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Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure
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PEDOT-7777; No. of Pages 5 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure Beata Zielnik-Jurkiewicz *, Anna Bielicka ENT Department, Children0 s Hospital, 4/24 Niekłan´ska Str. 03-924 Warsaw, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 August 2015 Received in revised form 22 September 2015 Accepted 23 September 2015 Available online xxx
Objectives: The emergence of antibiotic-resistant bacteria is a major cause of treatment failure in children with acute otitis media (AOM). This study aimed to analyze the types of bacterial strains in fluid isolated from the middle ear of children with AOM who did not respond to oral antibiotic treatment. We also determined the antibiotic resistance of the most frequently isolated bacterial strain (Streptococcus pneumoniae) found in these children. Methods: This was a prospective study of 157 children with AOM aged from 6 months to 7 years admitted due to unsuccessful oral antibiotic treatment. All children underwent a myringotomy, and samples of the middle ear fluid were collected for bacteriological examination. Results: Positive bacterial cultures were obtained in 104 patients (66.2%), with Streptococcus pneumoniae (39.69%), Haemophilus influenzae (16.03%) Staphylococcus aureus (16.03%), Staphylococcus haemolyticus (6.9%) and Streptococcus pyogenes (5.34%) found most frequently. The majority (65.4%) of S. pneumoniae strains were penicillin-intermediate-resistant or penicillin-resistant, and 67.2% strains of S. pneumoniae were multidrug-resistant. Conclusions: We identified S. pneumoniae as the most frequently isolated pathogen from the middle ear in children with AOM treatment failure and determined that the majority of strains were antibioticresistant. We propose that the microbiological identification of bacterial strains and their degree of antibiotic resistance should be performed prior to therapy in order to choose the most appropriate antibiotic therapy for children with AOM treatment failure. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Acute otitis media Streptococcus pneumoniae Antibiotic resistance Children
1. Introduction Acute otitis media (AOM) is a common infection in children caused by bacteria and viruses [1,2]. Antibiotic treatment of AOM is usually empiric, as the causative pathogens are not routinely identified prior to therapy due to the risks associated with tympanocentesis in children [3]. While first-line and second-line antibiotic treatment recommendations have been developed to treat children with AOM [3], the infection can persist in some cases, termed AOM treatment failure. AOM treatment failure can be defined as: (i) the persistence of clinical and otoscopic signs of AOM, despite one or several courses of antibiotic therapy; (ii) the recurrence of AOM in a short period of time after the antibiotic course is finished; (iii) intracranial/ intratemporal complications during AOM; or (iv) continued
* Corresponding author. Tel.: +48 22 5098276; fax: +48 22 5098276. E-mail address: [email protected] (B. Zielnik-Jurkiewicz).
tympanic membrane inflammation or acute symptoms, despite antibiotic therapy. The main causes of AOM treatment failure in children are Eustachian tube dysfunction, immaturity of the immune system in childhood, inappropriate administration of an antibiotic by parents, anatomy, previous or concurrent viral infection and antibiotic-resistant bacteria, among others [4]. Unfortunately, the prevalence of antibiotic-resistant bacteria typically causative of AOM is increasing and has become a major concern for effective treatment. The major bacterial pathogens responsible for AOM are Streptococcus pneumoniae, Haemophilus influenza and Moraxella catarrhalis (for recent reviews see [5,6]). Due to the excessive and improper use of antibiotics to treat infections, there has been a global increase in the prevalence of antibiotic-resistant bacterial strains, the severity of which can vary based on geographical location [7]. In Poland, data from the National Referral Center of Microbial Resistance (Krajowy Os´rodek Referencyjny ds. Lekowraz˙liwos´ci Drobnoustrojo´w) have shown increased resistance of the major causative bacterial agent of AOM (S. pneumoniae) to penicillin
http://dx.doi.org/10.1016/j.ijporl.2015.09.030 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: B. Zielnik-Jurkiewicz, A. Bielicka, Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.030
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and other antibiotics [8–12], with the first multidrug-resistant clones of S. pneumoniae described in 1978 [13]. However, whether the bacterial strains found in children with AOM treatment failure are resistant to multiple types of antibiotics remains unclear. In this prospective study, we aimed to identify the most commonly isolated bacterial strain in children with AOM in Poland. We performed a bacteriological analysis of the fluid isolated from the middle ear in children with AOM whose antibiotic treatment was unsuccessful. We also determined the antibiotic resistance profile of the most frequently isolated strain. Together, the results of our study will help us to understand the current failure of empirical antibiotic therapy in the treatment of AOM. 2. Materials and methods 2.1. Patients In this prospective study, we examined 157 children aged from 