PEDIATRICS Vol. 122 No. 1 July 2008, pp. 34-39 (doi:10.1542/peds.2007-2703)
ARTICLE |
Pneumococcal Mastoiditis in Children and the Emergence of Multidrug-Resistant Serotype 19A Isolates
a Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery
c Department of Pediatrics, Baylor College of Medicine, Houston, Texas
b Otolaryngology Service
d Infectious Diseases Service, Texas Children's Hospital, Houston, Texas
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ABSTRACT |
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OBJECTIVE. We review the impact of pneumococcal conjugate vaccine on pneumococcal mastoiditis in children at Texas Children's Hospital.
METHODS. The medical charts (including the number of pneumococcal conjugate vaccine doses) for children with pneumococcal mastoiditis treated at Texas Children's Hospital between January 1995 and June 2007 were reviewed retrospectively. Isolates were serotyped with the capsular swelling method. Pulsed-field gel electrophoresis was performed on the 19A isolates and multilocus sequence typing on selected 19A clones.
RESULTS. Forty-one pneumococcal mastoiditis cases were identified, and 19A (n = 19) was the most common serotype. Before the introduction of pneumococcal conjugate vaccine (from 1995 to December 1999), 0 of 12 cases were 19A. Between April 2000 and October 2006, 15 cases of pneumococcal mastoiditis occurred, and 5 were 19A. Fourteen cases of pneumococcal mastoiditis occurred between November 2006 and June 2007, all of which were 19A. Mastoiditis caused by 19A isolates was more likely to present with subperiosteal abscess and was more likely to need intraoperative mastoidectomy than was mastoiditis caused by non-19A isolates. Multidrug resistance was also common among the 19A isolates; 13 (68%) of the 19A isolates were resistant to all antibiotics tested routinely. Pulsed-field gel electrophoresis analysis placed 14 (74%) of the 19 serotype 19A isolates into a highly related group; 12 isolates were classified as closely related, and 2 were possibly related. Multilocus sequence typing analysis placed the pulsed-field gel electrophoresis cluster isolates into clonal complex 271 (sequence types 320 and 1451).
CONCLUSIONS. At Texas Children's Hospital, 19A has become the predominant serotype causing pneumococcal mastoiditis, partly related to the emergence of multidrug-resistant clonal complex 271 strains. Subperiosteal abscesses and the need for mastoidectomy were more common in children with mastoiditis caused by serotype 19A isolates, compared with isolates of other serotypes.
Key Words: Streptococcus pneumoniae • mastoiditis • serotype 19A
Abbreviations: MLST—multilocus sequence typing • PCV7—7-valent pneumococcal conjugate vaccine • PFGE—pulsed-field gel electrophoresis • CT—computed tomographic
The term mastoiditis describes a variety of suppurative complications of acute otitis media. Mastoiditis can be divided into acute and chronic, and the acute type can be subdivided into acute mastoiditis with periosteitis and coalescent mastoiditis.1,2 Mastoiditis primarily affects children <2 years of age. With the advent of antibiotics, mastoiditis became a relatively rare complication of acute otitis media, and the incidence rates were <6 cases per 100 000 children 
14 years of age in several studies.3,4
Acute mastoiditis with periosteitis is a collection of pus in the mastoid and can result in coalescent mastoiditis, a destructive infection of the mastoid bone and air cell system.1 This loss of bony architecture may expand and most often results in a subperiosteal abscess.5 Acute mastoiditis with periosteitis is classically treated with myringotomy for culture, intravenous antibiotic treatment for 3 to 4 days, and then 2 weeks of oral antibiotic therapy.6 The presence of coalescence, a subperiosteal abscess, or another intracranial complication is an indication for surgical intervention in the form of a mastoidectomy to drain and to debride the mastoid bone, in conjunction with tympanostomy tube placement.1
Streptococcus pneumoniae is the most common cause of mastoiditis among children.7 Before 2000, the predominant pneumococcal strain associated with mastoiditis was serogroup 19, primarily serotype 19F, which accounted for 57% of the isolates in one study.8 In 2000, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced for children <2 years of age.9 PCV7 contains the 7 most-common serotypes causing invasive infection in children in North America, that is, serotypes 4, 6B, 9V, 14, 18C, 23F, and 19F.9 By 2004, sharp decreases in the number of cases of invasive pneumococcal infections and in the proportion of penicillin-resistant isolates were reported.10,11 However, replacement of vaccine serotypes by nonvaccine serotypes, especially 19A, has occurred in isolates associated with nasopharyngeal colonization, otitis media, and invasive disease.11–20 In several studies, multidrug-resistant serotype 19A isolates have been encountered.13,14,16,17,19
Pai et al16 identified an increase in serotype 19A causing invasive pneumococcal disease in children <5 years of age by 2004. With the use of multilocus sequence typing (MLST), which characterizes the alleles present in multiple housekeeping genes through nucleotide sequencing, several 19A clonal complexes and their related sequence types, and not just an expansion of 1 clone, were determined to be responsible for the increase in serotype 19A cases. In addition, multidrug resistance was associated with specific clonal complexes.16
The objectives of this study were to determine whether the distribution of S pneumoniae serotypes causing mastoiditis in children without structural abnormalities of the ear at Texas Children's Hospital has changed since introduction of the PCV7 and how this might have affected management of the disease. Furthermore, if serotype 19A replacement has occurred, is this related to new clones or the expansion of existing clones?
