Carriage of resistant pneumococci by children in southern Israel and impact of conjugate vaccines on carriage Clin Miuobiol hfect 1999; 5: 4S29-4S37 Ron Dagan', Drora Fraser2, Noga Given'?' and Pablo Yagupsky' 'Pediatric Infectious Disease Unit, *Department of Epidemiology, 3Clinical Microbiology Laboratories, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Stveptococctrs prieumoniae is an important cause of morbi- dity and mortality worldwide [l]. Its main reservoir is the nasopharynx. From the nasopharynx, the organism can: (1) enter the bloodstream to cause invasive in- fections such as sepsis, meningitis and infections in remote foci such as arthritis, osteoniyelitis and cellulitis; (2) spread to adjacent mucosal tissues to cause mucosal infections such as otitis, sinusitis and pneumonia; and (3) be transmitted by direct contact and through aerosols to other individuals. Many individuals in a population are colonized with S. pneumoniae at any given time, and most children are colonized at some point during the first years of life [2-41. Resistance of piieumococci to antimicrobial agents, which was first reported in the mid-1960s [5,6], is increasing worldwide and has an enormous impact on clinicians, microbiologists, drug manufacturers, and public-health authorities [7,8-3 01. Antibiotic-resistant pneumococci are more often carried by infants and young children than by adults [ll-131. Furthermore, since most of the resistant strains belong to only a limited number of serotypes, which are also among the most common causes of pediatric infections [7,14-171, conjugate vaccines aimed at these antigens may provide a useful tool to reduce nasopharyngeal carriage and liniit the spread of resistant pneumococci. The goal of this communication is to describe the carriage of antibiotic-resistant S. pneumoniae in children in southern Israel and to review the current experience of the effect of the new conjugate pneumococcal vac- Corresponding author and reprint requests: Ron Dagan, Pediatric Infectious Disease Unit, Soroka University Medical Center, PO Box 151, Beer-Sheva 84101, Israel Tel: +972 7 640 0547 Fax: +972 7 623 2334 E-mail: [email protected]cines on carriage of S. pneumorziae in general, and that of antibiotic-resistant S. pneumoniue in particular, from studies in our region. The Negev region in southern Israel constitutes 60% of the land mass of the country while having less than 8% of the population. The area is largely desert, with high daytime temperatures, especially in the summer months, and low night-time temperatures, especially in the winter. There are about 20 days of rain annually. The two major population subgroups living in the area are Jews, largely concentrated in urban areas, and Bedouin Arabs, who are in transition from their tradi- tional nomadic ways to a semi-urban westernized lifestyle. While the Jewish population (over 77%) of the population) resembles that of the rest of Israel in socio- cultural and ethnic characteristics, except for the slightly lower overall socio-economic level, the Bedouins form a unique population group. They retain their traditions in certain aspects of their lives, including polygamy (up to four wives are allowed by Islamic law). This population has an extremely high birth rate. The high birth rate, low socio-economic status, over- crowding, bad housing conditions and poor hygienic conditions result in high rates of infectious diseases, including respiratory illness, gastroenteritis and parasitic infections. The morbidity and birth rate patterns among the Jewish population are similar to those of the developed nations. In contrast, the Bedouins have the lifestyle and morbidity and mortality patterns of developing populations, while modern diagnostic and health care delivery services are dl near at hand. CARRIAGE OF S. PNWMONlAEAND ANTIBIOTIC- RESISTANT S. PNEUMONIA€ DURING EARLY CHILDHOOD IN SOUTHERN ISRAEL We studied the carriage of S. pnrumoniac in healthy children during the first 2 years of life seen at maternal 4S29
Transcript
Carriage of resistant pneumococci by children in southern Israel and impact of conjugate vaccines on carriage
Clin Miuobiol h f e c t 1999; 5: 4S29-4S37
Ron Dagan', Drora Fraser2, Noga Given'?' and Pablo Yagupsky'
'Pediatric Infectious Disease Unit , *Department of Epidemiology, 3Clinical Microbiology Laboratories, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Stveptococctrs prieumoniae is an important cause of morbi- dity and mortality worldwide [l]. Its main reservoir is the nasopharynx. From the nasopharynx, the organism can: (1) enter the bloodstream to cause invasive in- fections such as sepsis, meningitis and infections in remote foci such as arthritis, osteoniyelitis and cellulitis; (2) spread to adjacent mucosal tissues to cause mucosal infections such as otitis, sinusitis and pneumonia; and (3) be transmitted by direct contact and through aerosols to other individuals. Many individuals in a population are colonized with S. pneumoniae at any given time, and most children are colonized at some point during the first years of life [2-41.
