Abstract

Objectives

The aim of this study was to evaluate susceptibility to common paediatric antibiotics for Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis isolated from 2005 through 2007.

Methods

Microdilution MIC assays were performed using CLSI-approved methods. S. pneumoniae 19A strains were identified by quellung reaction.

Results

Among 143 non-typeable H. influenzae, 42% produced β-lactamase. By 2007 breakpoints (PK/PD:CLSI), percentage susceptibility for non-typeable H. influenzae was: ceftriaxone = cefixime = high-dose amoxicillin/clavulanate (all 100%:100%) > standard-dose amoxicillin/clavulanate (91.6%:100%) > cefuroxime axetil (88.1%:99.3%) > cefdinir (83.9%:100%) > trimethoprim/sulfamethoxazole (73.4%:73.4%) >high-dose amoxicillin (58%:58%) > standard-dose amoxicillin (55.2%:58%) > cefprozil (28.7%:83.2%) > cefaclor (3.5%:83.2%) > azithromycin (0%:87.4%). Of 208 S. pneumoniae (42 serotype 19A), 86 were penicillin-susceptible, 60 were penicillin-intermediate and 62 were penicillin-resistant by 2007 CLSI breakpoints. Percentage susceptibility for all S. pneumoniae/19A by PD breakpoints was: ceftriaxone (95.2%/86.1%) > high-dose amoxicillin (89.4%/58.3%) > clindamycin (85%/58.3%) > standard-dose amoxicillin (73.5%/33.3%) > cefuroxime axetil (69.2%/36.1%), cefprozil (67.3%/33.3%) > cefdinir (59.1%/33.3%) > cefixime (57.7%/33.3%) > azithromycin (56.7%/33.3%) > trimethoprim/sulfamethoxazole (50.5%/25%) > penicillin (41.3%/19.4%) > cefaclor (28.8%/8.3%). Percentage M. catarrhalis (n = 62) susceptibility by PK/PD breakpoints was: high-dose amoxicillin/clavulanate = cefixime (100%) > azithromycin (98.4%) > ceftriaxone (96.8%) > standard-dose amoxicillin/clavulanate (88.7%) > cefdinir (80.6%) > cefprozil = cefuroxime axetil (37.1%) > high-dose amoxicillin (11.2%) > cefaclor (6.5%) > standard-dose amoxicillin (4.8%).

Conclusions

Despite high rates of β-lactamase production among non-typeable H. influenzae and M. catarrhalis, multiple oral treatment options exist for non-typeable H. influenzae and M. catarrhalis. Multidrug-resistant serotype 19A S. pneumoniae (∼20%) limits treatment options for ambulatory S. pneumoniae respiratory disease.

Introduction

Three major pathogens contribute to bacterial paediatric upper respiratory infections, non-typeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. The most common clinical presentation of such pathogens in children is acute otitis media (AOM). It appears that AOM frequency has decreased in the USA during the past 5 years, in part due to heptavalent pneumococcal conjugate vaccine (PCV-7) use.1,2 Nevertheless, community-acquired bacterial respiratory tract infection remains a frequent reason for children to seek medical care. Moreover, recent reports suggest that antibiotic resistance may not be decreasing, despite decreases in the proportion of paediatric respiratory isolates from among PCV-7 strains, which prior to 2000 encompassed most drug-resistant S. pneumoniae.3

This appears to be due to shifts in AOM pathogen prevalence, which have produced higher rates of antibiotic resistance among S. pneumoniae and non-typeable H. influenzae. One important factor has been serotype substitution among S. pneumoniae, particularly the emergence of serotypes 19A and 33.4,5 The emergence of 19A is of ongoing concern because increasing numbers of strains within this serotype exhibit high-level resistance to multiple drug classes. Drugs to which resistance has been prominent include penicillin, amoxicillin, oral cephalosporins, macrolides, clindamycin and trimethoprim/sulfamethoxazole. An additional factor has been the apparent increase in frequency of non-typeable H. influenzae isolates that produce β-lactamase,6,7 conferring resistance to amoxicillin and several oral cephalosporins, e.g. cefprozil and cefaclor.