6 months to 7 years (96 boys and 61 girls, with a mean age of 3 years and 3 months). All children were admitted to the Department of Otolaryngology, Children’s Hospital in Warsaw, Poland between 2010 and 2013 because of the failure of oral antibiotic therapy for treatment of AOM. AOM antibiotic treatment failure was defined as: (i) the persistence of clinical and otoscopic signs of AOM (i.e. fever, severe earache, bulging tympanic membrane) within 2–10 days of an initial diagnosis and after the prescription of initial or delayed antibiotic therapy and (ii) the recurrence of AOM after 6–30 days of finishing the antibiotic course. First-line and second-line antibiotic treatment was administered for a period of 2–10 days and based on recommendations described by Rosenfeld [3] as follows: amoxicillin (80–90 mg/kg/day), amoxicillin-clavulanate (90 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate), cefuroxime (30 mg/kg/day) and clindamycin (30–40 mg/kg/day). Children were referred for myringotomy due to: (i) increased clinical symptoms (fever, severe earache), and the observed presence of a bulging tympanic membrane with pus in the tympanic cavity upon otoscopic and microscopic examination; and (ii) AOM antibiotic treatment failure. Children with spontaneous perforation and a previously inserted ventilatory tube were excluded from this study. All children included in this study were immunized with the Haemophilus influenzae type B (Hib) vaccine. None of the children were immunized with the 7-valent pneumococcal conjugate vaccine (PCV-7) (Prevenar, Wyeth Pharmaceuticals), which was introduced for pediatric use in 2000 (for a review of the global data on this vaccine see [14]). All children attended a day care center or nursery school 2.2. Middle ear fluid (MEF) sample collection and analysis
agar was incubated at 36–37 8C with 5% CO2 for 24 h. After the incubation period, bacterial growth was determined using diagnostic discs and biochemical methods. Antibiotic sensitivity of S. pneumoniae was determined using standard disk and strip tests for oxacyline, erythromycin, clindamycin and sulfamethoxazole-trimetopim. In the case of oxycyline antibiotic-resistant strains, the sensitivity to cefotaxime was also evaluated. Definitions of antimicrobial susceptibility were based on laboratory standards. Susceptibility of isolated S. pneumoniae was determined by a disk diffusion technique containing different concentration gradients for the following antibiotics: penicillin, ampicillin, cefotaxime and ceftriaxone. Nonsusceptibility to three or more antibiotic classes was considered a multidrug-resistant strain. S. pneumoniae isolates were classified as penicillin-susceptible (S, MIC 0.06 mg/ml), penicillin intermediate-resistant (I, MIC > 0.06–2.0 mg/ml) and penicillin-resistant (R, MIC > 2.0 mg/ml). 2.3. Ethical approval The parents of the study subjects were informed of the method and purpose of the study and their consent was obtained. The study was approved by the Bioethics Committee in Warsaw, Poland. 3. Results 3.1. Common bacterial strains found in the MEF of children with AOM treatment failure Positive bacterial cultures were obtained in 104 children (66.2%) with AOM, while no bacterial etiological agents were identified in the remaining 33.8% of AOM children. A total of 131 different bacterial strains were isolated as two different bacteria were isolated in 27 children with AOM. The most frequently isolated pathogens were: S. pneumoniae (39.69%), H. influenzae (16.03%), S. aureus (16.03%), S. haemolyticus (6.9%) and S. pyogenes (5.34%); other bacteria were identified in 16.01% of all cases (Table 1). 3.2. Antibiotic resistance of the most commonly isolated bacterial strain Because S. pneumoniae was isolated most frequently (52/131, 39.69% of all strains), we focused on analyzing the antibiotic
Table 1 Bacteriological flora isolated from the middle ear fluid of children with treatment failure for acute otitis media. Bacteria
Myringotomy was performed in all children, and the MEF was collected for bacteriological examination. Briefly, the external ear canal was rinsed for 1 min with 70% ethanol. Then, under otomicroscopic visual control, a sterile suction trap was used to aspirate MEF samples by myringotomy through the intact tympanic membranes. All MEF samples were transferred to the Department of Laboratory Diagnostics Children’s Hospital in Warsaw, Poland within 2–6 h for plating at room temperature. Pathogenic bacteria in the MEF were identified using standard methods (www.eucast.org). Briefly, MEF was plated onto the following: Columbia agar with 5% sheep blood; Brain Heart Infusion (BHI) agar (for cultivation of H. influenza); MacConkey agar (for cultivation of Gram-negative bacilli); and Chapman agar (for cultivation of S. aureus). The Columbia agar, MacConkey agar and Chapman agar were incubated at 36–37 8C for 24 h. The BHI
Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Staphylococcus haemolyticus Streptococcus alpha-hemolytic Streptococcus pyogenes Streptococcus beta-hemolytic Escherichia coli ESBL (-) Enterobacter cloacae Klebsiella pneumoniae ESBL (-) Proteus mirabilis Acinetobacter Streptococcus mitis Pseudomonas aeruginosa Total strains
Number of isolated bacteria [%] 52 [39.69%] 21 [16.03%] 21 [16.03%] 9 [6.9%] 7 [5.34%] 7 [5.34%] 3 [2.29%] 3 [2.29%] 2 [1.52%] 2 [1.52%] 1 [0.76%] 1 [0.76%] 1 [0.76%] 1 [0.76%] 131 [100%]
Please cite this article in press as: B. Zielnik-Jurkiewicz, A. Bielicka, Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.030