Resistance of piieumococci to antimicrobial agents, which was first reported in the mid-1960s [5,6], is increasing worldwide and has an enormous impact on clinicians, microbiologists, drug manufacturers, and public-health authorities [7,8-3 01. Antibiotic-resistant pneumococci are more often carried by infants and young children than by adults [ll-131. Furthermore, since most of the resistant strains belong to only a limited number of serotypes, which are also among the most common causes of pediatric infections [7,14-171, conjugate vaccines aimed at these antigens may provide a useful tool to reduce nasopharyngeal carriage and liniit the spread of resistant pneumococci.
The goal of this communication is to describe the carriage of antibiotic-resistant S. pneumoniae in children in southern Israel and to review the current experience of the effect of the new conjugate pneumococcal vac-
Corresponding author and reprint requests:
Ron Dagan, Pediatric Infectious Disease Unit, Soroka University Medical Center, PO Box 151, Beer-Sheva 84101, Israel
cines on carriage of S. pneumorziae in general, and that of antibiotic-resistant S. pneumoniue in particular, from studies in our region.
The Negev region in southern Israel constitutes 60% of the land mass of the country while having less than 8% of the population. The area is largely desert, with high daytime temperatures, especially in the summer months, and low night-time temperatures, especially in the winter. There are about 20 days of rain annually.
The two major population subgroups living in the area are Jews, largely concentrated in urban areas, and Bedouin Arabs, who are in transition from their tradi- tional nomadic ways to a semi-urban westernized lifestyle. While the Jewish population (over 77%) of the population) resembles that of the rest of Israel in socio- cultural and ethnic characteristics, except for the slightly lower overall socio-economic level, the Bedouins form a unique population group. They retain their traditions in certain aspects of their lives, including polygamy (up to four wives are allowed by Islamic law). This population has an extremely high birth rate. The high birth rate, low socio-economic status, over- crowding, bad housing conditions and poor hygienic conditions result in high rates of infectious diseases, including respiratory illness, gastroenteritis and parasitic infections. The morbidity and birth rate patterns among the Jewish population are similar to those of the developed nations. In contrast, the Bedouins have the lifestyle and morbidity and mortality patterns of developing populations, while modern diagnostic and health care delivery services are dl near at hand.
CARRIAGE OF S. P N W M O N l A E A N D ANTIBIOTIC- RESISTANT S. PNEUMONIA€ DURING EARLY CHILDHOOD IN SOUTHERN ISRAEL
We studied the carriage of S. pnrumoniac in healthy children during the first 2 years of life seen at maternal
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child health centers during vaccination visits in the city of Beer-Sheva in southern Israel [18]. We were struck by the high prevalence of carriage of S. pneumoniae in general, and the carriage of resistant S. pneumoniae in particular, among these healthy children (Figure 1). Approximately one-quarter of the children carried S. pneumoniae at 2 months of age, the rate increasing gradually to almost two-thirds at age 24 months. More alarming was the carriage of resistant S. pneumoniae among these healthy children: 11% and 27% carried S. pneumoniae resistant to at least one antibiotic drug at ages 2 and 24 months, respectively, and 4% and 18%, respectively, carried S. pneumoniae resistant to 2 2 drugs.
Several important risk factors for the carriage of resistant S. pneumoniae were identified. They included recent antibiotic use (relative risk (RR) 2.6; confidence interval (CI) 1.9-3.5); the presence of older siblings at home (RR for penicillin-resistant S. pneumoniae 4.3; CI 1.0-18.1); and day-care attendance (RR 2.5; CI 2.2-2.9). It became obvious that not only was the day- care attendance important in itself, but also that the carriage of S. pneurnoniae in general and resistant S. pneumoniae in particular was associated with the size of the day-care center as measured by the number of children in the group (Figure 2).
The observation that factors such as the presence of siblings and day-care attendance pose a risk for carriage of S. pneumoniae implies that crowding is an
70 1 gj AII S. pneumoniae
Any resistance
Resistance to 22 drugs 6o i 50 1 40
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important factor which facilitates the spread of S. pneumoniae. We therefore compared the carriage among Jewish children initially studied [18] with the carriage among the Moslem Bedouin children in the region. This population is characterized by a high birth rate and overcrowding. In southern Israel, the crude birth rates in 1996 were 19.0/1000 and 55.9/1000 in Jews and Bedouins respectively. In addition, in Israel as a whole, only 4.3% of Jewish households had seven or more persons, while in the Moslem population 24.1% of households were overcrowded. As the birth rate of Negev Moslems is higher than that of the whole Moslem population of Israel (55.9/1000 and 37.2/1000 respectively), there is no doubt that the overcrowding rate in southern Israel is also higher [19]. The naso- pharyngeal carriage of S. pneumoniae among Bedouins was found to be 61%, 75% and 73% at ages 2, 6 and 12 months, respectively, compared with 26%, 39% and 38%, respectively, among the Jews (unpublished data). This higher carriage rate correlated with a 4.5-fold (P<O.OOOl) higher rate of invasive infections among the Bedouins than in the Jews [20].
