- Email: [email protected]
Complicated otitis media and its implications
Vaccine 26S (2008) G16–G19
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Complicated otitis media and its implications Eugene Leibovitz ∗ Pediatric Infectious Disease Unit, Soroka University Medical Center, Ben-Gurion University of the Negev, P.O. Box 151, 84101 Beer-Sheva, Israel
a r t i c l e
i n f o
Keywords: Recurrent otitis media Persistent otitis media Mastoiditis
a b s t r a c t Complicated otitis media (OM) is a common paediatric problem and includes two major entities: persistent acute OM (AOM) and recurrent AOM (R-AOM). Double-tympanocentesis studies comparing the microbiology of initial and recurrent episodes of AOM have demonstrated that most recurrent episodes occurring within 1 month after antibiotic therapy are new infections, not true bacteriological relapses. These findings have highlighted the importance of bacteriological eradication in the prevention of subsequent R-AOM episodes. The seven-valent pneumococcal conjugate vaccine (PCV7) targets Streptococcus pneumoniae, one of the main AOM pathogens, and data on the impact of PCV7 on complications of AOM, such as mastoiditis, are presented. © 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Persistent AOM
Complicated (difficult-to-treat, recalcitrant) acute otitis media (AOM) is a common paediatric problem, affecting almost 20% of children during their first few years of life [1,2]. It includes two major entities: persistent AOM and recurrent AOM (R-AOM). Whether persistent or R-AOM reflect persistence of the original infection or a new infection is debatable. Bacterial eradication in AOM is desirable but may be difficult to achieve. The assessment of bacterial eradication during antibiotic treatment of AOM and the association between eradication and clinical cure has been made possible using the ‘doubletympanocentesis’ procedure [3,4]. This method involves obtaining, by tympanocentesis, a sample of middle ear fluid (MEF) for culture immediately before initiation of treatment, and then performing a second tap and MEF culture during treatment (usually after 3–5 days). This article discusses the importance of bacteriological eradication of AOM pathogens in the MEF and nasopharynx, with particular emphasis on the prevention of subsequent recurrent episodes. Data on the changing incidence and epidemiology of acute mastoiditis are also reviewed. In addition, data on the impact of the seven-valent pneumococcal conjugate vaccine (PCV7; PrevnarTM /PrevenarTM1 ) on the microbiology of acute mastoiditis in children will be presented.
If signs and symptoms of AOM persist for 48–72 h after initiation of antibiotics, it is likely that antimicrobial therapy failed to treat the original infection. However, it is debatable whether this reflects persistence of the original infection, as a result of the lack of response to antibiotic therapy and lack of eradication of initial pathogens, or is in fact a new infection (persistence or reappearance of clinical signs and symptoms, and isolation of a new pathogen). A study of the effect of antibiotic treatment on the prevalence of pathogens subsequently isolated from the MEF in patients with AOM who had failed a course of antibiotic therapy found that Streptococcus pneumoniae was more prevalent after recent antibiotic treatment [5]. Furthermore, resistance of S. pneumoniae isolates to penicillin was higher in those patients who had recently received antibiotics compared with those not recently treated.
∗ Tel.: +972 8 640 0547; fax: +972 8 623 2334. E-mail addresses: [email protected], [email protected]. 1 Prevnar/Prevenar are trademarks of Wyeth Lederle Vaccines S.A., Pearl River, NY, USA. 0264-410X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2008.11.008
3. Recurrent AOM (R-AOM) Clinical R-AOM is defined as the reappearance of AOM after completion of treatment of an initial episode of AOM accompanied by clinical cure. True bacteriological R-AOM requires the presence of an organism identical to that isolated during the original AOM episode. Children under 2 years of age are at increased risk of RAOM and persistent middle ear effusion after an episode of AOM [1,6,7]. Other determinants of recurrence after an episode of AOM include male sex, sibling history of R-AOM, not being breastfed, primary clinical treatment failure, bilateral AOM, passive smoking, day-care attendance, season, and previous history of R-AOM [6]. R-AOM is common in otitis-prone children (classified as those children with ≥3 AOM episodes occurring in the previous 6 months,
E. Leibovitz / Vaccine 26S (2008) G16–G19