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Table 2 Degree of antibiotic resistance (susceptible (S), intermediate-resistant (I), or resistant (R)) of Streptococcus pneumonia in children with treatment failure for acute otitis media. Strains of Streptococcus pneumoniae with different antibiotic sensitivity
1
2
3
4
5
6
7
8
9
10
11
12
13
Percentage of Streptococcus pneumoniae sensitive to antibiotic
Penicillin Ceftriaxone Erythromycin Clindamycin Co-trimoxazole Ofloxacin Number of strains (%)
S S S S S S 8 (15.4)
S S S S R S 2 (3.9)
S S R S S S 1 (1.9)
S S R R R S 6 (11.5)
S I R R R S 1 (1.9)
I S S S R S 1 (1.9)
I S R R R S 13 (25)
R S S S R S 3 (5.8)
R I S S S S 2 (3.9)
R S R S R S 3 (5.8)
R S R R R S 6 (11.5)
R I R R R S 5 (9.6)
R R R R R S 1 (1.9)
34.6% 82.7% 30.8% 38.5% 21.2% 100% 52 strains (100%)
resistance of this bacterium. All 52 strains were divided into 13 groups based on their profiles of antibiotic resistance (Table 2). Only eight strains of S. pneumoniae (15.4%) were sensitive to all the antibiotics (Group 1). Multidrug resistance (i.e. non-susceptibility to three or more antibiotic classes) was present in 35 of the 52 (67.2%) strains (Groups 4, 5, 7, 10, 11, 12 and 13). Only 30.8% of strains of S. pneumoniae were susceptible to erythromycin, 38.5% were susceptible to clindamycin, and 21.2% were susceptible to cotrimoxazole. With regards to penicillin, 65.4% of isolated S. pneumoniae strains had reduced susceptibility, 26.9% showed intermediate-resistance, and 38.5% were highly resistant. All strains of S. pneumoniae were susceptible to ofloxacin and 82.7% of strains were susceptible to ceftriaxone. Finally, only 17 strains of S. pneumoniae (32.7%) remained sensitive to an antibiotic that had been orally administered prior to hospitalization (i.e. amoxicillin, clindamycin, cefuroxime and erythromycin). 4. Discussion Here, we assessed episodes where oral antibiotic treatment for AOM had failed in Polish children. We found that in 66% of children with AOM treatment failure (among 104 patients), the MEF contained pathogenic bacteria. This is higher than the previously reported number of cases of AOM that were bacteria-positive in children who had also received prior oral antibiotic therapy (i.e. 48 and 5358% reported by Intakorn et al. [15] and Li et al. [16], respectively). We could not identify the causative agent of the AOM in the remaining 34% of children in our study because thorough diagnostic testing on a broad spectrum of microbial pathogens was limited with the small amount of MEF obtained. In addition, current microbiological approaches cannot be used to evaluate all of the bacterial and viral causes of AOM concomitantly. However, our results are similar to previous studies, which report that 2530% of AOM cases have no bacterial cause [5,17,18]. The most frequently isolated bacterial pathogen responsible for AOM treatment failure in our study was S. pneumoniae, which accounted for 39.69% (52/131) of all strains. While a previous report by Grevers et al. found H. influenzae was most frequently (21%) isolated in children with AOM in Germany [19], we found that H. influenzae only accounted for 16.03% of strains in Poland. This difference can be partly explained by the types of vaccinations received by the children in our study compared with the study by Grevers et al. In particular, none of the examined children in our study were immunized with the pneumococcal conjugate vaccine (PCV). The PCV is not obligatorily used in Polish children, and there is a cost associated with the vaccine in Poland compared with other countries. Therefore, our results are similar to that seen in many countries in pre-vaccine years, whereby S. pneumoniae was a leading cause of AOM [20]. On the other hand, all of the children in our study had been given a H. influenzae type B (Hib) vaccine, which could explain the reduced number of H. influenzae positive cases. In
addition, our population of children attended either a day care center or a nursery school. As nasopharyngeal carriage of S. pneumoniae is reported to be at a high level (62% of the population) among children attending day care centers compared with children staying at home (22%) [21], this could also partly explain the increased frequency of S. pneumoniae strains found in our study population. The treatment of AOM with commonly prescribed oral antibiotics (i.e. amoxicillin, clindamycin, cefuroxime and erythromycin) was unsuccessful in many children in our study. Such treatment failures may be due to using too small of a dose of the antibiotic, using the antibiotic for too short of a period, poor antibiotic penetration to the middle ear space due to thick purulent secretion in this space, or the presence of antibiotic-resistant bacteria, as reported previously [15,22]. Indeed, up-to-date information on antibiotic resistance has important clinical implications for determining the best AOM treatment approach [22]. We found a high frequency (65.4%) of antibiotic-resistant S. pneumoniae in children with AOM who were previously treated with oral antibiotics. These isolated S. pneumoniae strains show great diversity with respect to their resistance, with 13 different patterns of antibiotic-resistance among the 52 isolated strains. The different patterns of resistance may be explained by the fact that the use of some antibiotics is limited. For example, all S. pneumoniae strains were still sensitive