To better characterize the spread of antibiotic- resistant S. pneumoniae in the day-care setting, we first studied the carriage in a day-care facility located in the city of Beer-Sheva, where nasopharyngeal cultures from S. pneumoniae were obtained every 2 weeks during a 10-month period [21]. Among the 48 children attend-
49
43
62
24 (n=53)
Age (months)
Figure 1 Nasopharyngeal carriage of S. pneumoniae in healthy Jewish infants in Beer-Shew at ages 2-24 months (adapted from Dagan et al [18]).
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O 10
a
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Antibiotic-resistant S. pneurnoniae
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Figure 2 Nasopharyngeal carriage of S. pneumoniae and antibiotic-resistant S. pneumoniae by day-care attendance and the number of children per day care group, during the second year of life in southern Israel (adapted from Dagan et al [ 181).
ing the day-care facility, S. pneumoniue was recovered in 362 of 573 (63%) of all cultures, and 60% of these isolates showed decreased susceptibility to 2 1 anti- biotic drugs. By molecular methods we showed an extensive clonal spread involving several clones. Clones exhibiting decreased antibiotic susceptibility were more frequently isolated and persisted longer than did fully susceptible clones. This points towards a biological advantage for antibiotic-resistant pneumococci in a ‘hostile’ environment where multiple antibiotic use occurs frequently.
We recently have studied children during the second and third year of life attendng eight day-care centers, each located in a different neighborhood in the city of Beer-Sheva, all within a 5-mile diameter [22]. The distribution of serotypes and antibiotic suscepti- bility differed significantly between day-care centers. Furthermore, even when the same serotype with identical antibiotic susceptibility patterns was found in various day-care centers, ribotype restriction showed homogeneity within day-care center, but variability between day-care centers. These findings emphasize the important role played by day-care facilities in the transmission and augmentation of nasopharyngeal carriage of resistant S. pneumoniae in the community. They also emphasize that it is extremely difficult to make any generalization on the prevalence of serotypes or resistance from isolated studies.
It is established that acquisition and carriage of S. pneumoniae is associated with the occurrence of acute otitis media [23], bacteremia [24-271 and pneumonia [28], but is the high rate of carriage of resistant S. pneurnoniae associated with identical rates of disease caused by resistant S. pneurnoniae? It is certainly difficult to answer this question directly. However, much indirect evidence exists, at least in the case of acute otitis media. One way to answer this question indirectly is to examine the correlation between S. pnwmoniae strains isolated from middle ear fluid in acute otitis media and those isolated at the same time from the nasopharynx. We have recently studied 112 pairs of isolates from middle ear fluid and nasopharynx obtained simultaneously from patients with acute otitis media (unpublished data). The main serotypes were 6B, 9V, 14, 18C, 19F, 19A and 23F, constituting together approximately 70% of all isolates. Of the 112 middle ear fluid isolates, 53% were penicillin susceptible and 47% were penicillin non-susceptible. In 90% of the cases, identical serotypes were isolated from both samples, and in 93‘%, identical susceptibility patterns were observed.
Another way to examine the predictability of susceptibility of causative agents of acute otitis media by the patterns of nasopharyngeal isolates is to compare the patterns between nasopharyngeal isolates in healthy children and those isolated from middle ear fluid in children with acute otitis media. We have been study-
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ing this issue in an ongoing research project conducted in Beer-Sheva. The results of our interim analysis are shown in Figure 3. The nasopharyngeal isolates were obtained from healthy children attending maternal children health centers for vaccination and day-care centers, and the middle ear fluid isolates were obtained from children from the same area with acute otitis media visiting pediatric clinics and the Pediatric Emer- gency Room at the Soroka University Medical Center. Resistance in general and penicillin resistance in parti- cular peaked at age 12-17 months, but was frequent among S. pneurnoniae isolates in all ages. A clear cor- relation in percentage of penicillin-resistant isolates and resistance to 2 1 antibiotic drugs was found in the nasopharyngeal isolates from healthy children and those from middle ear fluid from children with acute otitis media. The somewhat higher resistance rate among the middle ear fluid isolates is most probably due to the more frequent selection of treatment failures among the patients in whom tympanocentesis is performed.