Treatment guidelines and recommendations from the CDC or other organizations, e.g. the American Academy of Pediatrics (AAP),8 are updated at irregular intervals because it is not practical to change them as frequently as resistance data change. As new drugs enter the market or previously established drugs are re-introduced to the market during times when guidelines are not about to be changed, clinicians’ choices may need to include options in addition to those in published guidelines. Determining the evolving susceptibilities to a broader group of oral drugs that can be used in paediatric patients could facilitate alternative choices when the limited group of guideline drugs may no longer provide optimal outcomes. In addition, susceptibility breakpoints can differ between CLSI versions used by clinical laboratories and PK/PD breakpoints that can be calculated whenever new information becomes available. These PK/PD breakpoints are calculated from human population-based PK studies. The PK drug concentration data are compared with MIC distributions for each targeted bacterial species. A proposed PK/PD breakpoint (target of attainment) can be calculated. For example, for a β-lactam drug, this is based on the drug concentration of a proposed antibiotic dose being above the bacterial species’ MIC90 for ≥50% of the dosing interval. This proposed breakpoint is then validated in animal and subsequently in human clinical trials. In the past 10 years, PK/PD breakpoints have been reviewed and adapted frequently and therefore may currently allow more precise clinical decisions. However, breakpoints from either source may not be available for selected drugs and pathogens, leading to the need to consider both or either.

Ongoing surveillance for shifting patterns of resistance in paediatric pathogens remains important.9 We report here susceptibilities of strains of S. pneumoniae (including serotype 19A), non-typeable H. influenzae and M. catarrhalis isolated from paediatric patients at two centres in the Midwestern states in the USA during 2005–07, an era well after the universal use of PCV-7.

Materials and methods

Participating sites

We collected paediatric respiratory isolates from January 2005 to August 2007 from the laboratories at two freestanding children’s hospitals in the central area of the USA, one being the Kosair Children’s Hospital in Louisville, Kentucky, and the other being Children’s Mercy Hospital and Clinics in Kansas City, Missouri. This study was approved by the Institutional Review Boards for Human Safety at each institution.

Bacterial isolates and susceptibility testing

All isolates of S. pneumoniae, non-typeable H. influenzae and M. catarrhalis, from children up to 18 years of age, were eligible for inclusion. Duplicate isolates from the same patient were not utilized. After isolation and identification were performed at the local laboratory according to CLSI standard protocols, isolates were stored at −70°C in trypticase soy broth with 15% glycerol and 10% lysed horse blood. Final susceptibility testing was carried out at the Kansas City site for an extended panel of antimicrobials by the standard CLSI broth microdilution method using frozen 96-well antibiotic testing plates. These plates were produced using Mueller–Hinton broth with 5% lysed horse blood (Remel, Lenexa, KS, USA) for S. pneumoniae and Haemophilus test medium (Remel) for non-typeable H. influenzae and M. catarrhalis.

The antimicrobials tested were (ranges in mg/L): amoxicillin at 0.03–16; amoxicillin plus clavulanic acid using a 2:1 ratio at 0.03–16; cefaclor at 0.06–32; cefixime at 0.06–16; ceftriaxone at 0.03–8; cefprozil at 0.06–16; cefdinir at 0.03–16; azithromycin at 0.03–32; clindamycin at 0.03–16; and trimethoprim/sulfamethoxazole using a 1:19 ratio of trimethoprim to sulfamethoxazole at 0.06–16 of trimethoprim. The antibiotics tested against S. pneumoniae were identical to those tested against non-typeable H. influenzae and M. catarrhalis except that clindamycin was used only for S. pneumoniae. Breakpoint concentrations for interpretation of MIC data qualitatively were those published by CLSI as well as calculated PK/PD breakpoints1015 (Tables 1–4). When neither PK/PD nor CLSI breakpoints were available, BSAC breakpoints16 were utilized.