to ofloxacin as this antibiotic is only used rarely in some specific groups of children [23]. In addition, 82.7% of S. pneumoniae strains were still susceptible to ceftriaxone. Again, the improved sensitivity to this antibiotic may be because ceftriaxone is not widely used; it is only recommended in severe cases of AOM, with severe otalgia or fever up to 39 8C. We also found a high frequency (67.2%) of multidrug-resistant S. pneumoniae in our study. This is similar to previous studies on AOM treatment failure that indicate 40 or 55% of S. pneumoniae isolates were multidrug-resistant [18,24]. Many authors have reported that a large proportion of AOM is caused by multidrugresistant S. pneumoniae strains [11,12,23]. However, as the children in our study had already received oral antibiotic therapy (one or more antibiotic courses), it is not possible to determine whether the bacteria became multidrug-resistant during consecutive antibiotic therapies in the same patient, or whether the bacteria were resistant to many antibiotics before they infected the patient. Due to the prevalence of multidrug-resistant bacterial strains, many researchers now propose that antibiotic therapy in AOM should be restricted [25,26]. According to the recent recommendations by the American Academy of Pediatrics, children aged over 2 years with non-severe AOM without otorrhea should be offered two treatment options: first, antibiotics could be given at the time of diagnosis; or second, the child could undergo a period of observation of 48–72 h (with provision of symptomatic relief) and
Please cite this article in press as: B. Zielnik-Jurkiewicz, A. Bielicka, Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.030
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antibiotics are only given if the symptoms worsen or fail to improve within this period [27]. Indeed symptomatic relief (i.e. analgesic and antipyretic drugs) allows antibiotic therapy to be avoided in 66% of children with a non-severe course of AOM [28]. If antibiotics are administered, the right drug must be given for the most likely bacterial pathogen, and the pathogen’s susceptibility to the antibiotic should be considered. The differing antibiotic resistance profiles observed in bacteria isolated from the MEF affects not only the first-line of treatment in children with AOM treatment failure, but also the subsequent lines of therapy in children with persistent or recurrent AOM. While it is currently recommended to use antibiotic therapy, according to algorithms developed by the relevant authorities in each country [29,30], the judicious usage of antibiotics may reduce the incidence of antibiotic-resistant pneumococci in the future [31]. Finally, the widespread use of the PCV in Poland may curb the rapid increase of antibiotic resistance of S. pneumoniae as observed in other countries [31–33]. As S. pneumoniae is commonly reported as the most frequently isolated pathogen in AOM in many countries, the PCV is becoming a favorable option for AOM prevention [34,35]. Indeed, the benefit of the PCV on reducing the need for antibiotics to treat pneumococcal infections has previously been reported, with a concurrent small decline in AOM incidence [24,36]. By reducing the need for antibiotic treatment, the frequency of antibiotic-resistant S. pneumoniae strains is also reduced. Indeed, McGrath et al. observed decreasing AOM treatment failure rates could be due to lower prevalence of antibiotic-resistant strains of S. pneumoniae since the introduction of the PCV [33]. In our study on children who had not received the PCV, the majority of S. pneumoniae strains were antibiotic-resistant and there was a high degree of AOM treatment failure. In contrast, in a large, observational study of children with AOM in Boston, who received the vaccine and were treated with high-dose amoxicillin, the relapse rate was only 8.9% [37]. In 2010, a new vaccine (PCV13) was introduced that covers a common S. pneumoniae strain (i.e. serotype 19A) [38,39]. Therefore, implementation of this new vaccine may lower the overall prevalence of otitis media caused by S. pneumonia, and reduce the emergence of antibiotic-resistant strains. In summary, we demonstrated that S. pneumoniae is the most frequently isolated pathogen from the middle ear in children with AOM not responding to empirical antibiotic treatment. These S. pneumoniae isolates showed a high rate of resistance to penicillin, erythromycin, and clindamycin, with over half of the strains classified as multidrug-resistant. The rise of antibioticresistant bacteria, combined with the fact that AOM is one of the infections most frequently treated with antibiotics in children, means there is an urgent need to establish regulations for the proper diagnosis and treatment of AOM. We suggest the introduction of the PCV could reduce the need for antibiotic treatment of AOM in Poland. In addition, we propose that the microbiological identification of bacterial strains and their degree of antibiotic resistance should be performed prior to therapy in order to choose the most appropriate antibiotic for children with AOM treatment failure.
Conflict of interest None.
Funding No external funding source was involved in this study.
Acknowledgments The authors would like to thank Proper Medical Writing Sp. z o.o., in particular Julia Archbold, PhD, for language and technical corrections and Agnieszka Linkiewicz-Zegan for formatting the final version of our manuscript.