We can therefore conclude that, at least for acute otitis media, which is the most common reason for antibiotic prescription in children [29], carriage of resistant S. pneurnoniue in the community correlates with disease. This is important because of the strong correlation between the presence of antibiotic resistance among S. pneurnoniae causing acute otitis media and the
clinical and bacteriologic outcome [29-311. Therefore, children nowadays find themselves in a dangerous vicious cycle: environmental factors associated with frequent and close contacts, such as the presence of siblings, crowding and day-care attendance, increase the frequency of both acute otitis media episodes and anti- biotic resistance. High prevalence of antibiotic resistance decreases the frequency of successful treatment, which increases the frequency of antibiotic use, which in its turn selects for antibiotic resistance.
To prevent this ‘snowball’ effect, it seems reason- able to examine the effect of pneumococcal vaccine on the carriage and transmission of pneumococci in general, and that of antibiotic-resistant pneumococci in particular [7,32,33].
CONJUGATE PNEUMOCOCCAL VACCINES AND THEIR POTENTIAL EFFECT ON NASOPHARYNGEAL
S. PNEUMONlAE IN CHILDREN CARRIAGE AN0 SPREAD OF ANTIBIOTIC-RESISTANT
The new developments in conjugate pneumococcal vaccines are presented elsewhere in this supplement [34]. Table 1 summarizes the most frequent pneumo- coccal serotypes/serogroups associated with the various types of disease worldwide. Serotypes/groups 6, 9, 14, 18, 19 and 23 are the most frequently found serotypes
Figure 3 Proportion of isolates from nasopharynx of healthy Jewish children compared with those isolated from middle ear fluid in children with acute otitis media, by age group. R, resistance; Pen-NS, penicdlin non-susceptible; AOM, acute otitis media; NP, nasopharynx.
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Table 1 The most common worldwide pneumococcal scrotypes/groups associated with diseases and cat-1-iage
Developed world + + + + + + Developing world + + + + + + + +
Resistant S. pnrumoniae + + + + + +
in invasive diseases, mucosal infections and carriage (with the exception of types 1 and 5, which are frequently isolated in invasive disease in the developing world, but are rarely found in mucosal infection and are carried even more rarely even in endemic areas).
The worldwide finding that most resistance is found among the serotypes most likely to cause disease in children [14-171 is important. It suggests that if the newly developed vaccines are efficacious in reducing carriage of resistant S. pneumoniae, as was observed previously with the conjugate Haernoplzilus inzuenzae type b vaccines [35-391, the approach of reduction of spread of resistant organisms by immunization might be feasible, at least in part.
The first report to show that conjugate pneumo- coccal vaccines might reduce the carriage of S. pnrw- moniae in general and that of resistant S. pneurnoniae in particular was published by our group in 1996 [40]. In this study, we examined the effect of a seven-valent pneumococcal conjugate vaccine (which included serotypes 4, 6B, SV, 14, 18C, 19F and 23F, conjugated to the outer-membrane protein complex of Neirreria meningitis group B: Pnc-OMPC) on carriage of S. yneumoniae and resistant S. pneumoniae of the serotypes included in the vaccine.
Children aged 12-1 8 months were randomized to receive one dose of a conjugate heptavalent pneumo- coccal vaccine, two doses of the same vaccine, or one dose of a 23-valent native polysaccharide vaccine. Before immunization, pneumococcal serotypes included in the conjugate vaccine were isolated from 24% of the children, and an antibiotic-resistant pneumococcus was isolated from 22% of the children. The vaccines had no effect on carriage of non-vaccine-type pneumococci. In contrast, there was a significant reduction in carriage of vaccine-type pneumococci 3 months after one dose and 1 month after a second dose of conjugate vaccine (from 25% to 9% and 7%, respectively; P<0.001). No effect was seen after vaccination with the non- conjugate vaccine. One year after immunization, car- riage of antibiotic-resistant vaccine-type pneumococci in children receiving conjugate vaccine was still lower
than that in children receiving the non-conjugate vaccine (4% versus 1496, P=0.042) (Figure 4).
Shortly after this report, a second report was published by our group. This time, the effects of tetravalent (serotypes 6B, 14, 19F and 23F) vaccine in which the polysaccharides were conjugated to diph- theria toxoid (Pnc-D) or tetanus toxoid (Pnc-T) were compared to the effect of placebo when administered to infants in a randomized double-blind study [41]. The vaccines (or placebo) were injected at 2, 4 and 6 months of age. At 12 months of age, a native (non-con- jugate) polysaccharide vaccine was administered as a booster.