or ≥4 episodes in 1 year preceding the current AOM episode). By the age of 1 year, more than 60% of children will have experienced one episode of AOM and 17% will have suffered from at least three episodes [7]. Understanding the dynamics of AOM recurrence is important for appropriate therapeutic management. 4. Microbiology of initial and recurrent AOM episodes In a study carried out to determine the relationship between AOM pathogens isolated in 108 cases of early clinical R-AOM (3–4 weeks after completion of antibiotic treatment for the initial AOM episode) and the original pathogens causing the initial AOM episode, Leibovitz et al. [8] found that 54% of R-AOM episodes occurring within 1 month of completing antibiotic therapy were new infections. True bacteriological relapses comprised 28% of all cases; of these, S. pneumoniae, non-typable Haemophilus influenzae (NTHi), or both pathogens (mixed infection) were isolated in 43%, 40%, and 17% of cases, respectively. There was no growth in 18% of samples. Most true bacteriological R-AOM relapses developed within the first 2 weeks after completion of antibiotic therapy, but even during this time most recurrences were caused by a new pathogen. Furthermore, NTHi did not cause true bacteriological RAOM relapses beyond 2 weeks following completion of therapy. 5. Eradication of pathogens in initial and recurrent AOM episodes The relationship between the eradication of nasopharyngeal and MEF pathogens and AOM recurrence has been examined in two recent studies [9,10]. Libson et al. [10] explored the relationship between nasopharyngeal colonization with S. pneumoniae at the end of AOM therapy and the aetiology of the next episode of AOM occurring within 3 weeks after completion of antibiotic therapy. Nasopharyngeal cultures were obtained from 494/530 (93%) patients at the end of successful
G17
(bacteriological eradication and clinical improvement/cure) antibiotic treatment for AOM (Fig. 1). Of these, S. pneumoniae was isolated in 208/494 (42%) patients. AOM recurred in 130/494 (26%) patients: 66/208 (32%) patients with S. pneumoniae-positive nasopharyngeal cultures and 64/286 (22%) patients without S. pneumoniae-positive nasopharyngeal cultures at the end of therapy (p = 0.026). When R-AOM occurred, MEF cultures were positive for S. pneumoniae in 34/56 (61%) patients with S. pneumoniae-positive nasopharyngeal cultures and 17/47 (36%) patients without S. pneumoniae-positive nasopharyngeal cultures at the end of initial therapy (p = 0.022). The same serotype was identified in 24/30 (80%) S. pneumoniae pairs (isolated from the nasopharynx at end of therapy and from MEF at AOM recurrence); complete identity between isolates was found in 22/23 (96%) S. pneumoniae pairs available for examination using pulsed field gel electrophoresis (PFGE). The authors concluded that nasopharyngeal carriage of S. pneumoniae at the completion of successful antibiotic treatment of AOM predisposes to early clinical recurrence [10]. In an analysis of the outcome of 673 culture-positive patients with AOM enrolled in double-tympanocentesis studies, Asher et al. [9] reported that failure to eradicate MEF pathogens during antibiotic treatment was associated with clinical recurrences of AOM, even in patients showing clinical improvement or cure at the end of antibiotic treatment. On days 4–6, 189/673 (28%) patients had culture-positive MEF (Fig. 2) [9]. Patients with clinical improvement/cure on days 11–14 (end of treatment), despite having culture-positive MEF on days 4–6, had more episodes of R-AOM (53/151, 35%) than those with culture-negative MEF (114/476, 24%; p = 0.007). Of the 53 culture-positive patients with clinical improvement or cure on days 11–14, 41 (77%) underwent tympanocentesis when AOM recurred; 29/41 (71%) of these patients were culturepositive. PFGE identity between pathogens at recurrence and those persisting in the MEF on days 4–6 was found in 19/29 (66%) compared with 31/86 (36%) of the evaluable patients with recurrence and culture-negative MEF on days 4–6 (p = 0.005), demonstrating
Fig. 1. Role of eradication of Streptococcus pneumoniae from the nasopharynx in the prevention of AOM recurrences [10]. © 2005 by the Infectious Diseases Society of America. All rights reserved. Reprinted with permission. AOM, acute otitis media; Cx, culture; F/U, follow up; MEF, middle ear fluid; NP, nasopharyngeal; R-AOM, recurrent AOM; +, positive for Streptococcus pneumoniae; −, negative for S. pneumoniae.
G18
E. Leibovitz / Vaccine 26S (2008) G16–G19
Fig. 2. The role of eradication of MEF pathogens during antibiotic treatment [9]. Reproduced with permission from Asher et al. Persistence of pathogens despite clinical improvement in antibiotic-treated acute otitis media is associated with clinical and bacteriologic relapse. Pediatr Infect Dis J 2008;27(4):296–301. AOM, acute otitis media; CI, confidence interval; Cx (+), culture-positive; Cx (−), culture-negative; F/U, follow up; OR, odds ratio.
that the AOM recurrences were mostly caused by pathogens initially present in the MEF and persisting during treatment. From both studies, it is apparent that higher rates of clinical RAOM are mostly caused by pathogens persisting in the MEF and/or nasopharynx that are not eradicated by initial antibiotic treatment. These findings therefore highlight the importance of bacteriological eradication in the prevention of episodes of R-AOM.
period were somewhat different [16]. The authors reported no reduction in the number of AOM episodes in the pneumococcal vaccine group compared with the control group, and no changes in nasopharyngeal pneumococcal carriage. These results suggest that the impact of PCV7 may be greater if administered in early infancy than in older children, and that the vaccine may not be useful once R-AOM is established.