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PEDOT-7777; No. of Pages 5 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
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Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure Beata Zielnik-Jurkiewicz *, Anna Bielicka ENT Department, Children0 s Hospital, 4/24 Niekłan´ska Str. 03-924 Warsaw, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 August 2015 Received in revised form 22 September 2015 Accepted 23 September 2015 Available online xxx
Objectives: The emergence of antibiotic-resistant bacteria is a major cause of treatment failure in children with acute otitis media (AOM). This study aimed to analyze the types of bacterial strains in fluid isolated from the middle ear of children with AOM who did not respond to oral antibiotic treatment. We also determined the antibiotic resistance of the most frequently isolated bacterial strain (Streptococcus pneumoniae) found in these children. Methods: This was a prospective study of 157 children with AOM aged from 6 months to 7 years admitted due to unsuccessful oral antibiotic treatment. All children underwent a myringotomy, and samples of the middle ear fluid were collected for bacteriological examination. Results: Positive bacterial cultures were obtained in 104 patients (66.2%), with Streptococcus pneumoniae (39.69%), Haemophilus influenzae (16.03%) Staphylococcus aureus (16.03%), Staphylococcus haemolyticus (6.9%) and Streptococcus pyogenes (5.34%) found most frequently. The majority (65.4%) of S. pneumoniae strains were penicillin-intermediate-resistant or penicillin-resistant, and 67.2% strains of S. pneumoniae were multidrug-resistant. Conclusions: We identified S. pneumoniae as the most frequently isolated pathogen from the middle ear in children with AOM treatment failure and determined that the majority of strains were antibioticresistant. We propose that the microbiological identification of bacterial strains and their degree of antibiotic resistance should be performed prior to therapy in order to choose the most appropriate antibiotic therapy for children with AOM treatment failure. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Acute otitis media Streptococcus pneumoniae Antibiotic resistance Children
1. Introduction Acute otitis media (AOM) is a common infection in children caused by bacteria and viruses [1,2]. Antibiotic treatment of AOM is usually empiric, as the causative pathogens are not routinely identified prior to therapy due to the risks associated with tympanocentesis in children [3]. While first-line and second-line antibiotic treatment recommendations have been developed to treat children with AOM [3], the infection can persist in some cases, termed AOM treatment failure. AOM treatment failure can be defined as: (i) the persistence of clinical and otoscopic signs of AOM, despite one or several courses of antibiotic therapy; (ii) the recurrence of AOM in a short period of time after the antibiotic course is finished; (iii) intracranial/ intratemporal complications during AOM; or (iv) continued
* Corresponding author. Tel.: +48 22 5098276; fax: +48 22 5098276. E-mail address: [email protected] (B. Zielnik-Jurkiewicz).
tympanic membrane inflammation or acute symptoms, despite antibiotic therapy. The main causes of AOM treatment failure in children are Eustachian tube dysfunction, immaturity of the immune system in childhood, inappropriate administration of an antibiotic by parents, anatomy, previous or concurrent viral infection and antibiotic-resistant bacteria, among others [4]. Unfortunately, the prevalence of antibiotic-resistant bacteria typically causative of AOM is increasing and has become a major concern for effective treatment. The major bacterial pathogens responsible for AOM are Streptococcus pneumoniae, Haemophilus influenza and Moraxella catarrhalis (for recent reviews see [5,6]). Due to the excessive and improper use of antibiotics to treat infections, there has been a global increase in the prevalence of antibiotic-resistant bacterial strains, the severity of which can vary based on geographical location [7]. In Poland, data from the National Referral Center of Microbial Resistance (Krajowy Os´rodek Referencyjny ds. Lekowraz˙liwos´ci Drobnoustrojo´w) have shown increased resistance of the major causative bacterial agent of AOM (S. pneumoniae) to penicillin
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Please cite this article in press as: B. Zielnik-Jurkiewicz, A. Bielicka, Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.030
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and other antibiotics [8–12], with the first multidrug-resistant clones of S. pneumoniae described in 1978 [13]. However, whether the bacterial strains found in children with AOM treatment failure are resistant to multiple types of antibiotics remains unclear. In this prospective study, we aimed to identify the most commonly isolated bacterial strain in children with AOM in Poland. We performed a bacteriological analysis of the fluid isolated from the middle ear in children with AOM whose antibiotic treatment was unsuccessful. We also determined the antibiotic resistance profile of the most frequently isolated strain. Together, the results of our study will help us to understand the current failure of empirical antibiotic therapy in the treatment of AOM. 2. Materials and methods 2.1. Patients In this prospective study, we examined 157 children aged from 6 months to 7 years (96 boys and 61 girls, with