Pneumococcal

Pneumococcal

 

Pneumococcal is also known as S. pneumoniae or pneumococcal meningitis.

 

Staphylococcus aureus is a common commensal of humans and its primary habitat is the moist squamous epithelium of the anterior nares (1). About 20% of the population are always colonized with S. aureus, 60% are intermittent carriers, and 20% never carry the organism. As there is considerable evidence that carriage is an important risk factor for invasive infection (1, 2), it is surprising that so little is known about the bacterial factors that promote colonization of squamous epithelial surfaces and the host factors that determine whether an individual can be colonized or not.

 

Healthy individuals have a small but finite risk of contracting an invasive infection caused by S. aureus, and this risk is increased among carriers. Hospital patients who are catheterized or who have been treated surgically have a significantly higher rate of infection. In some, but not all, developed countries, many nosocomial infections are caused by S. aureus strains that are multiply resistant to antibiotics — known as methicillin-resistant Staphylococcus aureus (MRSA) (3, 4) — although the acronym MRSA is somewhat misleading because the semisynthetic β-lactam methicillin is no longer used to treat S. aureus infections….

 

…only Staphylococcus aureus and Staphylococcus epidermidis are significant in their interactions with humans. S. aureus colonizes mainly the nasal passages, but it may be found regularly in most other anatomical locales, including the the skin, oral cavity and gastrointestinal tract. S epidermidis is an inhabitant of the skin.

 

 

 

Vaccines:

 

For Adults:

There are more than 90 different types of pneumococcus bacteria-23 of these are covered in the current vaccination. The vaccine is injected into the body to stimulate the normal immune system to produce antibodies that are directed against pneumococcus bacteria. Pneumococcal vaccination does not protect against pneumonia caused by microbes other than pneumococcus bacteria, nor does it protect against pneumococcal bacteria strains not included in the vaccine…

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PNEUMOVAX® 23 (PNEUMOCOCCAL VACCINE POLYVALENT) 

 

Pneumococcal 23-valent polysaccharide vaccine is used in adults and selected children 24 months or older to stimulate active immunity to infection caused by the serotypes of S. pneumoniae contained in the vaccine.100 102 115 129 The vaccine commercially available in the US contains 23 capsular antigens that represent at least 85–90% of the serotypes that cause invasive pneumococcal infection in adults and children in the US.115

BRIEFING DOCUMENT Pneumococcal Adult Vaccine OPEN SESSION VRBPAC Meeting November 17th 2005

 

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For Children:

 

The heptavalent pneumococcal conjugate vaccine (PCV7) is recommended for use in children 23 months of age and younger. Although other pneumococcal vaccines are available, PCV7 represents the first pneumococcal vaccine approved for use in children younger than age 2.

 

Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) Prevnar®
FOR PEDIATRIC USE ONLY

 

PCV7 protects against seven pneumococcal capsular types (serotypes)—4, 6B, 9V, 14, 18C, 19F, and 23F

 

Licensed or In Development:

 

Potential Impact of Conjugate Pneumococcal Vaccines on Pediatric Pneumococcal Diseases

  

GSK’s paediatric pneumococcal candidate vaccine Synflorix™ receives positive opinion in Europe

Synflorix™

The paediatric vaccine is proposed to be indicated for active immunisation against invasive pneumococcal disease (IPD) and middle ear infections (acute otitis media) caused by Streptococcus pneumoniae in infants and children from 6 weeks up to 2 years. The European Marketing Authorisation for the vaccine is expected to be granted in the coming months. 10-valent pneumococcal vaccine.  Of these strains, serotypes 1 and 7F are on the rise in several Europe an countries and in many other parts of the world.6,7,8,9 The 10 serotypes included in GSK’s candidate vaccine are responsible for up to 90% of IPD in young children, and are responsible for a significant proportion of IPD globally.

Synflorix™ GSK’s candidate vaccine is a 10-valent, pneumococcal conjugate vaccine. It was designed with polysaccharides derived from 10 different strains of pneumococcus. Eight are linked to a novel carrier protein ‘D’ derived from a second major paediatric pathogen – non-typeable Haemophilus influenzae (NTHi)13. This novel carrier protein is intended to minimise the possibility of immune interference when co-administered with other vaccines.14 GSK’s robust clinical development programme includes trials in Europe, as well as Africa, Asia and Latin America. Antibody responses to co-administered paediatric vaccines are similar to those observed when the vaccine is given alone, indicating that the candidate vaccine does not interfere with these co-administered paediatric vaccines.15

A prototype 11-valent pneumococcal vaccine formulation, which used the same novel approach in conjugation technology and contained the 10 serotypes covered by the current candidate vaccine (along with another serotype for which efficacy was not demonstrated), offered 33.6 % reduction of clinical acute otitis media in a European trial.16

GSK’s pneumococcal candidate vaccine is expected to deliver broad public health benefit by offering coverage against three additional pneumococcal strains (serotypes 1, 5 and 7F) on top of the seven serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) which are covered in the existing paediatric pneumococcal vaccine.1 Serotypes 1, 5 and 7F are responsible for a significant burden of disease, accounting for 5-25% of all IPD cases.4

Synflorix;

Streptorix; Pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine; PHiD-CV; Streptococcus pnuemoniae capsular antigens–Haemophilus influenzae protein D conjugates vaccine.