Nasopharyngeal cultures were obtained at 2, 4, 6, 7, 12 and 13 months of age. In general, carriage of all pneuniococci (vaccine- and non-vaccine-related) was low at age 2 months and increased with age. However, for the vaccine-related serotypes (6A, 6B, 14, 19F and 23F), carriage was not increased with age in I'nc-D or Pnc-T recipients (Figure 5). Of all cultures obtained after the full primary series, seven of 72 (lo%), three of 62 (5%) and 19 of 70 (27%) were positive for the vaccine-related pneumococcal serotypes among the Pnc-D, Pnc-T and placebo recipients, respectively ( P =0.001 for Pnc-D versus placebo; P=0.014 for Pnc- T versus placebo). Most of the antibiotic-resistant isolates from the nasopharynx belonged to the vaccine- related serotypes.
These studies showed clearly that conjugate pneu- mococcal vaccines could reduce the carriage of S. pneumoniae and resistant S. pneumoniae of the serotypes included in the vaccines. Obaro et a1 [42] raised an important issue regarding the effect of conjugate pneumococcal vaccines on carriage. The research group in the Gambia studied the effect of the pentavalent pneuniococcal vaccine (which included serotypes 6B, 14, 18C, 19F and 23F) conjugated to C R M I C ) ~ (a non- toxic mutant of diphtheria toxin) on S. pneumoniae carriage in infants. In the Gambia, simultaneous car- riage of multiple serotypes was common. Under these circumstances, Obaro et a1 observed two opposite effects of the vaccine on carriage. (1) The serotypes
4 s 3 4 C l in ica l M i c r o b i o l o g y a n d I n f e c t i o n , V o l u m e 5 S u p p l e m e n t 4
0 Non-conjugate @l conjugate x 1 N conjugate x 2
Before 40 35 30 1 Resistant -V$ After 1 year
20 1 5 1 0 5 0
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Figure 4 Effect of 23-valent non-conjugate, one-dose seven-dent conjugate (Pnc-OMP X 1) and seven-dent two-dose conjugate (Pnc-OMPC X 2) vaccine on carriage of S. pneumoniae and resistant S. pneumoniae in children aged 12-18 months. VT, serotypes included in the vaccine (adapted from Austrian [32]).
- Pnc-T -Pnc-D - c Placebo 40
> tn 0 a
.- + .-
50 1
40
30
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10
0 2 4 6 7 1 2 1 3 2 4 6 7 12 13
Age (months)
Figure 5 The effect of a tetravalent (6B, 14, 19F and 23F) pneumococcal vaccine (either conjugated to tetanus toxoid (Pnc- T), or conjugated to hphtheria toxoid (Pnc-D)) on carriage of S. pneumoniae of the serotypes included in (6B, 14, 19F, 23F) or related to (6A) the vaccines, compared with placebo eflkct. VT, serotypes included in the vaccine.
included in the vaccine were commonly found in children aged 21 months who had not received any pneumococcal vaccine previously (the carriage rate was
83-90%). In contrast, those who had received the pentavalent conjugate vaccine at 2, 3 and 4 months of age carried the vaccine-related serotypes significantly
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less frequently (50%; P value versus controls <0.005). (2) Contrary to the effect observed with the vaccine serotypes, the other pneumococcal serotypes were carried significantly more often by the vaccine recipients than by the controls (77% versus 43%; P<0.005). This preliminary observation on the promotion of carriage of S. pneurnoniae serotype not included in the vaccine by conjugate vaccine was provocative and raised several questions and concerns.
Shortly after the observation from the Gambia, reduction of the serotypes included in the conjugate vaccine and replacement by other serotypes after immunization were confirmed by South African researchers, who immunized infants at ages 6, 10 and 14 weeks with a nine-valent (serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F) pneumococcal vaccine con- jugated to c R k l 1 9 7 [43].