Table 1

MIC50, MIC90 and percentage susceptible by CLSI and/or PK/PD for H. influenzae (n = 143); 60 produced β-lactamase

Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 ≤2 ≥4 0.5 16 55.2 58.0 
Amoxicillin, high dosea ≤4 ≥8 ≤4 ≥8 0.5 16 58.0 58.0 
Amoxicillin/clavulanate, standard dosea ≤0.5/0.25 ≥1.0/0.5 ≤2/1 ≥4/2 0.5 1.0 91.6 100 
Amoxicillin/clavulanate, high dosea ≤4/2 ≥8/4 ≤4/2 ≥8/4 0.5 1.0 100 100 
Azithromycin ≤0.12 ≥0.25 ≤4.0 — 2.0 87.4 
Cefaclor ≤0.5 ≥1.0 ≤8 ≥32 4.0 16 3.5 83.2 
Cefdinir ≤0.25 ≥1.0 ≤1.0 — 0.25 0.5 83.9 100 
Cefiximeb ≤1.0 ≥2.0 — — 0.03 0.06 100 100 
Cefprozil ≤1.0 ≥2.0 ≤8 ≥32 16 28.7 83.2 
Ceftriaxone ≤2.0 ≥4.0 ≤2.0 — 0.03 0.06 100 100 
Cefuroxime axetil ≤1.0 ≥2.0 ≤4 ≥16 0.5 2.0 88.1 99.3 
Trimethoprim/sulfamethoxazolec ≤0.5 ≥1.0 ≤0.5 ≥4.0 0.25 73.4 73.4 
Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 ≤2 ≥4 0.5 16 55.2 58.0 
Amoxicillin, high dosea ≤4 ≥8 ≤4 ≥8 0.5 16 58.0 58.0 
Amoxicillin/clavulanate, standard dosea ≤0.5/0.25 ≥1.0/0.5 ≤2/1 ≥4/2 0.5 1.0 91.6 100 
Amoxicillin/clavulanate, high dosea ≤4/2 ≥8/4 ≤4/2 ≥8/4 0.5 1.0 100 100 
Azithromycin ≤0.12 ≥0.25 ≤4.0 — 2.0 87.4 
Cefaclor ≤0.5 ≥1.0 ≤8 ≥32 4.0 16 3.5 83.2 
Cefdinir ≤0.25 ≥1.0 ≤1.0 — 0.25 0.5 83.9 100 
Cefiximeb ≤1.0 ≥2.0 — — 0.03 0.06 100 100 
Cefprozil ≤1.0 ≥2.0 ≤8 ≥32 16 28.7 83.2 
Ceftriaxone ≤2.0 ≥4.0 ≤2.0 — 0.03 0.06 100 100 
Cefuroxime axetil ≤1.0 ≥2.0 ≤4 ≥16 0.5 2.0 88.1 99.3 
Trimethoprim/sulfamethoxazolec ≤0.5 ≥1.0 ≤0.5 ≥4.0 0.25 73.4 73.4 

aStandard dose = 45 mg/kg/day and high dose = 90 mg/kg/day, each divided twice daily.

bBSAC breakpoint used here because no standard for CLSI or PD established.

cBased on trimethoprim concentration.

Table 2

MIC50, MIC90 and percentage susceptible by CLSI and/or PK/PD for S. pneumoniae (n = 208); penicillin-susceptible (n = 86), penicillin-intermediate (n = 60) and penicillin-resistant (n = 62)

Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 — — 0.06 73.5 — 
Amoxicillin, high dosea ≤2 ≥8 ≤2 ≥8 0.06 89.4 89.4 
Azithromycin ≤0.12 ≥0.25 ≤0.5 ≥2.0 0.3 16 56.7 62.7 
Cefaclor ≤0.5 ≥1.0 ≤1 ≥4 2.0 16 28.8 47.1 
Cefdinir ≤0.25 ≥1.0 ≤0.5 ≥2.0 0.25 16 59.1 59.1 
Cefiximeb ≤1.0 ≥2.0 — — 0.5 16 57.7 — 
Cefprozil ≤1.0 ≥2.0 ≤2 ≥8 0.25 16 67.3 71.2 
Ceftriaxone ≤2.0 ≥4.0 ≤1.0 ≥4.0 ≤0.03 95.2 88.9 
Cefuroxime axetil ≤1.0 ≥2.0 ≤1.0 ≥4.0 0.125 69.2 69.2 
Clindamycin ≤0.25 ≥0.5 ≤0.25 — ≤0.03 16 85.0 85.0 
Penicillin ≤0.06 ≥2.0 ≤0.06 ≥2.0 0.12 41.3 41.3 
Trimethoprim/sulfamethoxazolec ≤0.5 ≥1.0 ≤0.5 ≥4.0 0.5 16 50.5 50.5 
Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 — — 0.06 73.5 — 
Amoxicillin, high dosea ≤2 ≥8 ≤2 ≥8 0.06 89.4 89.4 
Azithromycin ≤0.12 ≥0.25 ≤0.5 ≥2.0 0.3 16 56.7 62.7 
Cefaclor ≤0.5 ≥1.0 ≤1 ≥4 2.0 16 28.8 47.1 
Cefdinir ≤0.25 ≥1.0 ≤0.5 ≥2.0 0.25 16 59.1 59.1 
Cefiximeb ≤1.0 ≥2.0 — — 0.5 16 57.7 — 
Cefprozil ≤1.0 ≥2.0 ≤2 ≥8 0.25 16 67.3 71.2 
Ceftriaxone ≤2.0 ≥4.0 ≤1.0 ≥4.0 ≤0.03 95.2 88.9 
Cefuroxime axetil ≤1.0 ≥2.0 ≤1.0 ≥4.0 0.125 69.2 69.2 
Clindamycin ≤0.25 ≥0.5 ≤0.25 — ≤0.03 16 85.0 85.0 
Penicillin ≤0.06 ≥2.0 ≤0.06 ≥2.0 0.12 41.3 41.3 
Trimethoprim/sulfamethoxazolec ≤0.5 ≥1.0 ≤0.5 ≥4.0 0.5 16 50.5 50.5 

aStandard dose = 45 mg/kg/day and high dose = 90 mg/kg/day, each divided twice daily. There was no difference in MICs whether or not clavulanate was present with amoxicillin.

bBSAC breakpoint used here because no standard for CLSI or PD established.

cBased on trimethoprim concentration.

Table 3

MIC50, MIC90 and percentage susceptible by CLSI and/or PK/PD for S. pneumoniae, serotype 19A (n = 42)

Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 — — 33.3 — 
Amoxicillin, high dosea ≤2 ≥8 ≤2 ≥8 58.3 58.3 
Azithromycin ≤0.12 ≥0.25 ≤0.5 ≥2.0 >16 33.3 33.3 
Cefaclor ≤0.5 ≥1.0 ≤1 ≥4 16 >16 8.3 11.1 
Cefdinir ≤0.25 ≥1.0 ≤0.5 ≥2.0 >16 33.3 33.3 
Cefiximeb ≤1.0 ≥2.0 — — 16 >16 33.3 — 
Cefprozil ≤1.0 ≥2.0 ≤2 ≥8 16 33.3 36.1 
Ceftriaxone ≤2.0 ≥4.0 ≤1.0 ≥4.0 0.5 86.1 66.7 
Cefuroxime axetil ≤1.0 ≥2.0 ≤1.0 ≥4.0 16 36.1 36.1 
Clindamycin ≤0.25 ≥0.5 ≤0.25 — 0.06 >16 58.3 58.3 
Penicillin ≤0.06 ≥2.0 ≤0.06 ≥2.0 19.4 19.4 
Trimethoprim/sulfamethoxazolec ≤0.5 ≥1.0 ≤0.5 ≥4.0 >16 25.0 25.0 
Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 — — 33.3 — 
Amoxicillin, high dosea ≤2 ≥8 ≤2 ≥8 58.3 58.3 
Azithromycin ≤0.12 ≥0.25 ≤0.5 ≥2.0 >16 33.3 33.3 
Cefaclor ≤0.5 ≥1.0 ≤1 ≥4 16 >16 8.3 11.1 
Cefdinir ≤0.25 ≥1.0 ≤0.5 ≥2.0 >16 33.3 33.3 
Cefiximeb ≤1.0 ≥2.0 — — 16 >16 33.3 — 
Cefprozil ≤1.0 ≥2.0 ≤2 ≥8 16 33.3 36.1 
Ceftriaxone ≤2.0 ≥4.0 ≤1.0 ≥4.0 0.5 86.1 66.7 
Cefuroxime axetil ≤1.0 ≥2.0 ≤1.0 ≥4.0 16 36.1 36.1 
Clindamycin ≤0.25 ≥0.5 ≤0.25 — 0.06 >16 58.3 58.3 
Penicillin ≤0.06 ≥2.0 ≤0.06 ≥2.0 19.4 19.4 
Trimethoprim/sulfamethoxazolec ≤0.5 ≥1.0 ≤0.5 ≥4.0 >16 25.0 25.0 

aStandard dose = 45 mg/kg/day and high dose = 90 mg/kg/day, each divided twice daily. There was no difference in MICs whether or not clavulanate was present with amoxicillin.

bBSAC breakpoint used here because no standard for CLSI or PD established.

cBased on trimethoprim concentration.