 

5th International Symposium on Pneumococci and Pneumococcal Diseases

 

 

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Public health potential of a 13vPnC vaccine for immunization of adults in the US PO4.07

Hackell, JG, Paradiso, PR, Siber, G

Wyeth Vaccines Research, Pearl River, NY, USA

 

The 13-valent pneumococcal conjugate (13vPnC) vaccine covers fewer serotypes than the 23-valent polysaccharide (23vPS) vaccine, but potentially has the additional benefits of a conjugate vaccine. This includes the ability to extend protection throughout the high-risk period by allowing revaccination, if necessary, without risk of induction of hyporesponsiveness (blunting of subsequent immune response).

 

Fry et al1 at CDC developed a model to look at the relative potential public health impact of various pneumococcal conjugate formulations, as compared to the currently available 23vPS vaccine in adults >65 years of age. The authors found a significant benefit of the conjugate vaccines based on the potential for more durable immunity and perhaps higher efficacy. We updated this model, using the rate of invasive pneumococcal disease (IPD) observed in 2004 (significantly lower than the 1998 data used in Fry et al). We also expanded the analysis to include 50-64 year olds. We assumed that 13vPnC had the same level of efficacy for the serotypes in the vaccine as 23vPS, but a longer duration of immunity, that could be sustained either through the induction of memory or through re-immunization, if needed.

 

We assumed vaccine uptake to be 60%, comparable to the current estimates for 23vPS uptake in >65 year olds. Similar to the original Fry et al estimates, the model predicts that more cases of IPD could be prevented with the 13vPnC vaccine compared to the cases currently prevented with the 23vPS vaccine (5544 vs 2979). The same is true for deaths due to IPD (895 vs 489). This is due in

part to the ability to extend the age of initial vaccination down to 50 years of age without the risk of diminished immune responsiveness later in life, and in part due to the ability to maintain immunity throughout the entire high-risk period.

(1Fry AM et al. Comparing potential benefits of new pneumococcal vaccines with the current polysaccharide vaccine in the elderly. Vaccine 2002; 21:303-311.)

 

 

Study Evaluating 13-Valent Pneumococcal Conjugate Vaccine In Healthy Infants

*in development

 

PCV13 includes the 13 most prevalent pneumococcal serotypes associated with serious PD. Seven of these (4, 6B, 9V, 14, 18C, 19F and 23F) are included in Prevenar* (Pneumococcal saccharide conjugated vaccine, adsorbed) — the current global standard in PD prevention in infants and young children. The six additional serotypes (1, 3, 5, 6A, 7F and 19A) are associated with the greatest burden of remaining invasive disease. Both Prevenar (also known as PCV7) and PCV13 use CRM197 — an immunological carrier protein with a 20-year history of use in pediatric vaccines.

 

Earlier this year, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to PCV13 for infants and toddlers. Fast Track designation is designed to facilitate review of products for serious or life-threatening conditions for which there is an unmet medical need. The Company expects to complete its U.S. filing for pediatric use of the vaccine in the first quarter of 2009, while initiating other pediatric filings in the near term. PCV13 is also being studied in global Phase 3 clinical trials in adults, with regulatory filings expected in 2010.

 

 

 

Update on Investigational 13-Valent Pneumococcal Conjugate Vaccine Dr. Peter Paradiso.  Wyeth Vaccines  (ACIP meeting 10/23/08)

 

Dr. Paradiso presented an update on investigational 13-valent pneumococcal conjugate vaccine. The current 7-valent vaccine, PREVNAR®, contains the serotypes that were the most prevalent in the US at the time this vaccine was launched (e.g., 4, 6B, 9V, 14,18C, 19F, and 23F). The 13-valent vaccine, PCV13, includes those seven serotypes and an additional six new conjugate vaccines covering serotypes 1, 3, 5, 6A, 7F, and 19A. The seven components that

are common within the vaccine are essentially identical in dosage and form to those found in PREVNAR® (e.g., 2 μg of each of those serotypes, except for 6B which is 4 μg). The six new serotypes are all conjugates of the same carrier protein as the original seven types in PREVNAR® (e.g., CRM197), using the same chemistry of reductive amination to the polysaccharide and in a dosage of 2 μg of each of those serotypes. Thus, the 13-valent vaccine essentially takes the PREVNAR® vaccine in its dosage form and adds the six new serotypes that make 13 all together. It is important to point this out, particularly as it relates to the seven original types, because the transition anticipated from 7-valent to 13-valent will be facilitated by the fact that those seven types are common and it should be possible to switch to the 13-valent at any point in the immunization program.