6. Role of PCV7 in reducing the burden of complicated AOM
7. Acute mastoiditis
A number of studies have examined the impact of PCV7 on the burden of AOM. Vaccine efficacy was initially assessed in the Northern California Kaiser Permanente trial group of 37,868 children followed for up to 3.5 years after immunization. The study revealed that PCV7 reduced visits for OM by 7.8%, antibiotic prescriptions by 5.7%, and tympanostomy tube placements by 24% [11,12]. Furthermore, frequent episodes of OM were reduced by 10% in children with three visits and by 26% in those with 10 visits within a 6-month period. In a population-based study in Tennessee and Rochester, New York, after the introduction of the vaccine into the routine childhood immunization schedule in the USA, Poehling et al. reported a significant reduction in visits for OM [13]. This reduction was much greater than that previously reported in various clinical trials, with a decline of 118 and 430 visits per 1000 children in Tennessee and Rochester, New York, respectively. In a subsequent analysis, comparison of the 2000–2001 with the 1998–1999 birth cohort found that frequent episodes of OM declined by 17% and 28%, while pressure-equalizing tube insertions declined by 16% and 23%, in the Tennessee and New York populations, respectively [14]. More recently, Zhou et al. [15] reported a decrease of 43% and 42%, respectively, in the number of ambulatory visits and antibiotic prescriptions attributable to AOM in 1997–1999 and in 2004 in a paediatric population <2 years of age who were vaccinated with PCV7. In comparison, in a double-blind, randomized study of 74 Belgian children aged 1–7 years with a history of R-AOM, who were immunized with PCV7 followed by a 23-valent pneumococcal polysaccharide booster, the results during a 26-month follow-up
Acute mastoiditis (local inflammation in the region of the temporal bone) is the most clinically important complication of AOM. In a 12-year retrospective study of children aged ≤14 years in Southern Israel, the average yearly incidence of 6.1 cases per 100,000 was greater than that previously reported in the literature, with a significant increase in the number of cases recorded during the study period (1990–2001) [17,18] (Fig. 3). The pathogen distribution in acute mastoiditis in this study differed from that of AOM, with significantly higher rates of group A Streptococcus and lower rates of H. influenzae being responsible for infection. An increase in the number of cases caused by S. pneumoniae occurred during the later years of the study; however, penicillin-non-susceptible S. pneumoniae played only a minor role in the aetiology of acute mastoiditis. In a review of US children presenting with suppurative complications of AOM between 1993 and 2000, a total of 104 complications occurred in 90 patients [19]. A trend towards an increasing number of suppurative complications of AOM – particularly those cases of mastoiditis requiring surgical intervention – was observed during the study period, corresponding to an increasing number of resistant S. pneumoniae isolates. 8. Acute mastoiditis in the PCV7 era Information on the impact of immunization with PCV7 on the aetiology of acute mastoiditis in children is scarce, but one US study has examined the aetiology of mastoiditis in the pre- (1995–2000) and post- (2001–2005) PCV7 eras in patients ≤19 years of age
E. Leibovitz / Vaccine 26S (2008) G16–G19
G19
Fig. 3. Yearly distribution of 116 episodes of acute mastoiditis: Southern Israel, 1990–2001 [17]. Reproduced with permission from Katz et al. Acute mastoiditis in Southern Israel: a twelve year retrospective study (1990 through 2001). Pediatr Infect Dis J 2003;22(10):878–882.
