Reduction in High Rates of Antibiotic-Nonsusceptible Invasive Pneumococcal Disease in Tennessee after Introduction of the Pneumococcal Conjugate Vaccine

Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 09/2004; 39(5):641-8. DOI: 10.1086/422653
Source: PubMed


Invasive pneumococcal disease (IPD) is a burgeoning problem, with rates of antibiotic-nonsusceptible IPD, in particular, increasing during the past decade. One measure to combat IPD is vaccination with the recently introduced 7-valent pneumococcal conjugate vaccine (PCV).
To evaluate the effects of the introduction of PCV in 2000 on the epidemiology of antibiotic-nonsusceptible IPD, a database of IPD cases from January 1995 through December 2002 identified through active surveillance in 5 Tennessee counties was examined. For each case, clinical data were collected, and antibiotic susceptibility testing and serotyping were performed on available isolates.
Among children younger than 2 years, IPD rates peaked at 235 cases per 100,000 in 1999 before decreasing, after PCV licensure, to 46 cases per 100,000 in 2002 (P<.001). The proportion of penicillin-nonsusceptible IPD isolates from this age group declined from 59.8% in 1999 to 30.4% in 2002 (P<.01). After 2001, similar decreases in IPD rates and in the proportion of antibiotic-nonsusceptible isolates recovered were seen among persons aged 2 years and older (P<.01). Rates of IPD due to PCV-associated serotypes declined after PCV introduction in all age groups (P<.001), whereas the rate of IPD due to nonvaccine serotypes increased among persons aged 2 years and older.
In the 2 years since licensure, widespread PCV vaccination of children has resulted in dramatic declines in the proportion of antibiotic-nonsusceptible isolates in Tennessee. PCV vaccination of children also appears to be a highly effective method for reducing the burden of IPD in adults.

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    • "In Northern California, U.S., a population-based study suggested that the high level of penicillin resistance decreased from 15% in 2000 to 5% in the first half of 2003 [39]. In Tennessee, U.S., the proportion of penicillin-nonsusceptible pneumococci decreased from 59.8% in 1999 to 30.4% in 2002 among children aged < 2 years [40]. "
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    ABSTRACT: The wide use of antimicrobial agents and 7-valent pneumococcal conjugate vaccine (PCV7) has led to major changes in the epidemiology of childhood pneumococcal diseases. In Korea, data on the population-based incidence of childhood invasive pneumococcal diseases (IPD) are not available; however, institution-based surveillance data suggest a substantial burden of childhood IPD. Following the introduction of the PCV7 in Korea in 2003, the proportion of IPD caused by vaccine-type pneumococci has decreased, while non-PCV7 serotypes, especially serotypes 19A and 6A, whose proportions had been increasing before the introduction of the vaccine, became predominant among childhood IPD isolates. This article reviews the overall impact of PCV7 utilization and summarizes the results obtained so far. Continuous monitoring and gathering of scientific evidence for the epidemiological transition of pneumococcal carriage and IPD will be important for the management of pneumococcal infections in Korea.
    06/2013; 45(2):145-158. DOI:10.3947/ic.2013.45.2.145
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    • "Data from the U.S. suggests significant reductions in antibiotic prescribing for paediatric cases of otitis media have occurred following licensing of PCV7 [37]. Similarly, a reduction in the incidence of antibiotic-non-susceptible IPD has also been reported, and has been attributed to widespread PCV7 vaccination [41]. This potential benefit is of significant importance in Malaysia where S. pneumoniae isolates have exhibited increased antibiotic resistance. "
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    ABSTRACT: Pneumococcal disease is the leading cause of vaccine-preventable death in children younger than 5 years of age worldwide. The World Health Organization recommends pneumococcal conjugate vaccine as a priority for inclusion into national childhood immunization programmes. Pneumococcal vaccine has yet to be included as part of the national vaccination programme in Malaysia although it has been available in the country since 2005. This study sought to estimate the disease burden of pneumococcal disease in Malaysia and to assess the cost effectiveness of routine infant vaccination with PCV7. A decision model was adapted taking into consideration prevalence, disease burden, treatment costs and outcomes for pneumococcal disease severe enough to result in a hospital admission. Disease burden were estimated from the medical records of 6 hospitals. Where local data was unavailable, model inputs were obtained from international and regional studies and from focus group discussions. The model incorporated the effects of herd protection on the unvaccinated adult population. At current vaccine prices, PCV7 vaccination of 90% of a hypothetical 550,000 birth cohort would incur costs of RM 439.6 million (US$128 million). Over a 10 year time horizon, vaccination would reduce episodes of pneumococcal hospitalisation by 9,585 cases to 73,845 hospitalisations with cost savings of RM 37.5 million (US$10.9 million) to the health system with 11,422.5 life years saved at a cost effectiveness ratio of RM 35,196 (US$10,261) per life year gained. PCV7 vaccination of infants is expected to be cost-effective for Malaysia with an incremental cost per life year gained of RM 35,196 (US$10,261). This is well below the WHO's threshold for cost effectiveness of public health interventions in Malaysia of RM 71,761 (US$20,922).