 

 

When considering the assessment of a new conjugate vaccine, the situation is different from that of developing PREVNAR®, given that PREVNAR® is now on the market. Thus immunogenicity must be considered as the correlate or the way to assess the new vaccine.  Wyeth has had some assistance in that consideration from many groups, particularly the World Health Organization, who have reviewed the data regarding efficacy and immune response for

PREVNAR® and established criteria by which they can consider comparing a new vaccine to an old vaccine. Weyth’s clinical trials are set up to compare the 13-valent vaccine to the standard of care, the 7-valent vaccine. The serological criteria used to assess PCV13 immunogenicity for the common serotypes in PREVNAR® and PCV13 are to examine non-inferiority to PCV7 in the percentage of children achieving > 0.35 ug/ml anticapsular antibody, and the non-inferiority toPCV7 types in geometric mean antibody concentration. For the six additional serotypes in PCV13, a comparison is made to the original types to examine non-inferiority in the percentage of children achieving 0.35 ug/ml anticapsular antibody compared to the lowest responses in PCV7, and non-inferiority in geometric mean anticapsular antibody concentration compared to the lowest responses in PCV7. In considering the entire immune response, good functional antibody that correlates with overall immunogenicity is an important parameter, given that it is

essential to show that a functional response is induced with the six new types and that this response correlates with the overall antibody response. For the immunization program and long-term immunity, boostability in the second year of life is also examined within a schedule that has been used for many conjugate vaccines over the years. There are additional predetermined analyses that may be examined should the primary criteria not be met. Wyeth is currently completing their Phase 3 Clinical Pediatric Program, which is extensive and global.

 

Wyeth is also in a Phase 3 program examining PCV13 for adults with the goals of studying the indication for the prevention of pneumococcal disease in adults; induction of a functional immune response in individuals >18 yrs of age that is non-inferior / superior to the polysaccharide; induction of immunological memory that allows periodic boosting of immunity; demonstration of no hyporesponsiveness; and ability to overcome hyporesponsiveness induced

by the polysaccharide. Unfortunately, the preliminary data show that those who have had the polysaccharide vaccine are hyporesponsive not only to another polysaccharide vaccine, but also to a conjugate vaccine. Therefore, a component of the program will be to examine whether that hyporesponsiveness can be overcome with a dose of the conjugate vaccine and be set up for a future booster of that response. This study is particularly focused on adults 58 years of age and older, but will go down to 18 years of age. This study will also include a large-scale effectiveness trial that just began in the Netherlands.

 

 

6th International Symposium on Pneumococci and Pneumococcal Diseases  8–12 June 2008, Reykjavik, Iceland

 

(pg 13)…The success and failure of pneumococcal clones depends on host, environmental and bacterial factors. Important host and environmental factors are immunity, heredity and antibiotic use. The widespread use of antibiotics and vaccination of children with a conjugated pneumococcal vaccine has provided an unprecedented selective pressure on pneumococci. Before the introduction of the 7-valent Prevnar vaccine in the United States in the year 2000, penicillin non-susceptible pneumococci had become 26% of all invasive isolates, but decreased following vaccination to 22% (2004, all ages). At the same time the proportion of clones belonging to serotype 19A increased from 2.5% to 36% (children ≤5 years old). Drastic changes in prevalence may also be unrelated to vaccination and antibiotic

use. Pneumococcal clones can spread in an epidemic fashion, apparently unrelated to external factors. A multidrug-resistant clone of serotype 19A increased markedly in the Bedouin population of southern Israel in the absence of vaccination, and the multidrugresistant clone Spain6B-ST90 spread fast and reached 19% of pneumococci carried by

healthy children in an Icelandic community with limited antimicrobial use. The bacterial factors related to successful spread are not known but surface pili could be important….

 

 

S10-KS2 Towards a protein-based vaccine against Streptococcus pneumoniae (pg.22)

 

The existing conjugated 7-valent Prevnar vaccine (PCV7) is effective against bacteremia and meningitis, when caused by the seven CPS serotypes included in the vaccine. However the pneumococcal serotype distribution changes dramatically from region to region, and in some developing countries PCV7 covers less than one third of disease causing strains. Furthermore, few years after the introduction of PCV7 in the US, phenomena of serotype replacement have been clearly demonstrated, thus limiting the overall effectiveness of the vaccine also in developed countries. Second-generation extended coverage glycoconjugate are in late stage of development, however, they will only partially address the unmet serotype coverage needs…

 

S12-KS1 Pneumococcal carriage and transmission (pg 27)

 

The pneumooccus is a normal component of nasopharyngeal flora and carriage is the reservoir of bacteria transmitted to others and a source of disease causing pneumococci in the host.