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METHODS |
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Patients
Since September 1, 1993, clinical isolates of S pneumoniae from normally sterile sites and middle ear cultures have been obtained prospectively from the Texas Children's Hospital clinical microbiology laboratory and stored frozen in the infectious disease research laboratory. Case reports describing the clinical and laboratory data were filled out for each infection by a research nurse.11 A retrospective chart review was performed for all patients in the study database with pneumococcal mastoiditis diagnosed between January 1995 and June 2007 at Texas Children's Hospital via middle ear fluid or mastoid bone specimens. The medical charts were reviewed for demographic, clinical, and microbiologic data, history, physical examination, and laboratory and radiographic evaluation findings, hospital course, and medical and surgical management for each patient. Documentation of administration of PCV7 was sought after February 2000 from chart notations or pediatricians’ records. A patient was deemed to have received a dose if it was
2 weeks before the onset of symptoms. The institutional research board of the Baylor College of Medicine approved this study.
Middle Ear Fluid Cultures
The records for all middle ear fluid cultures growing S pneumoniae that were collected during this period also were examined.
Serotyping
Pneumococcal isolates from patients with mastoiditis and from middle ear cultures underwent serotyping through the capsular swelling method, with commercially available antisera (Statens Seruminstitut, Copenhagen, Denmark; and Miravista Diagnostics, Indianapolis, IN).11
Antimicrobial Susceptibility Testing
Isolates were tested for susceptibility to clindamycin, erythromycin, and trimethoprim/sulfamethoxazole with the Kirby-Bauer disk diffusion technique. Minimal inhibitory concentrations were determined for penicillin and ceftriaxone through microbroth dilution with Mueller-Hinton medium supplemented with 3% lysed horse blood. Isolates were classified as susceptible, intermediate, or resistant by using Clinical and Laboratory Standards Institute breakpoints.21
Pulsed-Field Gel Electrophoresis and MLST
Pulsed-field gel electrophoresis (PFGE) was performed for the 19A serotypes. The bacterial DNA plugs were treated with SmaI and loaded onto a 1% agarose gel.22 PFGE patterns were compared by using GelComparII software (Applied Maths, Austin, TX), and genetic relatedness was determined by applying previously published criteria.23 On the basis of the PFGE results, selected, closely related and possibly related isolates were characterized further by using MLST and identification via the S pneumoniae database (http://spneumoniae.mlst.net).24,25 The housekeeping genesused were aroE, gdh, gki, recP, spi, xpt, and ddl.
Statistical Analyses
Dichotomous variables were analyzed by using the 
2 test or Fisher's exact test, and continuous variables were tested with Student's t test or the Kruskal-Wallis or Mann-Whitney U tests for nonparametric data (True Epistat, Richardson, TX).
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RESULTS |
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Patients
Forty-three children with pneumococcal mastoiditis were identified between January 1, 1995, and June 30, 2007, at Texas Children's Hospital (Fig 1 and Table 1). One patient who had a cochlear implant placed 3 months before his diagnosis of mastoiditis and 1 patient with a previous atresia repair were excluded from analysis (n = 41). The mean age of the patients was 23 months (range: 3 months to 12 years); 35 patients (85%) were <2 years of age, and 10 (24%) were <12 months of age. Twenty-five patients (61%) were male. The average length of time the children were ill before presentation was 5 days (range: 1–14 days). All presented with a clinical picture of acute mastoiditis. A history of otitis media was found for 20 children (49%). One child had an underlying condition (HIV), 1 had recurrent mastoiditis, and 1 had bilateral mastoiditis. Twenty-seven (66%) had received antibiotics in the month before the diagnosis of mastoiditis. The mean white blood cell count at admission was 15 610 cells per µL (range: 6400–27 470 cells per mm3). No child had positive blood culture results.
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Thirty-three children (80%) underwent computed tomographic (CT) scanning at presentation; 20 (61%) had evidence of coalescence, and 21 (64%) had a subperiosteal abscess (Fig 2). Twenty-seven children (66%) underwent mastoidectomy and pressure-equalization tube placement during their hospitalization. The remaining patients underwent middle ear tap, myringotomy, or pressure-equalization tube placement. Two patients (5%) had intracranial complications, that is, an epidural abscess and a sigmoid sinus thrombosis. All of the children received inpatient intravenous antibiotic therapy, and one third of the children were discharged with continued intravenous antibiotic therapy. The average length of stay was 8 days (range: 3–28 days).