in Washington and Boston [20]. No difference in the proportion of cases of paediatric mastoiditis caused by S. pneumoniae was reported in these two eras. However, an increase in resistance to ceftriaxone was seen, with ceftriaxone non-susceptibility found in 30% of post-PCV7 S. pneumoniae isolates compared with 7% of pre-PCV7 isolates. 9. Conclusions Studies have shown that most episodes of R-AOM occurring within 1 month of successful completion of antibiotic therapy for AOM are new infections. In addition, it has been demonstrated that the lack of eradication of pathogens of the MEF and/or nasopharynx during antibiotic treatment of the initial episode of AOM is associated with higher rates of clinical R-AOM, even if patients showed clinical improvement or cure at the end of therapy. The majority of these recurrences were shown to be caused by pathogens of the MEF and/or nasopharynx that were not eradicated initially by antibiotic treatment. The studies presented here therefore clearly emphasize the importance of bacteriological eradication in the prevention of R-AOM. Despite routine immunization with PCV7 in the USA, no reduction has been reported in the proportion of cases of acute mastoiditis caused by S. pneumoniae in the post-PCV7 era. Conflict of interest E.L. has received honoraria from GlaxoSmithKline to attend and present at a CME event at The European Society of Paediatric Otolaryngology in Budapest, 2008. He has nothing else to disclose. References [1] Arrieta A, Singh J. Management of recurrent and persistent acute otitis media: new options with familiar antibiotics. Pediatr Infect Dis J 2004;23(Suppl. 2):S115–24. [2] Leibovitz E. The challenge of recalcitrant acute otitis media: pathogens, resistance, and treatment strategy. Pediatr Infect Dis J 2007;26(Suppl. 10): S8–11. [3] Dagan R, Leibovitz E. Bacterial eradication in the treatment of otitis media. Lancet Infect Dis 2002;2(10):593–604. [4] Dagan R, Schneider S, Givon-Lavi N, Greenberg D, Leiberman A, Jacobs MR, et al. Failure to achieve early bacterial eradication increases clinical failure rate in acute otitis media in young children. Pediatr Infect Dis J 2008;27(3): 200–6.
[5] Leibovitz E, Raiz S, Piglansky L, Greenberg D, Yagupsky P, Fliss DM, et al. Resistance pattern of middle ear fluid isolates in acute otitis media recently treated with antibiotics. Pediatr Infect Dis J 1998;17(6):463–9. [6] Damoiseaux RAMJ, Rovers MM, Van Balen FAM, Hoes AW, de Melker RA. Longterm prognosis of acute otitis media in infancy: determinants of recurrent acute otitis media and persistent middle ear effusion. Fam Pract 2006;21: 40–5. [7] Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989;160:83–94. [8] Leibovitz E, Greenberg D, Piglansky L, Raiz S, Porat N, Press J, et al. Recurrent acute otitis media occurring within one month from completion of antibiotic therapy: relationship to the original pathogen. Pediatr Infect Dis J 2003;22(3):209–16. [9] Asher E, Dagan R, Greenberg D, Givon-Lavi N, Libson S, Porat N, et al. Persistence of pathogens despite clinical improvement in antibiotic-treated acute otitis media is associated with clinical and bacteriologic relapse. Pediatr Infect Dis J 2008;27(4):296–301. [10] Libson S, Dagan R, Greenberg D, Porat N, Trepler R, Leiberman A, et al. Nasopharyngeal carriage of Streptococcus pneumoniae at the completion of successful antibiotic treatment of acute otitis media predisposes to early clinical recurrence. J Infect Dis 2005;191(11):1869–75. [11] Black S, Shinefield H, Fireman BH, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187–95. [12] Fireman B, Black SB, Shinefield HR, Lee J. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003;22:10–6. [13] Poehling KA, Lafleur BJ, Szilagyi PG, Edwards KM, Mitchel E, Barth R, et al. Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics 2004;114:755–61. [14] Poehling KA, Szilagyi PG, Grijalva CG, Martin SW, LaFleur B, Mitchel E, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics 2007;119(4):707–15. [15] Zhou F, Shefer A, Kong Y, Nuorti JP. Trends in acute otitis media-related health care utilization by privately insured young children in the United States, 1997–2004. Pediatrics 2008;121(2):253–60. [16] Veenhoven R, Bogaert D, Uiterwaal C, Brouwer C, Kiezebrink H, Bruin H, et al. Effect of conjugate pneumococcal vaccine followed by a polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study. Lancet 2003;361:2189–95. [17] Katz A, Leibovitz E, Greenberg D, Raiz S, Greenwald-Maimon M, Leiberman A, et al. Acute mastoiditis in Southern Israel: a twelve year retrospective study (1990 through 2001). Pediatr Infect Dis J 2003;22(10): 878–82. [18] Van Zuijlen DA, Schilder AG, van Balen FA, Hoes AW. National differences in incidence of acute mastoiditis: relationship to prescribing patterns of antibiotics for acute otitis media? Pediatr Infect Dis J 2001;20(2):140–4. [19] Zapalac JS, Billings KR, Schwade ND, Roland PS. Suppurative complications of acute otitis media in the era of antibiotic resistance. Arch Otolaryngol Head Neck Surg 2002;128(6):660–3. [20] Roddy MG, Glazier SS, Agrawal D. Pediatric mastoiditis in the pneumococcal conjugate vaccine era: symptom duration guides empiric antimicrobial therapy. Pediatr Emerg Care 2007;23(11):779–84.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Complicated otitis media and its implications Eugene Leibovitz ∗ Pediatric Infectious Disease Unit, Soroka University Medical Center, Ben-Gurion University of the Negev, P.O. Box 151, 84101 Beer-Sheva, Israel