The prevalence of colonization varies greatly globally, by age and by serotype. The main reasons for this are the differences in the exposure and the host immunity. The exposure is affected by several factors like family size, day care attendance and viral infections. Transmission of pneumococci is characterised by microepidemics within families and day care facilities….

 

…Pneumococcal carriage induces production of antibodies to pneumocccal protein and polysaccharide antigens, but the role of these ’natural’ antibodies in prevention subsequent acquisition has been addressed in only few studies. These studies suggest that antipolysaccharide antibodies, at least to certain serotypes, can be associated with the risk of

subsequent colonization. Epidemiological studies among Israeli children suggest that previous colonization can prevent homotypic colonization, while a study among Bangladeshi infants could not show homotypic but showed heterotypic protection. A study using human colonization model found association of anti-protein antibodies, but not of antipolysaccharide antibodies and type 23F pneumococcal colonization. Animal studies suggest that CD4 T cells rather than antibodies offer the main mechanism for protection against colonization. Finally, studies on human mucosal T cells and cytokine production suggest that cell mediated immunity has a role in prevention and termination of pneumococcal carriage.

 

 

P1-017 Population-based strain surveillance of invasive serotype 19A pneumococci recovered in the United States: 2006 (pg 96)

 

Background: Pneumococcal serotype 19A has increased in frequency as a cause of invasive

disease since introduction of the 7 valent pneumococcal conjugate vaccine (PCV7) in the

U.S. in 2000. Serotype 19A isolates have become increasingly resistant, primarily because of

the rapid emergence of clonal complex (CC) 320 isolates highly related to multi-resistant

clone Taiwan19F-14, but also through the emergence of other strains.We assessed all available invasive isolates and predicted 19A disease rates from areas under continuous surveillance from1999 -2006 through CDC’s Active Bacterial Core surveillance (ABCs, about 18 million persons)…

Results: Serotype 19A incidence has been incrementally increasing annually. Between 1999 and 2005 incidence increased more than 3-fold in children < 5 years (from 2.6 cases/100,000 to 8.9 cases/100,000). Incidence of serotype 19A disease in this age group further increased to 10.7 cases/100,000 during 2006. Between 1999 and 2005, the proportion of 19A isolates from all age groups that were penicillin-resistant (MICs > 2 ug/ml) increased from 6.7% to 35% and further increased to 36.2% during 2006. The CC320 complex increased from 21% of type 19A during 2005 isolates to 24% during 2006. Other 19A strains that appear to be derived from major PCV7-serotype strains increased during 2006 relative to 2005.

Conclusions: These updated results indicate that serotype 19A continues to increase as a cause of invasive disease and resistant infections. While most of the increase in resistant infections is related to a single CC, multiple strains are contributing to the problem.

 

5th International Symposium on Pneumococci and Pneumococcal Diseases

 

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5th International Symposium on Pneumococci and Pneumococcal Diseases (pg 260)

 

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5th International Symposium on Pneumococci and Pneumococcal Diseases (pg 269)

 

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Pneumococcal Resistance

 

…pneumococcal strains with decreased susceptibility to penicillin were identified in Australia and New Guinea in the 1960s and in South Africa in the 1970s. Isolates nonsusceptible (minimal inhibitory concentration [MIC] ≥0.1 µg/mL) or resistant (MIC ≥2.0 µg/mL) to penicillin and other antimicrobial agents became increasingly prevalent in many other countries during the 1980s. Drug-resistant strains were relatively uncommon in the United States (US) throughout the 1980s and penicillin remained the drug of choice for empiric treatment of life-threatening pneumococcal infections. However, a rapid increase in the prevalence of isolates nonsusceptible or resistant to penicillin occurred in the US during the late 1980s and early 1990s (Figure 1). In some parts of the US, over 35% of pneumococcal isolates are now nonsusceptible to penicillin. Concomitant with the emergence of penicillin-resistant strains, pneumococci with decreased susceptibility to other classes of antimicrobial agents also became more prevalent, making selection of therapy difficult. Strains susceptible only to vancomycin have been isolated…

 

 

Vaccine Escape Recombinants Emerge after Pneumococcal Vaccination in the United States

 

The Centers for Disease Control and Prevention (CDC) has been monitoring invasive pneumococcal disease since 1995 through the Active Bacterial Core (ABC) surveillance program [6,14,30] and as a result, the post-vaccination increase in nonvaccine serotype 19A disease in the US was quickly detected. Serotype 19A strains collected by the CDC through 2005 were genotyped by MLST, which revealed that vaccine escape strains had begun to emerge in 2003 [14,15]. These strains possessed an MLST genotype, ST695, that had always been associated with vaccine serotype 4 (ST6954), but now expressed a serotype 19A capsule (ST69519A). These strains were detected only 3 y after vaccine implementation, but rapidly increased in prevalence. The first three strains were detected in 2003; two strains were detected in 2004; and 32 strains were detected in 2005, some of which had evolved further. Moreover, in 2005, two new types of serotype 19A vaccine escape strains emerged, ST236519A (n = 4) and ST89919A (n = 1); these appeared to represent new recombinational events that also occurred between serotype 4 recipients and serotype 19A donors. The aim of this study was to sequence the regions upstream and downstream of the capsular locus, including both PBPs, to identify the putative recombinational event(s) that resulted in these vaccine escape strains.