a mean age of 3 years and 3 months). All children were admitted to the Department of Otolaryngology, Children’s Hospital in Warsaw, Poland between 2010 and 2013 because of the failure of oral antibiotic therapy for treatment of AOM. AOM antibiotic treatment failure was defined as: (i) the persistence of clinical and otoscopic signs of AOM (i.e. fever, severe earache, bulging tympanic membrane) within 2–10 days of an initial diagnosis and after the prescription of initial or delayed antibiotic therapy and (ii) the recurrence of AOM after 6–30 days of finishing the antibiotic course. First-line and second-line antibiotic treatment was administered for a period of 2–10 days and based on recommendations described by Rosenfeld [3] as follows: amoxicillin (80–90 mg/kg/day), amoxicillin-clavulanate (90 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate), cefuroxime (30 mg/kg/day) and clindamycin (30–40 mg/kg/day). Children were referred for myringotomy due to: (i) increased clinical symptoms (fever, severe earache), and the observed presence of a bulging tympanic membrane with pus in the tympanic cavity upon otoscopic and microscopic examination; and (ii) AOM antibiotic treatment failure. Children with spontaneous perforation and a previously inserted ventilatory tube were excluded from this study. All children included in this study were immunized with the Haemophilus influenzae type B (Hib) vaccine. None of the children were immunized with the 7-valent pneumococcal conjugate vaccine (PCV-7) (Prevenar, Wyeth Pharmaceuticals), which was introduced for pediatric use in 2000 (for a review of the global data on this vaccine see [14]). All children attended a day care center or nursery school 2.2. Middle ear fluid (MEF) sample collection and analysis
agar was incubated at 36–37 8C with 5% CO2 for 24 h. After the incubation period, bacterial growth was determined using diagnostic discs and biochemical methods. Antibiotic sensitivity of S. pneumoniae was determined using standard disk and strip tests for oxacyline, erythromycin, clindamycin and sulfamethoxazole-trimetopim. In the case of oxycyline antibiotic-resistant strains, the sensitivity to cefotaxime was also evaluated. Definitions of antimicrobial susceptibility were based on laboratory standards. Susceptibility of isolated S. pneumoniae was determined by a disk diffusion technique containing different concentration gradients for the following antibiotics: penicillin, ampicillin, cefotaxime and ceftriaxone. Nonsusceptibility to three or more antibiotic classes was considered a multidrug-resistant strain. S. pneumoniae isolates were classified as penicillin-susceptible (S, MIC 0.06 mg/ml), penicillin intermediate-resistant (I, MIC > 0.06–2.0 mg/ml) and penicillin-resistant (R, MIC > 2.0 mg/ml). 2.3. Ethical approval The parents of the study subjects were informed of the method and purpose of the study and their consent was obtained. The study was approved by the Bioethics Committee in Warsaw, Poland. 3. Results 3.1. Common bacterial strains found in the MEF of children with AOM treatment failure Positive bacterial cultures were obtained in 104 children (66.2%) with AOM, while no bacterial etiological agents were identified in the remaining 33.8% of AOM children. A total of 131 different bacterial strains were isolated as two different bacteria were isolated in 27 children with AOM. The most frequently isolated pathogens were: S. pneumoniae (39.69%), H. influenzae (16.03%), S. aureus (16.03%), S. haemolyticus (6.9%) and S. pyogenes (5.34%); other bacteria were identified in 16.01% of all cases (Table 1). 3.2. Antibiotic resistance of the most commonly isolated bacterial strain Because S. pneumoniae was isolated most frequently (52/131, 39.69% of all strains), we focused on analyzing the antibiotic
Table 1 Bacteriological flora isolated from the middle ear fluid of children with treatment failure for acute otitis media. Bacteria
Myringotomy was performed in all children, and the MEF was collected for bacteriological examination. Briefly, the external ear canal was rinsed for 1 min with 70% ethanol. Then, under otomicroscopic visual control, a sterile suction trap was used to aspirate MEF samples by myringotomy through the intact tympanic membranes. All MEF samples were transferred to the Department of Laboratory Diagnostics Children’s Hospital in Warsaw, Poland within 2–6 h for plating at room temperature. Pathogenic bacteria in the MEF were identified using standard methods (www.eucast.org). Briefly, MEF was plated onto the following: Columbia agar with 5% sheep blood; Brain Heart Infusion (BHI) agar (for cultivation of H. influenza); MacConkey agar (for cultivation of Gram-negative bacilli); and Chapman agar (for cultivation of S. aureus). The Columbia agar, MacConkey agar and Chapman agar were incubated at 36–37 8C for 24 h. The BHI
Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Staphylococcus haemolyticus Streptococcus alpha-hemolytic Streptococcus pyogenes Streptococcus beta-hemolytic Escherichia coli ESBL (-) Enterobacter cloacae Klebsiella pneumoniae ESBL (-) Proteus mirabilis Acinetobacter Streptococcus mitis Pseudomonas aeruginosa Total strains
Number of isolated bacteria [%] 52 [39.69%] 21 [16.03%] 21 [16.03%] 9 [6.9%] 7 [5.34%] 7 [5.34%] 3 [2.29%] 3 [2.29%] 2 [1.52%] 2 [1.52%] 1 [0.76%] 1 [0.76%] 1 [0.76%] 1 [0.76%] 131 [100%]
Please cite this article in press as: B. Zielnik-Jurkiewicz, A. Bielicka, Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.030