Table 4

MIC50, MIC90 and percentage susceptible by CLSI and/or PK/PD for M. catarrhalis (n = 62); 59 produced β-lactamase

Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 — — ≥16 4.8 4.8 
Amoxicillin, high dosea ≤2 ≥8 — — ≥16 11.2 4.8 
Amoxicillin/clavulanate, standard dosea ≤0.5/0.25 ≥1.0/0.5 — — 0.25 88.7 — 
Amoxicillin/clavulanate, high dosea ≤2/1 ≥8/4 ≤4/2 ≥8/4 0.25 100 — 
Azithromycin ≤0.12 ≥0.25 ≤2.0 ≥8.0 0.06 0.06 98.4 100 
Cefaclor ≤0.5 ≥1.0 ≤8 ≥32 6.5 95.2 
Cefdinir ≤0.25 ≥1.0 — — 0.25 80.6 — 
Cefiximeb ≤1.0 ≥2.0 — — 0.25 0.25 100 — 
Cefprozil ≤1.0 ≥2.0 — — 37.1 — 
Ceftriaxone ≤2.0 ≥4.0 ≤2.0 — 0.25 96.8 96.8 
Cefuroxime axetil ≤1.0 ≥2.0 ≤4.0 ≥16.0 37.1 98.4 
Drugs PD susceptible breakpoint PD resistant breakpoint CLSI susceptible breakpoint CLSI resistant breakpoint MIC50 MIC90 PK/PD percentage susceptible CLSI percentage susceptible 
Amoxicillin, standard dosea ≤0.5 ≥1.0 — — ≥16 4.8 4.8 
Amoxicillin, high dosea ≤2 ≥8 — — ≥16 11.2 4.8 
Amoxicillin/clavulanate, standard dosea ≤0.5/0.25 ≥1.0/0.5 — — 0.25 88.7 — 
Amoxicillin/clavulanate, high dosea ≤2/1 ≥8/4 ≤4/2 ≥8/4 0.25 100 — 
Azithromycin ≤0.12 ≥0.25 ≤2.0 ≥8.0 0.06 0.06 98.4 100 
Cefaclor ≤0.5 ≥1.0 ≤8 ≥32 6.5 95.2 
Cefdinir ≤0.25 ≥1.0 — — 0.25 80.6 — 
Cefiximeb ≤1.0 ≥2.0 — — 0.25 0.25 100 — 
Cefprozil ≤1.0 ≥2.0 — — 37.1 — 
Ceftriaxone ≤2.0 ≥4.0 ≤2.0 — 0.25 96.8 96.8 
Cefuroxime axetil ≤1.0 ≥2.0 ≤4.0 ≥16.0 37.1 98.4 

aStandard dose = 45 mg/kg/day and high dose = 90 mg/kg/day, each divided twice daily. Production of β-lactamase by M. catarrhalis is considered by CLSI to predict amoxicillin resistance.

bBSAC breakpoint used here because no standard for CLSI is established.

Quality control

Control strains used with daily testing for each pathogen were those recommended by the CLSI (non-typeable H. influenzae ATCC 49247 and ATCC 49766, and S. pneumoniae ATCC 49619) and the results were acceptable if the control strains exhibited values within published limits. Further, 20 previously tested isolates of S. pneumoniae and non-typeable H. influenzae and 15 isolates of M. catarrhalis were tested for consistency before the first experimental and after the last experimental isolates were tested. Growth properties of liquid media used to reconstitute plates [Mueller–Hinton broth with 5% lysed horse blood (Remel) for S. pneumoniae and Haemophilus test medium (Remel)] were monitored and used only if performance was satisfactory. Selected isolates were also confirmed with Etests (AB Biodisk, Solna, Sweden).