a r t i c l e
i n f o
Keywords: Recurrent otitis media Persistent otitis media Mastoiditis
a b s t r a c t Complicated otitis media (OM) is a common paediatric problem and includes two major entities: persistent acute OM (AOM) and recurrent AOM (R-AOM). Double-tympanocentesis studies comparing the microbiology of initial and recurrent episodes of AOM have demonstrated that most recurrent episodes occurring within 1 month after antibiotic therapy are new infections, not true bacteriological relapses. These findings have highlighted the importance of bacteriological eradication in the prevention of subsequent R-AOM episodes. The seven-valent pneumococcal conjugate vaccine (PCV7) targets Streptococcus pneumoniae, one of the main AOM pathogens, and data on the impact of PCV7 on complications of AOM, such as mastoiditis, are presented. © 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Persistent AOM
Complicated (difficult-to-treat, recalcitrant) acute otitis media (AOM) is a common paediatric problem, affecting almost 20% of children during their first few years of life [1,2]. It includes two major entities: persistent AOM and recurrent AOM (R-AOM). Whether persistent or R-AOM reflect persistence of the original infection or a new infection is debatable. Bacterial eradication in AOM is desirable but may be difficult to achieve. The assessment of bacterial eradication during antibiotic treatment of AOM and the association between eradication and clinical cure has been made possible using the ‘doubletympanocentesis’ procedure [3,4]. This method involves obtaining, by tympanocentesis, a sample of middle ear fluid (MEF) for culture immediately before initiation of treatment, and then performing a second tap and MEF culture during treatment (usually after 3–5 days). This article discusses the importance of bacteriological eradication of AOM pathogens in the MEF and nasopharynx, with particular emphasis on the prevention of subsequent recurrent episodes. Data on the changing incidence and epidemiology of acute mastoiditis are also reviewed. In addition, data on the impact of the seven-valent pneumococcal conjugate vaccine (PCV7; PrevnarTM /PrevenarTM1 ) on the microbiology of acute mastoiditis in children will be presented.
If signs and symptoms of AOM persist for 48–72 h after initiation of antibiotics, it is likely that antimicrobial therapy failed to treat the original infection. However, it is debatable whether this reflects persistence of the original infection, as a result of the lack of response to antibiotic therapy and lack of eradication of initial pathogens, or is in fact a new infection (persistence or reappearance of clinical signs and symptoms, and isolation of a new pathogen). A study of the effect of antibiotic treatment on the prevalence of pathogens subsequently isolated from the MEF in patients with AOM who had failed a course of antibiotic therapy found that Streptococcus pneumoniae was more prevalent after recent antibiotic treatment [5]. Furthermore, resistance of S. pneumoniae isolates to penicillin was higher in those patients who had recently received antibiotics compared with those not recently treated.
∗ Tel.: +972 8 640 0547; fax: +972 8 623 2334. E-mail addresses: [email protected], [email protected]. 1 Prevnar/Prevenar are trademarks of Wyeth Lederle Vaccines S.A., Pearl River, NY, USA. 0264-410X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2008.11.008
3. Recurrent AOM (R-AOM) Clinical R-AOM is defined as the reappearance of AOM after completion of treatment of an initial episode of AOM accompanied by clinical cure. True bacteriological R-AOM requires the presence of an organism identical to that isolated during the original AOM episode. Children under 2 years of age are at increased risk of RAOM and persistent middle ear effusion after an episode of AOM [1,6,7]. Other determinants of recurrence after an episode of AOM include male sex, sibling history of R-AOM, not being breastfed, primary clinical treatment failure, bilateral AOM, passive smoking, day-care attendance, season, and previous history of R-AOM [6]. R-AOM is common in otitis-prone children (classified as those children with ≥3 AOM episodes occurring in the previous 6 months,
E. Leibovitz / Vaccine 26S (2008) G16–G19