    BMC Infectious Diseases 09/2011; 11(1):248. DOI:10.1186/1471-2334-11-248 · 2.61 Impact Factor
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    ABSTRACT: Aims: This thesis investigated the prevalence of and trends in antimicrobial resistance in pneumococci in Finland, determined the genetic basis of macrolide resistance and evaluated the level of telithromycin nonsusceptibility prior to its widespread usage. In addition, the clonality of telithromycin-resistant and penicillin-resistant isolates was examined. Results: Of the 1007 pneumococci collected in 2002, 21.5%, 12.1%, and 14.4% were non-susceptible to erythromycin, penicillin and tetracycline, respectively. Multiresistance was detected in 10.5% of the isolates. Only 0.1% of the isolates were non-susceptible to ceftriaxone (non-meningitis breakpoint) and <1.5% to fluoroquinolones. Two isolates were nonsusceptible to linezolide. Among invasive pneumococci (n=3571) collected in 2002-2006, erythromycin resistance increased from 16% (2002) to 28% (2006) (Poisson regression, p < 0.0001), penicillin non-susceptibility from 8% to 16% (< 0.0001) and penicillin resistance from 0.8% to 3.7% (p = 0.03). Tetracycline resistance remained stable (~10%), as did the proportion of multiresistant isolates (~5%). Levofloxacin and ceftriaxone resistance was rare. In both sets of collections of pneumococci, the highest prevalence of erythromycin resistance was among isolates derived from 0- to 2-year-old children: in 2006, 45.8% of isolates were resistant to erythromycin in this age group. In 2002, disk diffusion testing revealed 26/1007 (2.6%) pneumococcal isolates that produced one to several clearly visible colonies inside the growth inhibition zone, indicating heterogeneous resistance to telithromycin. This type of telithromycin resistance has not been previously described. All such isolates were erm(B) positive, but the exact underlying mechanism of telithromycin resistance remained unresolved. Telithromycin resistant isolates had seven distinct sequence types, of which ST193 was the most frequent (n = 19). ST193 isolates were all 19A serotype variants of the PMEN clone Greece21-30. Among penicillin resistant isolates in 2002-2006, a total of 25 sequence types were found that distributed into ten clonal lineages. The most common clonal complex was CC156, accounting for 61% of all penicillin resistant isolates. The majority of the penicillin-resistant pneumococci were representatives of single to triple locus variants of the following PMEN clones: Spain9V ST156, Taiwan19F ST236, Spain23F ST81, and England14 ST9. In 2002, the most frequent macrolide resistance gene was the mef gene (49%), followed by erm(B) (41%). A double mechanism [mef(E)+erm(B)] was detected in 5 (2.3%) isolates. Of the mef genes, 89% had the mef(E) subclass and 11% had mef(A). Mutation was detected in 16 isolates, of which 14 isolates (6.4%) had no other known resistance factor. In 2002-2006 the macrolide gene distribution was the following: 56% of the macrolide resistant isolates had mef gene and 31% had erm(B). Only two isolates had both mef(E) and erm(B). mef(E) was the most common mef subtype (72%). Conclusions: The main observation of this thesis was the presence ofheterogeneous telithromycin resistance among pneumococci carrying erm(B). Such isolates harbour a minor population of bacterial cells capable of expressing high level telithromycin resistance in vitro, which may be clinically significant. Because dilution methods do not favour the detection of this resistance type, the disk diffusion susceptibility testing of erm(B)-positive pneumococci is recommended. Due to the high prevalence of resistance, macrolides cannot be recommended as the first line drugs for the treatment of pneumococcal infections. Apart from macrolide resistance, the proportion of penicillin non-susceptible isolates is rising. Pneumokokki on yksi yleisimmistä taudinaiheuttajista Suomessa. Se aiheuttaa lasten korvatulehduksia, keuhkotulehduksia ja vakavia yleisinfektioita. Tässä tutkimuksessa selvitettiin