Our group undertook an extensive study to determine if carriage in toddlers attending day-care centers (which, as detailed above, are probably the main location associated with amplification and spread of resistant S. pneumoniae in the community) is affected by immunization. In a double-blind prospective randoni- ized study involving 264 toddlers during their second
and third years of life, we immunized 132 toddlers with a nine-valent (containing serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F) pneumococcal vaccine conjugated to c w 1 9 7 [44]. A nasopharyngeal culture was obtained before and once monthly after immunization for 1 year, and bi-monthly during the second year. Although the study will be completed only during the first quarter of 1999, an interim analysis was done after 18 months of follow-up by a statistician not belonging to the study group [44]. At this time, 3646 cultures were obtained, with 2364 (68%) cultures being positive for S. pneu- rnoniae. Of the 2364 pneumococcal isolates, 53%, 38% and 9% were resistant to at least one antibiotic, non- susceptible to penicillin and resistant to 1 3 drugs, respectively. The interim analysis showed the following points: (1) the carriage of pneumococci included in the vaccine was significantly reduced in vaccinees com- pared with controls; (2 ) the carriage of antibiotic- resistant pneumococci was significantly reduced in vaccinees compared with controls; (3) the total carriage of S. pneumoniae was significantly reduced compared with controls; and (4) the carriage of pneumococcal serotypes not included in the vaccine was significantly increased compared with controls (Figure 6).
Figure 6 Effect of a nine-valent conjugate vaccine on the nasopharyngeal carriage of S. pneumoniae of the serotypes included in the vaccine (A), of antibiotic-resistant S. pneumoniae (B), of total S. pneumoniae (C), and of S. pneumoniae of other serotypes not included in the vaccine (D), in 132 children, compared with 132 receiving control vaccine. Children were 12-35 months of age. At each determination, 66-132 children were examined.
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The effect was observed mainly in those starting the study during their second year of life, and was almost not significant for those starting the study during the third year of life (not shown in the figure).
What is the significance of the effect of conjugate vaccines on pneumococcal carriage observed so far? It is certain that some news is good: (1) the reduction of carriage of S. pneumoniae and resistant S. pneumoniae of the vaccine types suggests a potential for a strong herd immunity effect, permitting reduction of spread of the serotypes most commonly associated with disease and antibiotic resistance in the community; (2) the strong mucosal effect of the vaccine expressed by the reduction of nasopharyngeal carriage suggests that children may also be protected from otitis media, and thus permits us to be optimistic and to hope that the high efficacy against invasive pneumococcal infections shown recently with one conjugate vaccine [45] may not be confined to invasive infections, but may also show, in the future, efficacy against the much more common mucosal infections; and (3) the effect of the vaccines on carriage may allow us in future to use reduction of carriage as an important surrogate of efficacy, if no placebo-controlled efficacy studies are allowed after introduction of pneumococcal conjugate vaccines to the immunization programs.
However, some questions have been raised which should be answered before the optimism becomes reality. (1) Does the increase in the carriage of the serotypes not included in the vaccine represent a future threat? In other words, will it be associated with increased pneumococcal disease with these serotypes? (2) Will resistance spread to the serotypes not included in the vaccine that will now be carried more often?
Certainly, these questions are important and cannot be answered in the immediate future. However, it is biologically plausible to assume that the replacement of carriage will not be associated with a replacement in disease, at least not to the same extent. The serotypes included in the vaccines, and especially the ones most resistant to antibiotics, are also most often less immuno- genic in children and can therefore be carried for long periods. This phenomenon allows them to be exposed to antibiotics for a longer period of time and thus to become more resistant. It can be speculated that the serotypes not included in the vaccine, which are also more immunogenic and therefore are carried for a shorter period of time, will have consequently less chance to become antibiotic resistant. However, anti- biotic resistance does also exist among some serotypes not included in the vaccine, especially in serotypes such as 6A and 19A, which are also quite important in disease, especially in otitis media. Although we do expect cross-protection between 6B and 6A, such
cross-protection may not occur with 19F and 19A. Thus, some doubts still remain in regard to the beneficial effect of the conjugate vaccines on the pneumococcal nasopharyngeal flora, and it is possible that in the future some additional serotypes that are antibiotic resistant and cause disease will be added to the currently developed conjugate vaccine.
In conclusion, carriage of antibiotic-resistant S. pneumoniae is frequent and is increasing worldwide, especially among infants and toddlers in crowded conditions. The use of vaccines may be one of the most efficient ways to fight this phenomenon, but other strategies, such as restriction of antibiotic use, are still extremely important.