or ≥4 episodes in 1 year preceding the current AOM episode). By the age of 1 year, more than 60% of children will have experienced one episode of AOM and 17% will have suffered from at least three episodes [7]. Understanding the dynamics of AOM recurrence is important for appropriate therapeutic management. 4. Microbiology of initial and recurrent AOM episodes In a study carried out to determine the relationship between AOM pathogens isolated in 108 cases of early clinical R-AOM (3–4 weeks after completion of antibiotic treatment for the initial AOM episode) and the original pathogens causing the initial AOM episode, Leibovitz et al. [8] found that 54% of R-AOM episodes occurring within 1 month of completing antibiotic therapy were new infections. True bacteriological relapses comprised 28% of all cases; of these, S. pneumoniae, non-typable Haemophilus influenzae (NTHi), or both pathogens (mixed infection) were isolated in 43%, 40%, and 17% of cases, respectively. There was no growth in 18% of samples. Most true bacteriological R-AOM relapses developed within the first 2 weeks after completion of antibiotic therapy, but even during this time most recurrences were caused by a new pathogen. Furthermore, NTHi did not cause true bacteriological RAOM relapses beyond 2 weeks following completion of therapy. 5. Eradication of pathogens in initial and recurrent AOM episodes The relationship between the eradication of nasopharyngeal and MEF pathogens and AOM recurrence has been examined in two recent studies [9,10]. Libson et al. [10] explored the relationship between nasopharyngeal colonization with S. pneumoniae at the end of AOM therapy and the aetiology of the next episode of AOM occurring within 3 weeks after completion of antibiotic therapy. Nasopharyngeal cultures were obtained from 494/530 (93%) patients at the end of successful
G17
(bacteriological eradication and clinical improvement/cure) antibiotic treatment for AOM (Fig. 1). Of these, S. pneumoniae was isolated in 208/494 (42%) patients. AOM recurred in 130/494 (26%) patients: 66/208 (32%) patients with S. pneumoniae-positive nasopharyngeal cultures and 64/286 (22%) patients without S. pneumoniae-positive nasopharyngeal cultures at the end of therapy (p = 0.026). When R-AOM occurred, MEF cultures were positive for S. pneumoniae in 34/56 (61%) patients with S. pneumoniae-positive nasopharyngeal cultures and 17/47 (36%) patients without S. pneumoniae-positive nasopharyngeal cultures at the end of initial therapy (p = 0.022). The same serotype was identified in 24/30 (80%) S. pneumoniae pairs (isolated from the nasopharynx at end of therapy and from MEF at AOM recurrence); complete identity between isolates was found in 22/23 (96%) S. pneumoniae pairs available for examination using pulsed field gel electrophoresis (PFGE). The authors concluded that nasopharyngeal carriage of S. pneumoniae at the completion of successful antibiotic treatment of AOM predisposes to early clinical recurrence [10]. In an analysis of the outcome of 673 culture-positive patients with AOM enrolled in double-tympanocentesis studies, Asher et al. [9] reported that failure to eradicate MEF pathogens during antibiotic treatment was associated with clinical recurrences of AOM, even in patients showing clinical improvement or cure at the end of antibiotic treatment. On days 4–6, 189/673 (28%) patients had culture-positive MEF (Fig. 2) [9]. Patients with clinical improvement/cure on days 11–14 (end of treatment), despite having culture-positive MEF on days 4–6, had more episodes of R-AOM (53/151, 35%) than those with culture-negative MEF (114/476, 24%; p = 0.007). Of the 53 culture-positive patients with clinical improvement or cure on days 11–14, 41 (77%) underwent tympanocentesis when AOM recurred; 29/41 (71%) of these patients were culturepositive. PFGE identity between pathogens at recurrence and those persisting in the MEF on days 4–6 was found in 19/29 (66%) compared with 31/86 (36%) of the evaluable patients with recurrence and culture-negative MEF on days 4–6 (p = 0.005), demonstrating
Fig. 1. Role of eradication of Streptococcus pneumoniae from the nasopharynx in the prevention of AOM recurrences [10]. © 2005 by the Infectious Diseases Society of America. All rights reserved. Reprinted with permission. AOM, acute otitis media; Cx, culture; F/U, follow up; MEF, middle ear fluid; NP, nasopharyngeal; R-AOM, recurrent AOM; +, positive for Streptococcus pneumoniae; −, negative for S. pneumoniae.
G18
E. Leibovitz / Vaccine 26S (2008) G16–G19
Fig. 2. The role of eradication of MEF pathogens during antibiotic treatment [9]. Reproduced with permission from Asher et al. Persistence of pathogens despite clinical improvement in antibiotic-treated acute otitis media is associated with clinical and bacteriologic relapse. Pediatr Infect Dis J 2008;27(4):296–301. AOM, acute otitis media; CI, confidence interval; Cx (+), culture-positive; Cx (−), culture-negative; F/U, follow up; OR, odds ratio.
that the AOM recurrences were mostly caused by pathogens initially present in the MEF and persisting during treatment. From both studies, it is apparent that higher rates of clinical RAOM are mostly caused by pathogens persisting in the MEF and/or nasopharynx that are not eradicated by initial antibiotic treatment. These findings therefore highlight the importance of bacteriological eradication in the prevention of episodes of R-AOM.
period were somewhat different [16]. The authors reported no reduction in the number of AOM episodes in the pneumococcal vaccine group compared with the control group, and no changes in nasopharyngeal pneumococcal carriage. These results suggest that the impact of PCV7 may be greater if administered in early infancy than in older children, and that the vaccine may not be useful once R-AOM is established.