 

Maintaining protection against invasive bacteria with protein–polysaccharide conjugate vaccines

Maintaining protection against invasive bacteria with protein–polysaccharide conjugate vaccines

Polysaccharide-encapsulated organisms are the leading cause of bacterial meningitis and pneumonia in children. The use of protein–polysaccharide conjugate vaccines in developed countries over the past two decades has markedly decreased the burden of disease and mortality from these organisms through direct protection of the immunized and through herd immunity. In the next decade, the widespread use of conjugate vaccines in the developing world should prevent millions of deaths. In this Science and Society article, we describe how vaccine-induced immunity wanes rapidly after vaccination in early childhood and argue that strategies that sustain protection in the population must be considered.

Rethinking Replacement and Resistance

Rethinking Replacement and Resistance  (The Journal of Infectious Diseases 2009;199:771–773)

 

Before 2000, the year in which the 7‐valent pneumococcal conjugate vaccine (PCV7; Prevnar, Wyeth) was introduced into the US infant immunization schedule, most antibiotic‐resistant strains of Streptococcus pneumoniae belonged to serotypes included in PCV7. During just the first 3 years after vaccine introduction, we observed profound reductions in the incidence of invasive pneumococcal disease (e.g., bacteremia and meningitis) caused by vaccine serotypes and their associated antibiotic‐resistant strains, not only among vaccinated children but also among persons too young [1] and too old [2] to receive the vaccine. The dramatic success of PCV7 in reducing pneumococcal disease in wealthy countries [36]—and the potential benefits to poor countries [7, 8]—have led to World Health Organization recommendations for the global introduction of conjugate vaccines [9] and to extraordinary efforts to finance vaccine purchase and delivery to the poorest countries of the world [10].

At the same time we were heralding the benefits of PCV7, we were alert to the unintended consequence of serotype replacement. This phenomenon, demonstrated convincingly in randomized, controlled trials [11], occurs when serotypes not included in a conjugate vaccine colonize the nasopharynx and “replace” the vaccine serotypes whose colonization is prevented by the vaccine. The net effect is that PCV7 does not reduce the overall prevalence of nasopharyngeal colonization. PCV7 serotypes are, on average, better suited to causing invasive disease than non‐PCV7 serotypes [12, 13]; therefore, vaccine‐induced elimination of PCV7 serotypes from the nasopharynx leads to a net reduction in invasive disease and antibiotic resistance. Of all the serotypes, 19A may come closest to having certain characteristics that make it a successful replacement serotype. First, serotype 19A has relatively high propensities for colonizing the nasopharynx (to maximize transmissibility) and for causing invasive disease. Second, serotype 19A was associated with antibiotic resistance even before the introduction of PCV7; therefore, when exposed to antibiotics prescribed for upper respiratory tract infections, it had a selective advantage over other, more susceptible serotypes. Finally, PCV7 has no efficacy against serotype 19A.

Increases in the incidence of serotype 19A associated with otitis [14], mastoiditis [15], and invasive disease [1618] have been described in multiple US settings since 2000, making it impossible to ignore the temporal association between the introduction of PCV7 and the emergence of serotype 19A. It seemed safe to assume that PCV7 had caused replacement with serotype 19A. There were hints, however, that we might have been presumptuous in attributing the rise of serotype 19A exclusively to the use of PCV7. In multiple studies conducted before PCV7 introduction, serotype 19A was identified as an antibiotic‐resistant serotype, not only in the United States [19] but in other parts of the world as well [20, 21]. Until now, the strongest evidence against PCV7‐induced serotype replacement was that the incidence of serotype 19A seemed to be increasing in Korea [22], France, and Belgium [23] before the introduction of PCV7. The article by Dagan et al. [24] in this issue of the Journal pushes us to question our assumptions about serotype replacement even more forcefully.

The authors describe the emergence of serotype 19A as a cause of otitis media among Bedouin children in southern Israel who, along with their Jewish counterparts, had not received PCV7. During 1999–2006, the proportion of otitis media cases among Bedouin children caused by serotype 19A increased from 8% to 14%. Among Jewish children over the same time period, the prevalence of serotype 19A varied between 8% and 14% without a clear upward or downward trend. These findings are not particularly striking until one examines the susceptibility patterns and clones of serotype 19A strains in these 2 groups. A stable 38% of serotype 19A strains causing otitis in Jewish children from 2002 to 2006 were resistant to penicillin, with very few isolates resistant to macrolides or multiple agents. In contrast, the Bedouin population experienced a dramatic increase in the prevalence of 2 multidrug‐resistant pneumococcal clones (ST‐276 and ST‐2928) of serotype 19A over the same time period. Why the difference?