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Pneumococcal Isolates Associated With Mastoiditis
The first case of 19A pneumococcal mastoiditis was identified in 2003 and represented 1 of the 2 cases that year (Fig 1). In 2004 and 2005, 19A accounted for 3 of 6 isolates. However, all pneumococcal mastoiditis cases in 2006 and the first 6 months of 2007 were caused by 19A isolates. All of the patients with 19A underwent CT scanning at admission, compared with only 64% of the non-19A group (P = .004) (Table 1). All children with 19A mastoiditis had subperiosteal abscesses, compared with only 2 (21%) in the non-19A group (P < .001). There were 9 patients with serotype 19F isolates, 4 of whom presented with subperiosteal abscesses and 1 with sigmoid sinus thrombosis. Eighty-nine percent of the 19A group proceeded to a mastoidectomy, compared with 45% of the non-19A group (P = .007). A serotype 19A isolate was recovered from all 13 patients who had received 3 or 4 doses of PCV7.
Pulsed-Field Gel Electrophoresis
Pulsed-field genotyping through PFGE was performed for the 19A serotypes. Eight of the isolates were indistinguishable (clone A1). Four isolates were closely related, with 3 band differences (clones A2, A3, A4, and A5). Two additional isolates were identical to each other and had 5 band differences from A1; these were deemed possibly related and were labeled clone A6. Five isolates had 7 band differences each and were considered unrelated isolates. They are identified as clones B, C, D, and E (n = 2) (Fig 3).
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The first two 19A isolates identified in 2003 and 2004 were members of the clone B to E group. The A1-6 group did not appear until later in 2004. In 2007, 8 of the 9 isolates were clone A1-6.
The antibiotic resistance patterns were different for clone A1-6 (n = 14) and clone B to E (n = 5) isolates. All 14 clone A1-6 isolates had penicillin minimal inhibitory concentrations of 2 µg/mL, whereas the values for the 5 clone B to E isolates were between 0.1 and 0.5 µg/mL (P < .001). The ceftriaxone minimal inhibitory concentration for all clone A1-6 isolates was 1.0 µg/mL, whereas only 1 of the clone B to E isolates had a ceftriaxone minimal inhibitory concentration of 1.0 µg/mL (4 isolates had minimal inhibitory concentrations of 0.25 µg/mL). In addition, 13 of 14 clone A1-6 isolates were nonsusceptible to clindamycin, whereas all of the clone B to E isolates were susceptible to clindamycin (P = .0005). Resistance to erythromycin occurred in all clone A1-6 isolates, compared with none of the clone B to E isolates (P < .001).
Multilocus Sequence Typing
The predominant, closely related, and possibly related 19A clones were selected for MLST. Clones A1, A2, A3, A4, and A6 were identified as sequence type 320, and clone A5 was consistent with sequence type 1451. Sequence types 320 and 1451 are grouped within clonal complex 271.
Middle Ear Fluid Cultures
Over the study period, 432 cultures of middle ear fluid from children with acute otitis media, otitis media with effusion, or otorrhea yielded S pneumoniae. The average number of cultures collected per year was 32 (maximum of 60 in 1999) (Fig 4). Since 2000, the number of pneumococcal middle ear cultures collected per year decreased from an average of 38 to 27 isolates per year. In 1994, only one 19A serotype isolate (7%) was present in middle ear cultures. The frequency began to increase yearly in 2001, and 19A accounted for 50% of isolates by 2006 (P < .001). In the first 6 months of 2007, 60% of the middle ear pneumococcal isolates were 19A.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Since the introduction of PCV7, the incidence of invasive pneumococcal infection has been reduced substantially in young children and even in infants <60 days of age, before the age of the first PCV7 dose.10,11,26 A decrease in the frequency of acute otitis media and the need for pressure equalization tubes also has been associated with PCV7, but not to the same degree as invasive pneumococcal infections.26–28 One concern has been the emergence of serotype replacement in invasive disease, and this was noted by several investigators.13,14,16,18–20,29 Serotype 19A was the major nonvaccine serotype causing invasive disease in those studies. Serotype 19A also has been an important serotype colonizing the nasopharynx of children in the post-PCV7 era.17
At Texas Children's Hospital, the number of pneumococcal mastoiditis cases increased in 2006 and 2007. Because our study was limited to children whose cultures yielded S pneumoniae, we cannot determine from this study what proportion of mastoiditis cases are pneumococcal. We also cannot determine from these data whether the incidence of all mastoiditis is changing. The demographic characteristics of our patient population are similar to those identified in previous studies.8 Almost one fourth of our patients were <12 months of age, and boys outnumbered girls. The middle ear culture data are limited because there was no standardized protocol for the collection of specimens. The indications for culture varied widely. Some practitioners routinely cultured all middle ear effusions at the time of tube placement, some patients had acute otitis media, and other specimens represented otorrhea. These data are more useful for surveillance and examination of serotype distributions before and after introduction of the vaccine.
