/day (type 1) to 0.0031/day (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval= 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes.
CONCLUSIONS
Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine.
doi:10.1097/EDE.0b013e31824f2f32
PMCID: PMC3670084  PMID: 22441543

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