Results

Summary of isolates

From January 2005 to August 2007, we tested 143 non-typeable H. influenzae (Table 1), 208 S. pneumoniae (42 were type 19A) (Tables 2 and 3) and 62 M. catarrhalis (Table 4). The percentages of isolates exhibiting various MIC values are listed in Tables 5–9. MIC distributions tended toward higher values in β-lactamase-producing versus β-lactamase-non-producing non-typeable H. influenzae (Table 6 versus Table 5) and the 19A subset of S. pneumoniae compared with all S. pneumoniae (Table 8 versus Table 7).

Table 5

Percentage of β-lactamase-non-producing non-typeable H. influenzae (n = 83) exhibiting differing MIC values

 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥8 
Ceftriaxone 78.3 20.5 1.2 — — — — — — 
Cefixime 65.1 27.7 7.2 — — — — — — 
Cefdinir — 8.4 41.0 41.0 9.6 — — — — 
Amoxicillin/clavulanate — — 3.6 38.6 54.2 2.4 1.2 — — 
Amoxicillin — — 3.6 38.6 54.2 2.4 1.2 — — 
Cefprozil — — — 1.2 10.8 30.1 34.9 16.9 6.0 
Cefaclor — — 1.2 — 4.8 21.7 25.3 30.1 16.9 
Cefuroxime — — 14.3 26.5 34.9 19.3 2.4 1.2 1.2 
Azithromycin — — — 4.8 4.8 10.8 30.1 34.9 14.5 
Trimethoprim/sulfamethoxazolea — — 4.8 77.1 1.2 — 4.8 7.2 4.8 
 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥8 
Ceftriaxone 78.3 20.5 1.2 — — — — — — 
Cefixime 65.1 27.7 7.2 — — — — — — 
Cefdinir — 8.4 41.0 41.0 9.6 — — — — 
Amoxicillin/clavulanate — — 3.6 38.6 54.2 2.4 1.2 — — 
Amoxicillin — — 3.6 38.6 54.2 2.4 1.2 — — 
Cefprozil — — — 1.2 10.8 30.1 34.9 16.9 6.0 
Cefaclor — — 1.2 — 4.8 21.7 25.3 30.1 16.9 
Cefuroxime — — 14.3 26.5 34.9 19.3 2.4 1.2 1.2 
Azithromycin — — — 4.8 4.8 10.8 30.1 34.9 14.5 
Trimethoprim/sulfamethoxazolea — — 4.8 77.1 1.2 — 4.8 7.2 4.8 

Percentages are rounded off and that is why the rows do not always total 100%.

aBased on trimethoprim component.

Table 6

Percentage of β-lactamase-producing non-typeable H. influenzae (n = 60) exhibiting differing MIC values

 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥8 
Ceftriaxone 91.7 6.7 1.7 — — — — — — 
Cefixime 76.7 10.0 13.3 — — — — — — 
Cefdinir — 3.3 20.0 51.7 23.3 1.7 — — — 
Amoxicillin/clavulanate — — 1.7 25.0 58.3 10.0 5.0 — — 
Cefuroxime — — 1.7 23.3 28.3 25.0 16.7 5.0 — 
Trimethoprim/sulfamethoxazolea — — — 58.3 1.7 1.7 — 16.7 21.7 
Azithromycin — — — — 1.7 40.0 20.0 28.3 10.0 
Cefprozil — — — — — 10.0 20.0 15.0 55.0 
Cefaclor — — — — — 13.3 18.3 5.0 63.3 
Amoxicillin — — — — — — — — 100.0 
 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥8 
Ceftriaxone 91.7 6.7 1.7 — — — — — — 
Cefixime 76.7 10.0 13.3 — — — — — — 
Cefdinir — 3.3 20.0 51.7 23.3 1.7 — — — 
Amoxicillin/clavulanate — — 1.7 25.0 58.3 10.0 5.0 — — 
Cefuroxime — — 1.7 23.3 28.3 25.0 16.7 5.0 — 
Trimethoprim/sulfamethoxazolea — — — 58.3 1.7 1.7 — 16.7 21.7 
Azithromycin — — — — 1.7 40.0 20.0 28.3 10.0 
Cefprozil — — — — — 10.0 20.0 15.0 55.0 
Cefaclor — — — — — 13.3 18.3 5.0 63.3 
Amoxicillin — — — — — — — — 100.0 

Percentages are rounded off and that is why the rows do not always total 100%.

aBased on trimethoprim component.