6. Role of PCV7 in reducing the burden of complicated AOM
7. Acute mastoiditis
A number of studies have examined the impact of PCV7 on the burden of AOM. Vaccine efficacy was initially assessed in the Northern California Kaiser Permanente trial group of 37,868 children followed for up to 3.5 years after immunization. The study revealed that PCV7 reduced visits for OM by 7.8%, antibiotic prescriptions by 5.7%, and tympanostomy tube placements by 24% [11,12]. Furthermore, frequent episodes of OM were reduced by 10% in children with three visits and by 26% in those with 10 visits within a 6-month period. In a population-based study in Tennessee and Rochester, New York, after the introduction of the vaccine into the routine childhood immunization schedule in the USA, Poehling et al. reported a significant reduction in visits for OM [13]. This reduction was much greater than that previously reported in various clinical trials, with a decline of 118 and 430 visits per 1000 children in Tennessee and Rochester, New York, respectively. In a subsequent analysis, comparison of the 2000–2001 with the 1998–1999 birth cohort found that frequent episodes of OM declined by 17% and 28%, while pressure-equalizing tube insertions declined by 16% and 23%, in the Tennessee and New York populations, respectively [14]. More recently, Zhou et al. [15] reported a decrease of 43% and 42%, respectively, in the number of ambulatory visits and antibiotic prescriptions attributable to AOM in 1997–1999 and in 2004 in a paediatric population <2 years of age who were vaccinated with PCV7. In comparison, in a double-blind, randomized study of 74 Belgian children aged 1–7 years with a history of R-AOM, who were immunized with PCV7 followed by a 23-valent pneumococcal polysaccharide booster, the results during a 26-month follow-up
Acute mastoiditis (local inflammation in the region of the temporal bone) is the most clinically important complication of AOM. In a 12-year retrospective study of children aged ≤14 years in Southern Israel, the average yearly incidence of 6.1 cases per 100,000 was greater than that previously reported in the literature, with a significant increase in the number of cases recorded during the study period (1990–2001) [17,18] (Fig. 3). The pathogen distribution in acute mastoiditis in this study differed from that of AOM, with significantly higher rates of group A Streptococcus and lower rates of H. influenzae being responsible for infection. An increase in the number of cases caused by S. pneumoniae occurred during the later years of the study; however, penicillin-non-susceptible S. pneumoniae played only a minor role in the aetiology of acute mastoiditis. In a review of US children presenting with suppurative complications of AOM between 1993 and 2000, a total of 104 complications occurred in 90 patients [19]. A trend towards an increasing number of suppurative complications of AOM – particularly those cases of mastoiditis requiring surgical intervention – was observed during the study period, corresponding to an increasing number of resistant S. pneumoniae isolates. 8. Acute mastoiditis in the PCV7 era Information on the impact of immunization with PCV7 on the aetiology of acute mastoiditis in children is scarce, but one US study has examined the aetiology of mastoiditis in the pre- (1995–2000) and post- (2001–2005) PCV7 eras in patients ≤19 years of age
E. Leibovitz / Vaccine 26S (2008) G16–G19
G19
Fig. 3. Yearly distribution of 116 episodes of acute mastoiditis: Southern Israel, 1990–2001 [17]. Reproduced with permission from Katz et al. Acute mastoiditis in Southern Israel: a twelve year retrospective study (1990 through 2001). Pediatr Infect Dis J 2003;22(10):878–882.