References 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Robbins JB, Austrian R , Lee CJ, et al. Considerations for formulating the second-generation pneumococcal capsular poly- saccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis 1983; 148: 1136-59. Gray BM, Turner ME, Dillon H C Jr. Epidemiologic studies of Streptococcus pneumoniae in infants: the effects of season and age on pneumococcal acquisition and carriage in the first 24 months of life. Am J Epidemiol 1982; 116: 692-703. Musher DM. Infections caused by Streptococcus pneurnoniae: clinical spectrum, pathogenesis, immunity and treatment. Clin Infect Dis 1992; 14: 801-9. Hendley JO, Sande MA, Stewart PM, Gwaltney JM. Spread of Streptococcus pneurnofiiae in families: carriage rates and distribution of types. J Infect Dis 1975; 1 3 2 55-61. Kisiak JW, Razavi LM, Daly AK, Finland M. Susceptibility of pneumococci to nine antibiotics. Am J Med Sci 1965; 250:
Hansman D, Bullen M. A resistant pneumococcus. Lancet 1967; 2: 264-5. Munford RS, Murphy T V Antimicrobial resistance in Strepto- coccus pneumoniae: can immunization prevent its spread? J Invest Med 1994; 42: 613-21. Friedland IR, McCracken GH Jr. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994; 331: 377-82. Appelbaum PC. Antimicrobial resistance in Streptococcus pneu- moniae: an overview. Clin Infect Dis 1992; 15: 77-83. Tomasz A. The pneumococcus at the gates. N Engl J Med 1995; 333: 514-15. Koornhof HJ, Wasas A, Klugman K. Antimicrobial resistance in Streptococcus pneurnoniae: a South African perspective. Clin Infect Dis J 1992; 15: 84-94. Radetsky MS, Johansen T, Lauer B, et al. Multiply resistant pneumococcus causing meningitis: its epidemiology within a day-care centre. Lancet 1981; 2: 771-3. Reichler MR, AUphin AA, Breiman RE et al. The spread of multiply resistant Streptococcus pneurnoniae at a day care center in Ohio. J Infect Dis 1992; 166: 1346-53. Dagan R, Yagupsky I?, Goldbart A, Wasas A, Klugman K. Increasing prevalence of penicillin-resistant pneumococcal in- fections in children in southern Israel: implications for future immunization policies. Pediatr Infect Dis J 1994; 13: 782-6. Breiinan R, Butler J, Tenover F, Elliott J, Facklam R. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994; 271: 1831-5.
261-8.
D a g a n e t a l : I m m u n i z a t i o n a n d c a r r i a g e of r e s i s t a n t p n e u m o n i a e 4 s 3 7
16. Haglund LA, Istre GR, Pickett DA, Welch DF, Fine DP, the Pneuniococcus Study Group. Invasive pneumococcal disease in central Oklahoma: emergence of high-level penicillin resistance and multiple antibiotic resistance. J Infect Dis 1993; 168: 1532-6.
17. Welby P, Keller P, Cromien J. Tebas P, Storch G. Resistance to penicillin and non-beta-lactam antibiotics of Streptococcus pncumoniue at a children’s hospital. Pediatr Infect Dis J 1994; 13:
18. Dagan R, Melanied R, Muallem M, Piglansky L, Yagupsky I? Nasopharyngeal colonization with antibiotic-resistant pneumo- cocci during the first two years of life in southern Israel: relation to serotypes likely to be included in the pneumococcal conjugate vaccines. J Infect Dis 1996; 174: 1352-5.
19. Central Bureau of Statistics. Statistical Abstracts of Israel, 1997, Val. 48. Jerusalem: Herned Press Ltd, 1997.
20. Fraser D, Yagupsky P, Dagan K. A decade of pediatric invasive pneumococcal disease (IPD) in two populations resihng in Israel: implications for vaccine choice. In: Pneuiiiococcal Vaccines for the World, October, Washington DC, 1998: 26.
21. Yagupsky F‘, Porat N, Fraser D, et al. Acquisition, carriage, and transniission of pneumococci with decreased antibiotic suscepti- bility in young children attending a day care facility in southern Israel. J Infect Dis 1998; 177: 1003-12.
22. Givon N, Fraser D, Porat N, Dagan R. Day care centers as a site for development and amplification of Streptococcus pneumoniae nasopharyngeal carriage [abstract 3051. Am J Epidemiol 1998; 147: S77.
23. Faden H, lluffy L, Wasielewski R, et al. Relationship between nasopharyngeal colonization and the developnient ofotitis media in children. J Infect Dis 1997; 175: 1440-5.
24. Mastro TD, Ghahor A, Nomani NK, et al. Antimicrobial resistance of pneumococci in children with acute lower respiratory tract infection in Pakistan. Lancet 1991; 337: 156-9.
25. Lehmann D, Gratten M, Montgomery J. Susceptibility of pneuinococcal carriage isolates to penicillin provides a conser- vative estimate of susceptibility of invasive pneumococci. Pediati- Infect Dis J 1997; 16: 297-305.