One hypothesis is that Bedouin children may have had greater exposure to antibiotics than Jewish children. In fact, in the 20% of both populations for whom data were available, modest reductions in overall antibiotic use, including amoxicillin and cephalosporins, were observed. Azithromycin prescriptions, on the other hand, increased markedly in both groups—antibiotic replacement, so to speak. This is important for 2 reasons. First, azithromycin may promote macrolide resistance better than other macrolides because of its long half‐life and low extracellular concentrations [25]. Macrolide resistance often travels with other resistance determinants, so it is plausible that the dramatic increase in multidrug resistance can be attributed to increased azithromycin use. Second, azithromycin use increased dramatically in the United States after its licensure in 1991 at the same time that overall antibiotic use was declining [26] and the prevalence of multidrug‐resistant S. pneumoniae was increasing [27]. This pattern suggests that the appearance of multidrug‐resistant serotype 19A in the United States and southern Israel may somehow have been a response to the introduction and increased use of azithromycin. However, if Bedouin and Jewish children both experienced important increases in azithromycin use, why were the increases in multidrug‐resistant serotype 19A confined to the Bedouin population? A careful look at differences between these populations may shed light on this question.

One important difference relates to seasonal patterns of antibiotic use. Antibiotic prescribing among Jewish children declines substantially in warm months and is accompanied by reductions in antibiotic resistance, whereas, among Bedouins, antibiotic prescribing and the prevalence of antibiotic resistance are more consistent year‐round [28]. This more stable antibiotic pressure may force strains colonizing Bedouin children to maintain multidrug‐resistance determinants despite the fitness costs required to do so [29]. There are also important socioeconomic disparities to consider. According to Dagan et al., Jews and Bedouins live side by side without intermingling. Bedouins have lower family incomes, but their birth rates and family sizes are more than double those of their Jewish counterparts. If living conditions among Bedouins favor more intense transmission, this may be sufficient to overcome any growth costs paid by the organism to sustain multiple resistance determinants [30]. Similar relationships between socioeconomic factors and pneumococcal colonization and transmission have been described in other settings [18, 3134].

Is the emergence of serotype 19A in the PCV7 era entirely attributable to antibiotic use, and is the introduction of PCV7 pure coincidence? It is hard to imagine that increases in serotype 19A causing otitis and invasive disease are not in some way related to the introduction of PCV7, and evidence of increased genetic diversity within serotype 19A, including some antibiotic‐susceptible clones, suggests that a serotype‐specific selection process is at work [16]. But Dagan et al.’s study reminds us to consider how other important factors, such as antibiotics, contribute to well‐documented trends in individual pneumococcal serotypes in the absence of PCV7 [3537]. It is a cautionary note to resist the temptation to attribute all increases in nonvaccine serotypes to the introduction of PCV7, as biologically plausible as that relationship may be. As we prepare for the availability of pneumococcal conjugate vaccines with expanded valency and as the introduction of conjugate vaccine moves forward among vulnerable populations of the world’s poor, Dagan et al. remind us that vaccines do not cause antibiotic resistance, antibiotics do.

 

See Also:

Introduction and Proliferation of Multidrug‐Resistant Streptococcus pneumoniae Serotype 19A Clones That Cause Acute Otitis Media in an Unvaccinated Population

(The Journal of Infectious Diseases 2009;199:776–785)

Effect of Pneumococcal Conjugate Vaccine on Pneumococcal Meningitis

Effect of Pneumococcal Conjugate Vaccine on Pneumococcal Meningitis  

ABSTRACT

Background Invasive pneumococcal disease declined among children and adults after the introduction of the pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in 2000, but its effect on pneumococcal meningitis is unclear. Methods We examined trends in pneumococcal meningitis from 1998 through 2005 using active, population-based surveillance data from eight sites in the United States. Isolates were grouped into PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), PCV7-related serotypes (6A, 9A, 9L, 9N, 18A, 18B, 18F, 19B, 19C, 23A, and 23B), and non-PCV7 serotypes (all others). Changes in the incidence of pneumococcal meningitis were assessed against baseline values from 1998–1999.