in Washington and Boston [20]. No difference in the proportion of cases of paediatric mastoiditis caused by S. pneumoniae was reported in these two eras. However, an increase in resistance to ceftriaxone was seen, with ceftriaxone non-susceptibility found in 30% of post-PCV7 S. pneumoniae isolates compared with 7% of pre-PCV7 isolates. 9. Conclusions Studies have shown that most episodes of R-AOM occurring within 1 month of successful completion of antibiotic therapy for AOM are new infections. In addition, it has been demonstrated that the lack of eradication of pathogens of the MEF and/or nasopharynx during antibiotic treatment of the initial episode of AOM is associated with higher rates of clinical R-AOM, even if patients showed clinical improvement or cure at the end of therapy. The majority of these recurrences were shown to be caused by pathogens of the MEF and/or nasopharynx that were not eradicated initially by antibiotic treatment. The studies presented here therefore clearly emphasize the importance of bacteriological eradication in the prevention of R-AOM. Despite routine immunization with PCV7 in the USA, no reduction has been reported in the proportion of cases of acute mastoiditis caused by S. pneumoniae in the post-PCV7 era. Conflict of interest E.L. has received honoraria from GlaxoSmithKline to attend and present at a CME event at The European Society of Paediatric Otolaryngology in Budapest, 2008. He has nothing else to disclose. References [1] Arrieta A, Singh J. Management of recurrent and persistent acute otitis media: new options with familiar antibiotics. Pediatr Infect Dis J 2004;23(Suppl. 2):S115–24. [2] Leibovitz E. The challenge of recalcitrant acute otitis media: pathogens, resistance, and treatment strategy. Pediatr Infect Dis J 2007;26(Suppl. 10): S8–11. [3] Dagan R, Leibovitz E. Bacterial eradication in the treatment of otitis media. Lancet Infect Dis 2002;2(10):593–604. [4] Dagan R, Schneider S, Givon-Lavi N, Greenberg D, Leiberman A, Jacobs MR, et al. Failure to achieve early bacterial eradication increases clinical failure rate in acute otitis media in young children. Pediatr Infect Dis J 2008;27(3): 200–6.
[5] Leibovitz E, Raiz S, Piglansky L, Greenberg D, Yagupsky P, Fliss DM, et al. Resistance pattern of middle ear fluid isolates in acute otitis media recently treated with antibiotics. Pediatr Infect Dis J 1998;17(6):463–9. [6] Damoiseaux RAMJ, Rovers MM, Van Balen FAM, Hoes AW, de Melker RA. Longterm prognosis of acute otitis media in infancy: determinants of recurrent acute otitis media and persistent middle ear effusion. Fam Pract 2006;21: 40–5. [7] Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989;160:83–94. [8] Leibovitz E, Greenberg D, Piglansky L, Raiz S, Porat N, Press J, et al. Recurrent acute otitis media occurring within one month from completion of antibiotic therapy: relationship to the original pathogen. Pediatr Infect Dis J 2003;22(3):209–16. [9] Asher E, Dagan R, Greenberg D, Givon-Lavi N, Libson S, Porat N, et al. Persistence of pathogens despite clinical improvement in antibiotic-treated acute otitis media is associated with clinical and bacteriologic relapse. Pediatr Infect Dis J 2008;27(4):296–301. [10] Libson S, Dagan R, Greenberg D, Porat N, Trepler R, Leiberman A, et al. Nasopharyngeal carriage of Streptococcus pneumoniae at the completion of successful antibiotic treatment of acute otitis media predisposes to early clinical recurrence. J Infect Dis 2005;191(11):1869–75. [11] Black S, Shinefield H, Fireman BH, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187–95. [12] Fireman B, Black SB, Shinefield HR, Lee J. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003;22:10–6. [13] Poehling KA, Lafleur BJ, Szilagyi PG, Edwards KM, Mitchel E, Barth R, et al. Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics 2004;114:755–61. [14] Poehling KA, Szilagyi PG, Grijalva CG, Martin SW, LaFleur B, Mitchel E, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics 2007;119(4):707–15. [15] Zhou F, Shefer A, Kong Y, Nuorti JP. Trends in acute otitis media-related health care utilization by privately insured young children in the United States, 1997–2004. Pediatrics 2008;121(2):253–60. [16] Veenhoven R, Bogaert D, Uiterwaal C, Brouwer C, Kiezebrink H, Bruin H, et al. Effect of conjugate pneumococcal vaccine followed by a polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study. Lancet 2003;361:2189–95. [17] Katz A, Leibovitz E, Greenberg D, Raiz S, Greenwald-Maimon M, Leiberman A, et al. Acute mastoiditis in Southern Israel: a twelve year retrospective study (1990 through 2001). Pediatr Infect Dis J 2003;22(10): 878–82. [18] Van Zuijlen DA, Schilder AG, van Balen FA, Hoes AW. National differences in incidence of acute mastoiditis: relationship to prescribing patterns of antibiotics for acute otitis media? Pediatr Infect Dis J 2001;20(2):140–4. [19] Zapalac JS, Billings KR, Schwade ND, Roland PS. Suppurative complications of acute otitis media in the era of antibiotic resistance. Arch Otolaryngol Head Neck Surg 2002;128(6):660–3. [20] Roddy MG, Glazier SS, Agrawal D. Pediatric mastoiditis in the pneumococcal conjugate vaccine era: symptom duration guides empiric antimicrobial therapy. Pediatr Emerg Care 2007;23(11):779–84.