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Table 2 Degree of antibiotic resistance (susceptible (S), intermediate-resistant (I), or resistant (R)) of Streptococcus pneumonia in children with treatment failure for acute otitis media. Strains of Streptococcus pneumoniae with different antibiotic sensitivity
1
2
3
4
5
6
7
8
9
10
11
12
13
Percentage of Streptococcus pneumoniae sensitive to antibiotic
Penicillin Ceftriaxone Erythromycin Clindamycin Co-trimoxazole Ofloxacin Number of strains (%)
S S S S S S 8 (15.4)
S S S S R S 2 (3.9)
S S R S S S 1 (1.9)
S S R R R S 6 (11.5)
S I R R R S 1 (1.9)
I S S S R S 1 (1.9)
I S R R R S 13 (25)
R S S S R S 3 (5.8)
R I S S S S 2 (3.9)
R S R S R S 3 (5.8)
R S R R R S 6 (11.5)
R I R R R S 5 (9.6)
R R R R R S 1 (1.9)
34.6% 82.7% 30.8% 38.5% 21.2% 100% 52 strains (100%)
resistance of this bacterium. All 52 strains were divided into 13 groups based on their profiles of antibiotic resistance (Table 2). Only eight strains of S. pneumoniae (15.4%) were sensitive to all the antibiotics (Group 1). Multidrug resistance (i.e. non-susceptibility to three or more antibiotic classes) was present in 35 of the 52 (67.2%) strains (Groups 4, 5, 7, 10, 11, 12 and 13). Only 30.8% of strains of S. pneumoniae were susceptible to erythromycin, 38.5% were susceptible to clindamycin, and 21.2% were susceptible to cotrimoxazole. With regards to penicillin, 65.4% of isolated S. pneumoniae strains had reduced susceptibility, 26.9% showed intermediate-resistance, and 38.5% were highly resistant. All strains of S. pneumoniae were susceptible to ofloxacin and 82.7% of strains were susceptible to ceftriaxone. Finally, only 17 strains of S. pneumoniae (32.7%) remained sensitive to an antibiotic that had been orally administered prior to hospitalization (i.e. amoxicillin, clindamycin, cefuroxime and erythromycin). 4. Discussion Here, we assessed episodes where oral antibiotic treatment for AOM had failed in Polish children. We found that in 66% of children with AOM treatment failure (among 104 patients), the MEF contained pathogenic bacteria. This is higher than the previously reported number of cases of AOM that were bacteria-positive in children who had also received prior oral antibiotic therapy (i.e. 48 and 5358% reported by Intakorn et al. [15] and Li et al. [16], respectively). We could not identify the causative agent of the AOM in the remaining 34% of children in our study because thorough diagnostic testing on a broad spectrum of microbial pathogens was limited with the small amount of MEF obtained. In addition, current microbiological approaches cannot be used to evaluate all of the bacterial and viral causes of AOM concomitantly. However, our results are similar to previous studies, which report that 2530% of AOM cases have no bacterial cause [5,17,18]. The most frequently isolated bacterial pathogen responsible for AOM treatment failure in our study was S. pneumoniae, which accounted for 39.69% (52/131) of all strains. While a previous report by Grevers et al. found H. influenzae was most frequently (21%) isolated in children with AOM in Germany [19], we found that H. influenzae only accounted for 16.03% of strains in Poland. This difference can be partly explained by the types of vaccinations received by the children in our study compared with the study by Grevers et al. In particular, none of the examined children in our study were immunized with the pneumococcal conjugate vaccine (PCV). The PCV is not obligatorily used in Polish children, and there is a cost associated with the vaccine in Poland compared with other countries. Therefore, our results are similar to that seen in many countries in pre-vaccine years, whereby S. pneumoniae was a leading cause of AOM [20]. On the other hand, all of the children in our study had been given a H. influenzae type B (Hib) vaccine, which could explain the reduced number of H. influenzae positive cases. In
addition, our population of children attended either a day care center or a nursery school. As nasopharyngeal carriage of S. pneumoniae is reported to be at a high level (62% of the population) among children attending day care centers compared with children staying at home (22%) [21], this could also partly explain the increased frequency of S. pneumoniae strains found in our study population. The treatment of AOM with commonly prescribed oral antibiotics (i.e. amoxicillin, clindamycin, cefuroxime and erythromycin) was unsuccessful in many children in our study. Such treatment failures may be due to using too small of a dose of the antibiotic, using the antibiotic for too short of a period, poor antibiotic penetration to the middle ear space due to thick purulent secretion in this space, or the presence of antibiotic-resistant bacteria, as reported previously [15,22]. Indeed, up-to-date information on antibiotic resistance has important clinical implications for determining the best AOM treatment approach [22]. We found a high frequency (65.4%) of antibiotic-resistant S. pneumoniae in children with AOM who were previously treated with oral antibiotics. These isolated S. pneumoniae strains show great diversity with respect to their resistance, with 13 different patterns of antibiotic-resistance among the 52 isolated strains. The different patterns of resistance may be explained by the fact that the use of some antibiotics is limited. For example, all S. pneumoniae strains were still sensitive to ofloxacin as this antibiotic is only used rarely in some specific groups of children [23]. In addition, 82.7% of