Results We identified 1379 cases of pneumococcal meningitis. The incidence declined from 1.13 cases to 0.79 case per 100,000 persons between 1998–1999 and 2004–2005 (a 30.1% decline, P<0.001). Among persons younger than 2 years of age and those 65 years of age or older, the incidence decreased during the study period by 64.0% and 54.0%, respectively (P<0.001 for both groups). Rates of PCV7-serotype meningitis declined from 0.66 case to 0.18 case (a 73.3% decline, P<0.001) among patients of all ages. Although rates of PCV7-related–serotype disease decreased by 32.1% (P=0.08), rates of non-PCV7–serotype disease increased from 0.32 to 0.51 (an increase of 60.5%, P<0.001). The percentages of cases from non-PCV7 serotypes 19A, 22F, and 35B each increased significantly during the study period. On average, 27.8% of isolates were nonsusceptible to penicillin, but fewer isolates were nonsusceptible to chloramphenicol (5.7%), meropenem (16.6%), and cefotaxime (11.8%). The proportion of penicillin-nonsusceptible isolates decreased between 1998 and 2003 (from 32.0% to 19.4%, P=0.01) but increased between 2003 and 2005 (from 19.4% to 30.1%, P=0.03).

Conclusions Rates of pneumococcal meningitis have decreased among children and adults since PCV7 was introduced. Although the overall effect of the vaccine remains substantial, a recent increase in meningitis caused by non-PCV7 serotypes, including strains nonsusceptible to antibiotics, is a concern.

 

NEJM:

Volume 360:244-256

 

January 15, 2009

Also:

Pediatric Vaccine Effectively Prevents Pneumococcal Meningitis, Study Suggests

ScienceDaily (Jan. 16, 2009) — A standard pediatric vaccine used to prevent several common types of life-threatening infections also effectively reduced the rates of another disease, pneumococcal meningitis, in children and adults, according to a multi-center study led by the University of Pittsburgh School of Medicine. The study, published in the Jan. 15 issue of the New England Journal of Medicine and based on a detailed review of pneumococcal meningitis cases, also noted an increase in strains of pneumococcal meningitis not covered by the vaccine and those resistant to antibiotics.

An often deadly disease, pneumococcal meningitis is an infection in the brain and spinal cord membranes caused by the pneumococcus – a bacterium that also causes pneumonia and other serious infections. The highest rates of pneumococcal infections occur in very young children. There are approximately 2,700 cases of pneumococcal meningitis in the U.S. every year.

After reviewing 1,379 cases of pneumococcal meningitis from 1998 through 2005, study authors found rates of the disease decreased in children and adults after the introduction of pediatric pneumococcal conjugate vaccine (PCV7) in 2000. PCV7 protects against seven of the most common pneumococcal types, which account for over 80 percent of pneumococcal disease in young children. PCV7 is not administered to adults.

According to the study, incidence rates for pneumococcal meningitis in all age groups declined 30.1 percent from 1998-1999 to 2004-2005. After PCV7 was made available, the incidence of meningitis decreased by 64 percent in children and by 54 percent in older adults.

“When you immunize children, they are much less likely to carry pneumococcal strains covered by the vaccine in the back of the throat,” explained Lee Harrison, M.D., senior author of the study and professor of medicine, University of Pittsburgh School of Medicine. “When vaccinated children don’t carry these virulent strains, they don’t end up transmitting them to other children, their parents and grandparents.” Prior to the study, conflicting data existed on the vaccine’s effect on the incidence of meningitis in adults, he said.

The authors also observed that non-PCV7 strains increased by 60.5 percent from the 1998-1999 period to 2004-2005, and the percentage of strains that were not sensitive to penicillin, which initially declined, increased from 19.4 percent in 2003 to 30.1 percent in 2005.

“PCV7 has been highly successful in preventing pneumococcal meningitis, but it remains a very serious and deadly disease,” said Dr. Harrison. “Of the patients in our study, 8 percent of children and 22 percent of adults died. These findings indicate the need to continue to explore new methods of prevention with a special emphasis on strains that are not covered by PCV7 and strains that are drug resistant. Next-generation vaccines are in development and patients and physicians need to avoid unnecessary use of antibiotics.”

In addition to Dr. Harrison, who conducted this study in collaboration with the Johns Hopkins Bloomberg School of Public Health, co-authors of the study include first author Heather Hsu, M.P.H. and Kathleen Shutt, both at the University of Pittsburgh; Matthew Moore, M.D., M.P.H., Bernard Beall, Ph.D., and Cynthia Whitney, M.D., M.P.H., Centers for Disease Control and Prevention; Nancy Bennett, M.D., University of Rochester; Allen Craig, M.D., Tennessee Department of Health; Monica Farley, M.D., Emory University; James Jorgensen, Ph.D., University of Texas Health Sciences Center; Catherine Lexau, Ph.D., M.P.H., Minnesota Department of Health; Susan Petit, M.P.H., Connecticut Department of Health; Arthur Reingold, M.D., University of California Berkeley; William Schaffner, M.D., Vanderbilt University School of Medicine; and Ann Thomas, M.D., Oregon State Public Health Division.

The study was funded by the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases.