Before 2000, serogroup 19, particularly serotype 19F, was the predominant type isolated from middle ear fluid in otitis media.30 In our data, serogroup 19 has constituted 30% of all middle ear isolates since 2004. Kaplan et al8 hypothesized that serogroup 19 isolates might have a unique ability to persist or to invade the mastoid air cells. Since 2003, serotype 19A has been by far the most common serotype causing pneumococcal mastoiditis in our patient population. The first case of 19A mastoiditis was identified in 2003. Between November 2006 and June 2007, there were 13 cases of pneumococcal mastoiditis at Texas Children's Hospital; all required intraoperative mastoidectomy, and all were attributable to serotype 19A. To place this in context, only 15 cases of pneumococcal mastoiditis were detected during the period from January 2000 to October 2006, and 5 (33%) of those cases were attributable to 19A. The number of pneumococcal mastoiditis cases seems to be increasing, and the pneumococcal mastoiditis cases are more complex, requiring more surgery.
Antibiotic resistance was a major issue among the 19A serotype isolates. Among the serotype 19A isolates, clone A1–6 isolates and clone B to F isolates, as determined through PFGE, differed in terms of antibiotic susceptibility. MLST confirmed that the clone A1–3 isolates are sequence type 320 and the clone A4 isolate is sequence type 1451. The 2 sequence types have been grouped into clonal complex 271.16 This clonal complex has been associated only with serogroup 19 and accounted for 23% of prevaccine type 19F isolates in children <5 years of age with invasive pneumococcal disease.25 It has known association with full penicillin resistance and multidrug resistance.13,16
Clinically, the 19A and non-19A patients were very similar with respect to age and gender. They also presented in similar manners, in terms of duration of illness before presentation, previous otitis media, previous antibiotic treatment, and white blood cell counts at admission. All patients had postauricular swelling and proptosis. Only the CT scan findings differed between these groups; remarkably, all patients with serotype 19A isolates had subperiosteal abscesses on CT scans of the mastoid bones, compared with 21% of children with non–serotype 19A isolates. This difference is critical for the management of pneumococcal mastoiditis by otolaryngologists. Classically, noncoalescent mastoiditis is treated with intravenous antibiotic therapy and myringotomy or tympanostomy tube placement. If this conservative treatment fails, then the patient is taken to the operating room for a mastoidectomy. Among our patient population, children are now presenting with more-complicated disease with not only coalescence but also subperiosteal abscesses. In the prevaccine era, children with serotype 19F isolates were one half as likely as those with serotype 19A isolates to present with a subperiosteal abscess. The severity of presentation often requires surgical intervention before a trial of antibiotic therapy. Surgery usually involves a mastoidectomy and tympanostomy tube placement, with the attendant risks to the dura, sigmoid sinus, and facial nerve, particularly given its lateral course in very young children. This allows drainage of the antrum both via the middle ear and external auditory canal and postauricularly.
Since the introduction of PCV7, serotype 19A has emerged as the dominant serotype recovered from children with acute pneumococcal mastoiditis seen at Texas Children's Hospital. A similar phenomenon is likely in communities where PCV7 is administered routinely to young infants. Subperiosteal abscesses seem to be more common in children with mastoiditis caused by serotype 19A isolates, which also are likely to be resistant to multiple antibiotics. When mastoiditis in young children is caused by serotype 19A S pneumoniae, physicians should be aware that this infection may be more aggressive and, depending on the circulating clones, more complicated to treat because of resistance to multiple antibiotics.
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ACKNOWLEDGMENTS |
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This work was supported in part by a grant from Wyeth.
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FOOTNOTES |
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Accepted Nov 5, 2007.
Address correspondence to Sheldon L. Kaplan, MD, Texas Children's Hospital, Feigin Center, Suite 1150, MC 3-2371, 6621 Fannin, Houston, TX 77030. E-mail: skaplan{at}bcm.edu
Financial Disclosure: Dr Kaplan received a grant from Wyeth for a pneumococcal surveillance study; the other authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject To our knowledge, this is the first report describing the emergence of serotype 19A Streptococcus pneumoniae causing acute mastoiditis in children.
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| What This Study Adds This report describes the emergence of serotype 19A pneumococcal isolates causing acute mastoiditis. The clinical findings associated with 19A mastoiditis were more severe than those associated with non–serotype 19A isolates, and the 19A isolates were often resistant to multiple antibiotics.
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