S. pneumoniae strains were still susceptible to ceftriaxone. Again, the improved sensitivity to this antibiotic may be because ceftriaxone is not widely used; it is only recommended in severe cases of AOM, with severe otalgia or fever up to 39 8C. We also found a high frequency (67.2%) of multidrug-resistant S. pneumoniae in our study. This is similar to previous studies on AOM treatment failure that indicate 40 or 55% of S. pneumoniae isolates were multidrug-resistant [18,24]. Many authors have reported that a large proportion of AOM is caused by multidrugresistant S. pneumoniae strains [11,12,23]. However, as the children in our study had already received oral antibiotic therapy (one or more antibiotic courses), it is not possible to determine whether the bacteria became multidrug-resistant during consecutive antibiotic therapies in the same patient, or whether the bacteria were resistant to many antibiotics before they infected the patient. Due to the prevalence of multidrug-resistant bacterial strains, many researchers now propose that antibiotic therapy in AOM should be restricted [25,26]. According to the recent recommendations by the American Academy of Pediatrics, children aged over 2 years with non-severe AOM without otorrhea should be offered two treatment options: first, antibiotics could be given at the time of diagnosis; or second, the child could undergo a period of observation of 48–72 h (with provision of symptomatic relief) and
Please cite this article in press as: B. Zielnik-Jurkiewicz, A. Bielicka, Antibiotic resistance of Streptococcus pneumoniae in children with acute otitis media treatment failure, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.030
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antibiotics are only given if the symptoms worsen or fail to improve within this period [27]. Indeed symptomatic relief (i.e. analgesic and antipyretic drugs) allows antibiotic therapy to be avoided in 66% of children with a non-severe course of AOM [28]. If antibiotics are administered, the right drug must be given for the most likely bacterial pathogen, and the pathogen’s susceptibility to the antibiotic should be considered. The differing antibiotic resistance profiles observed in bacteria isolated from the MEF affects not only the first-line of treatment in children with AOM treatment failure, but also the subsequent lines of therapy in children with persistent or recurrent AOM. While it is currently recommended to use antibiotic therapy, according to algorithms developed by the relevant authorities in each country [29,30], the judicious usage of antibiotics may reduce the incidence of antibiotic-resistant pneumococci in the future [31]. Finally, the widespread use of the PCV in Poland may curb the rapid increase of antibiotic resistance of S. pneumoniae as observed in other countries [31–33]. As S. pneumoniae is commonly reported as the most frequently isolated pathogen in AOM in many countries, the PCV is becoming a favorable option for AOM prevention [34,35]. Indeed, the benefit of the PCV on reducing the need for antibiotics to treat pneumococcal infections has previously been reported, with a concurrent small decline in AOM incidence [24,36]. By reducing the need for antibiotic treatment, the frequency of antibiotic-resistant S. pneumoniae strains is also reduced. Indeed, McGrath et al. observed decreasing AOM treatment failure rates could be due to lower prevalence of antibiotic-resistant strains of S. pneumoniae since the introduction of the PCV [33]. In our study on children who had not received the PCV, the majority of S. pneumoniae strains were antibiotic-resistant and there was a high degree of AOM treatment failure. In contrast, in a large, observational study of children with AOM in Boston, who received the vaccine and were treated with high-dose amoxicillin, the relapse rate was only 8.9% [37]. In 2010, a new vaccine (PCV13) was introduced that covers a common S. pneumoniae strain (i.e. serotype 19A) [38,39]. Therefore, implementation of this new vaccine may lower the overall prevalence of otitis media caused by S. pneumonia, and reduce the emergence of antibiotic-resistant strains. In summary, we demonstrated that S. pneumoniae is the most frequently isolated pathogen from the middle ear in children with AOM not responding to empirical antibiotic treatment. These S. pneumoniae isolates showed a high rate of resistance to penicillin, erythromycin, and clindamycin, with over half of the strains classified as multidrug-resistant. The rise of antibioticresistant bacteria, combined with the fact that AOM is one of the infections most frequently treated with antibiotics in children, means there is an urgent need to establish regulations for the proper diagnosis and treatment of AOM. We suggest the introduction of the PCV could reduce the need for antibiotic treatment of AOM in Poland. In addition, we propose that the microbiological identification of bacterial strains and their degree of antibiotic resistance should be performed prior to therapy in order to choose the most appropriate antibiotic for children with AOM treatment failure.
Conflict of interest None.
Funding No external funding source was involved in this study.
Acknowledgments The authors would like to thank Proper Medical Writing Sp. z o.o., in particular Julia Archbold, PhD, for language and technical corrections and Agnieszka Linkiewicz-Zegan for formatting the final version of our manuscript.
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