Serotype 19A of Streptococcus pneumoniae

19A Linked to Necrotizing Pneumonia

Pediatric News  Volume 42, Issue 12, Page 12 (December 2008)

 

WASHINGTON — Serotype 19A of Streptococcus pneumoniae is the culprit behind some complicated cases of necrotizing pneumonia in young children, based on findings from four cases that occurred between September 7, 2007, and March 30, 2008, at a single hospital.

“Severe necrotizing pneumonia caused by this serotype had not previously been reported in children,” explained Dr. Susan Wootton of the University of Texas, Houston, who presented the cases with her associates in a poster at the jointly held annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

The 19A strain is one of several that are not included in the current pneumococcal conjugate vaccine, PCV7. Data from the Centers for Disease Control and Prevention that also were presented at the meeting showed an increase in invasive pneumococcal disease from nonvaccine serotypes in all age groups.

The four children ranged in age from 3 to 4 years (mean age, 3.4 years). Of these, three were previously healthy and one had asthma. All four had been vaccinated with PCV7. S. pneumoniae was isolated from pleural fluid in three cases and from blood in three cases.

Chest radiographs revealed multilobar infiltrates in four children, empyema in three children, and pneumatoceles in two children. Overall, three children were admitted to the intensive care unit and intubated 5–22 days, with an average of 11 days. In addition, three children had abscesses that required surgical drainage. The hospital stays ranged from 11 to 28 days (average stay, 19 days).

Serotype 19A has not previously been reported as a cause of complicated pneumonia in children, but these cases suggest that it should now be considered in the differential diagnosis, Dr. Wootton and her associates noted.

This study was limited by its small size and narrow geographical scope, and more research is needed to assess the large-scale impact of serotype 19A on necrotizing pneumonia. But the results support the need for an expanded pneumococcal vaccine for children in the United States, they said.

Dr. Wootton stated that she had no financial conflicts to disclose.

Invasive, paediatric, vaccine strains of Streptococcus pneumoniae: Are there differences in clinical characteristics?

Invasive, paediatric, vaccine strains of Streptococcus pneumoniae: Are there differences in clinical characteristics?

Abstract

Invasive pneumococcal infections in 777 adults caused by ‘invasive’ (1, 7; n=187), ‘paediatric’ (6, 9, 14, 19, 23; n=304) and other (n=286) serogroups were compared. Infections caused by ‘invasive’ strains caused pneumonia more often than other serogroups and were more often isolated from younger patients without concomitant conditions and had lower case-fatality rate than ‘paediatric’ and other strains. The 2 latter groups differed little from each other. Infections caused by strains in the 7-valent pneumococcal conjugate vaccine differed little from infections caused by non-vaccine types indicating that widespread use of this vaccine will not markedly change the clinical characteristics of invasive pneumococcal infections in adults.

Emergence of Streptococcus pneumoniae Serotypes

Emergence of Streptococcus pneumoniae Serotypes 19A, 6C, and 22F and Serogroup 15 in Cleveland, Ohio, in Relation to Introduction of the Protein-Conjugated Pneumococcal Vaccine

Clinical Infectious Diseases 2008;47:1388–1395    2008

Background.  A 7-valent conjugate pneumococcal vaccine (PCV7) was introduced in 2000.

Methods.  We determined serotypes and assessed antimicrobial susceptibility of 1235 invasive and noninvasive isolates of Streptococcus pneumoniae recovered from children and adults at University Hospitals Case Medical Center (Cleveland, OH) during the period 1999–2007.

Results.  The annual number of cases of S. pneumoniae infection decreased from 218 in 2000 to 86–130 during the period 2002–2007, with the number of cases involving invasive strains decreasing from 96 to 18–35. For 1999 versus 2005–2007, the annual incidence of vaccine serotypes decreased by 92% (95% confidence interval [CI], −96.3% to −87.0%), whereas that of vaccine-related and nonvaccine serotypes increased 207.4% (95% CI, 135.0%–297.7%) and 18.4% (95% CI, −10.0% to 52.3%), respectively. Serotypes 19A, 6C, and 22F and serogroup 15 accounted for most of these increases. For the period 2005–2007, antimicrobial susceptibility testing revealed that ceftriaxone was the most active parenteral β-lactam for both meningeal and nonmeningeal infections (72% and 88% of isolates, respectively, were susceptible to this agent); only 52% were susceptible to penicillin G at the meningeal breakpoint, whereas 77% were susceptible at the new nonmeningeal breakpoint of 2 μg/mL. Amoxicillin was the most active oral β-lactam (72% of isolates were susceptible), whereas 53% of isolates were susceptible to azithromycin, 69% to clindamycin, 63% to trimethoprim-sulfamethoxazole, and 100% to levofloxacin.

Conclusions.  This study documents decreases in the incidence of infections involving vaccine serotypes, increases in infections involving other serotypes, and decreases in the activity of macrolides and clindamycin after conjugate vaccine introduction.