26. Lloyd-Evans N, O’Dempsey TJD, Baldeh I, et al. Nasopharyn- geal carriage of pneumococci in Gambian children and in their families. Pediatr Infect Dis J 1996; 15: 866-71.
27. Gray BM, Converse GM 111, Dillon HC Jr. Epidemiologic studm of Strrptococcus pneimoniue in infants: acquisition, carriage and infection during the first 24 months of life. J lnfect Dis 1980; 142: 923-33.
28. Hodges RG, Macleod CM, Bernhard WG. Epidemc pneumo- coccal pneumonia: 111. Pneumococcal carrier studies. Am J Hyg 1946; 44: 207-30.
29. Ilagan R. Can the choice ofantibiotics for therapy ofacute otitis media be logical? EurJ Chn Microbiol Infect Dis 1998; 17: 1-5.
30. Leibovitz E, Kaiz S, Piglansky L, et al. Resistance pattern of nuddle ear fluid isolates in acute otitis media recently treated with antibiotics. Pediatr Infect Dis J 1998; 17: 463-9.
31. lhgan R, Leibovitz E, Greenberg D, Yagupsky P, Fliss DM, Leibernian A. Early erahcation of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome. Pediatr Infect Ilis J
32. Austrian R. Confronting drug-resistant pneumococci. Ann
33. Klein DL. Pneumococcal conjugate vaccines. Review and update.
281-7.
1998; 17: 776-82.
Intern Med 1994; 121: 807-9.
Microb Drug Resist 1995; 1: 48-59.
34. Klein D, Eskola J. Development and testing of Streptococcus pneumoniae conjugate vaccines. Clin Miirobiol Infect 1999; 5:
35. Mohle-Boetani JC, Ajello G, Breneniaii E, et al. Carriage of Haemophilus influenzae type b in children after widespread vacci- nation with conjugate Haemophilirs i n $ h t z a e type b vaccines. Pediatr Infect Dis J 1993; 12: 589-93.
36. Murphy TY Pastor P, Medley F, Osterholin MT, Granoff DM. Decreased Huemophilus colonization in children vaccinated with Huemophilus injuenzae type b conjugate vaccine. J Pediatr 1993;
37. Takala AK, Santosham M, Alnieido-Hill J, et al. Vaccination with Haemophilus injurnzac type b meniiigococcal protein con- jugate vaccine reduces oropharyngeal carriage of HaemopMus influcnrae type b aiiiong American lndnn children. Pediatr Infect Dis J 1993; 12: 593-9.
38. Takala AK, Eskola J, Leinonen M, et al. Reduction in oropharyngeal carriage of Harmoplrilus iu$uenzae type b (Hib) in children immunized with an Hib conjugate vaccine. J Infect Dis
39. Rarbour ML, Mayon-White RT, Crook DW, Coles C, Moxon ER. The influence of Haemophilus irjiirenzae type b conjugate vaccine (PRP-T) on oropharyngeal carriage of Haemophilus i+wrizae type b in infants under 12 months of age [abstract 3041. In: Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA. Washington DC: American Society for Microbiology, 1993: 175.
40. I$agan R, Melamed R, Muallein M, et al. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J Infect
41. Ilagan K, Muallem M, Melamed K, Leroy 0, Yagupsky F? Reduction of pneumococcal nasopharyngeal carriage in early infancy after iniiiiuiiization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Llis J 1997; 16: 1060-4.
42. Obaro SK, Adegbola RA, Banya WA, Greenwood UM. Carriage of pneuniococci after pneuniococcal vaccination. Lancet 1996; 348: 272.
43. Mbelle N, Wasar A, Huebner R, Kimura A, Chang I, Kiniiira A. Immunogenicity and impact on carriage of 9-valeiit pneunio- coccal conjugate given to infants in Soweto, South Africa [abstract LB211. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto. Washington DC: American Society for Microbiology, 1997: 13.
44. Dagan R, Givon N, Yagupsky l’, et al. Effect of a 9-valent pneumococcal vaccine conjugated to CRMiv7 (PncCRM9) on nasopharyngeal carriage of vaccine type and non-vaccine type S. pneumoniae (Pnc) strains among day-care center (IICC) attendees [abstract G-521. In: Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, California. Washington DC: American Society for Micro- biology, 1998: 299.
45. Black S, Shinefield H, Ray P, et al. Efficacy of heptavalent conjugate pneumococcal vaccine (Wyeth Lederle) in 37,000 infants and children: results of the northern California Kaiscr Pernianente efficacy trial [abstract LB91. In: Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemo- therapy, San Diego, California. Washington DC: American Society for Microbiology, 1998: 23.