pneumokokkibakteerin mikrobilääkeresistenssin esiintyvyyttä ja trendejä Suomessa ja testattiin kantojen herkkyyttä telitromysiinille ennen sen laajamittaista käyttöönottoa. Lisäksi tutkittiin makrolidiresistenssimekanismeja sekä resistenttien pneumokokkien klonaalisuutta. Tutkimus perustuu kahteen aineistoon, joista ensimmäinen käsittää 1007 pneumokokkikantaa, jotka on kerätty vuonna 2002. Toinen aineisto käsittää kaikki Suomessa eristetyt invasiiviset pneumokokit vuosilta 2002–2006 (n = 3571). Tulokset: Vuonna 2002 kerätystä 1007 pneumokokkikannasta 21.5 %, 12.1 %, 14.4 % oli herkkyydeltään heikentyneitä erytromysiinille, penisilliinille ja tetrasykliinille. Kannoista 10.5 % oli multiresistenttejä. Vain 0.1 % kannoista oli herkkydeltään heikentyneitä keftriaksonille ja <1.5 % fluorokinoloneille. Vuosina 2002–2006, erytromysiiniresistenssi nousi 16 %:sta (2002) 28 %:iin (2006) (p < 0.0001). Penisilliinille ei-herkkien kantojen osuus nousi 8 %:sta 16 %:iin (< 0.0001) ja penisilliinille resistenttien kantojen osuus 0.8 %:sta 3.7 %:iin (p = 0.03). Tetrasykliiniresistenssi pysyi tasaisena (~10 %), kuten myös multiresistenttien kantojen osuus (~5 %). Levofloksasiini- ja keftriaksoniresistenssi oli harvinaista. Molemmissa aineistoissa korkein makrolidiresistenssi havaittiin pneumokokeissa, jotka olivat peräisin 0-2 vuotiailta lapsilta. Vuonna 2006 tässä ikäryhmässä jo 46 % pneumokokeista oli resistentteijä erytromysiinille. Vuonna 2002 kerätyistä pneumokokeista 26 (2.6 %) kannassa todettiin kiekkoherkkyystestauksessa heterogeenista resistenssiä telitromysiinille. Näillä kannoilla telitromysiinikiekon estovyöhykkeen sisällä havaittiin selkeitä pesäkkeitä, joiden lukumäärä vaihteli. Aiemmin tällaista telitromysiiniresistenssiä ei ole dokumentoitu. Kaikilla telitromysiini-resistenteillä kannoilla oli erm(B) makrolidiresistenssigeeni, mutta telitromysiiniresistenssin tarkempi mekanismi ei kuitenkaan selvinnyt. Telitromysiiniresistentit pneumokokit edustivat seitsemää eri genotyyppiä. Vuonna 2002–2006 penisilliiniresistenttit kannat olivat peräisin 10 klonaalisesta linjasta. Valtaosa penisilliinille resistenteistä pneumokokeista oli läheistä sukua laajalti levinneille pneumokokkiklooneille. Vuonna 2002 yleisin makrolidiresistenssimekanismi oli mef geeni (49 %). Tämä geeni koodaa pumppumekanismia, joka pumppaa makrolidimolekyylejä ulos bakteerisolusta. erm(B) geeni löytyi 41 % erytromysiinille resistenteistä pneumokokeista. Tämä geeni koodaa metylaasientsyymiä, joka muuttaa lääkeaineen sitoutumiskohtaa bakteerisolussa siten, että lääkeaine ei pysty siihen sitoutumaan. Kuudellatoista makrolidiresistentillä pneumokokilla löytyi mutaatio joko ribosomissa tai ribosomaalisissa proteiineissa. Myös mutaation johdosta lääkeaineen sitoutumiskohta muuttuu siten, että bakteeri tulee vastustuskykyiseksi mikrobilääkkeelle. Vuosina 2002–2006 invasiivisten pneumokokkien makrolidiresistenssigeenijakauma oli samankaltainen. Johtopäätökset: Tämän tutkimuksen päähavainto oli pneumokokkien heterogeenisen telitromysiiniresistenssin löytyminen. Yhteistä kannoille oli erm(B) makrolidiresistenssigeenin löytyminen genomista. Tällaisilla bakteerikannoilla on yksittäisiä bakteerisoluja, jotka ovat kykeneviä ilmentämään korkea-asteista telitromysiiniresistenssiä laboratoriolosuhteissa. Kuvatunkaltaisella resistenssillä saattaa olla kliinistä merkitystä. Koska mikrobilääkeherkkyystutkimuksissa laimennosmenetelmät eivät suosi heterogeenisen telitromysiiniresistenssin havaitsemista, erytromysiinille resistentit pneumokokit tulisi testata kiekkoherkkyysmenetelmällä. Tutkimuksessa havaittiin myös että pneumokokkien makrolidiresistenssi on huolestuttavasti lisääntynyt ja että se on erityisen korkea kannoilla, jotka ovat peräisin pienten lasten infektioista. Tästä syystä makrolideja ei voi suositella ensisijaislääkityksenä pneumokokki-infektioiden hoitoon. Makrolidiresistenssin ohella myös penisilliinille herkkyydeltään heikentyneiden kantojen osuus nousi jyrkästi tutkimusajanjaksolla.
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