Table 7

Percentage of all serotypes of Streptococcus pneumoniae (n = 208) exhibiting differing MIC values

 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥16 
Penicillin 40.4 7.2 5.3 7.7 7.2 4.8 12.0 10.6 4.3 0.5 
Amoxicillin 39.4 11.1 3.8 5.3 13.9 5.8 5.3 4.8 8.2 2.3 
Ceftriaxone 56.7 4.8 1.4 8.2 7.2 10.6 6.3 3.8 1.0 — 
Clindamycin 62.9 7.7 12.5 1.9 — — 3.9 — — 11.0 
Cefuroxime 42.3 5.8 3.8 4.8 8.2 4.3 4.8 9.1 11.5 5.3 
Azithromycin 53.8 0.5 2.4 0.5 1.0 1.9 5.8 7.7 8.2 18.2 
Cefprozil 9.6 11.1 26.4 7.7 6.7 5.8 3.8 6.7 10.1 12.0 
Cefdinir 6.7 8.7 18.3 17.3 8.2 4.8 3.8 3.8 10.6 17.9 
Cefixime — 0.5 9.6 16.8 25.5 5.3 5.8 3.4 5.8 27.4 
Cefaclor — — — — 28.8 18.3 5.3 6.3 5.3 36.1 
Trimethoprim/sulfamethoxazolea — — 18.3 27.9 4.3 4.8 5.3 8.2 14.4 16.8 
 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥16 
Penicillin 40.4 7.2 5.3 7.7 7.2 4.8 12.0 10.6 4.3 0.5 
Amoxicillin 39.4 11.1 3.8 5.3 13.9 5.8 5.3 4.8 8.2 2.3 
Ceftriaxone 56.7 4.8 1.4 8.2 7.2 10.6 6.3 3.8 1.0 — 
Clindamycin 62.9 7.7 12.5 1.9 — — 3.9 — — 11.0 
Cefuroxime 42.3 5.8 3.8 4.8 8.2 4.3 4.8 9.1 11.5 5.3 
Azithromycin 53.8 0.5 2.4 0.5 1.0 1.9 5.8 7.7 8.2 18.2 
Cefprozil 9.6 11.1 26.4 7.7 6.7 5.8 3.8 6.7 10.1 12.0 
Cefdinir 6.7 8.7 18.3 17.3 8.2 4.8 3.8 3.8 10.6 17.9 
Cefixime — 0.5 9.6 16.8 25.5 5.3 5.8 3.4 5.8 27.4 
Cefaclor — — — — 28.8 18.3 5.3 6.3 5.3 36.1 
Trimethoprim/sulfamethoxazolea — — 18.3 27.9 4.3 4.8 5.3 8.2 14.4 16.8 

Percentages are rounded off and that is why the rows do not always total 100%.

aBased on trimethoprim component.

Table 8

Percentage of 19A serotype Streptococcus pneumoniae (n = 42) exhibiting differing MIC values

 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥16 
Penicillin 2.8 16.7 5.6 8.3 2.8 2.8 16.7 30.6 11.1 2.8 
Amoxicillin 13.9 5.6 5.6 8.3 — 5.6 2.8 16.7 36.1 5.6 
Cefaclor — — — — 8.3 11.1 2.8 11.1 — 66.7 
Cefixime — — 2.8 5.6 11.1 13.9 — — 8.3 58.3 
Cefdinir — 2.8 11.1 5.6 13.9 — — 2.8 16.7 47.2 
Cefprozil — 2.8 16.7 2.8 11.1 — 2.8 8.3 16.7 38.9 
Cefuroxime 19.4 — 2.8 11.1 — 2.8 — 11.1 33.3 19.5 
Ceftriaxone 33.3 — — 2.8 11.1 19.4 19.4 11.1 2.8 — 
Azithromycin 33.3 — — — — — 5.6 5.6 11.1 44.4 
Clindamycin 47.2 5.6 2.8 2.8 — — 11.1 — — 20.5 
Trimethoprim/sulfamethoxazolea — — 5.6 16.7 2.8 — 2.8 8.3 13.9 50 
 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥16 
Penicillin 2.8 16.7 5.6 8.3 2.8 2.8 16.7 30.6 11.1 2.8 
Amoxicillin 13.9 5.6 5.6 8.3 — 5.6 2.8 16.7 36.1 5.6 
Cefaclor — — — — 8.3 11.1 2.8 11.1 — 66.7 
Cefixime — — 2.8 5.6 11.1 13.9 — — 8.3 58.3 
Cefdinir — 2.8 11.1 5.6 13.9 — — 2.8 16.7 47.2 
Cefprozil — 2.8 16.7 2.8 11.1 — 2.8 8.3 16.7 38.9 
Cefuroxime 19.4 — 2.8 11.1 — 2.8 — 11.1 33.3 19.5 
Ceftriaxone 33.3 — — 2.8 11.1 19.4 19.4 11.1 2.8 — 
Azithromycin 33.3 — — — — — 5.6 5.6 11.1 44.4 
Clindamycin 47.2 5.6 2.8 2.8 — — 11.1 — — 20.5 
Trimethoprim/sulfamethoxazolea — — 5.6 16.7 2.8 — 2.8 8.3 13.9 50 

Percentages are rounded off and that is why the rows do not always total 100%.

aBased on trimethoprim component.

Table 9

Percentage of M. catarrhalis (n = 62) exhibiting differing MIC values

 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥16 
Azithromycin 1.6 88.7 8.1 1.6 — — — — — — 
Cefixime — 19.4 29 43.5 8.1 — — — — — 
Amoxicillin/clavulanate — 19.4 27.4 22.6 19.4 6.5 4.8 — — — 
Ceftriaxone — 1.6 22.6 25.8 27.4 4.8 14.5 3.2 — — 
Cefdinir — 3.2 19.4 29 29 9.7 8.1 1.6 — — 
Cefuroxime — — — 1.6 17.7 17.7 54.8 6.5 1.6 — 
Cefprozil — — — 1.6 16.1 19.4 38.7 16.1 8.1 — 
Cefaclor — — — — 6.5 22.6 35.5 25.8 4.8 4.8 
Amoxicillin — — — 1.6 3.2 3.2 3.2 9.7 37.1 41.9 
 MIC (mg/L)
 
 ≤0.03 0.06 0.12 0.25 0.5 ≥16 
Azithromycin 1.6 88.7 8.1 1.6 — — — — — — 
Cefixime — 19.4 29 43.5 8.1 — — — — — 
Amoxicillin/clavulanate — 19.4 27.4 22.6 19.4 6.5 4.8 — — — 
Ceftriaxone — 1.6 22.6 25.8 27.4 4.8 14.5 3.2 — — 
Cefdinir — 3.2 19.4 29 29 9.7 8.1 1.6 — — 
Cefuroxime — — — 1.6 17.7 17.7 54.8 6.5 1.6 — 
Cefprozil — — — 1.6 16.1 19.4 38.7 16.1 8.1 — 
Cefaclor — — — — 6.5 22.6 35.5 25.8 4.8 4.8 
Amoxicillin — — — 1.6 3.2 3.2 3.2 9.7 37.1 41.9 

Percentages are rounded off and that is why the rows do not always total 100%.

Non-typeable H. influenzae (Tables 1, 5 and 6)

Among non-typeable H. influenzae, 42% (n = 60) produced β-lactamase. No β-lactamase-negative ampicillin-resistant strains were isolated. In some analyses, non-typeable H. influenzae are divided for ease of discussion into two groups: β-lactamase producers and non-producers.

The third-generation cephalosporins exhibited the highest activity against non-typeable H. influenzae whether analysing β-lactamase producers or non-producers. Thus, ceftriaxone and cefixime had the lowest MIC50 and MIC90 (Table 1) values as well as the highest proportion of non-typeable H. influenzae isolates that were susceptible by either PK/PD or CLSI breakpoints (Table 1). Cefdinir, another third-generation cephalosporin, exhibited an MIC50 at the PK/PD resistance breakpoint. In contrast, both cefixime and ceftriaxone exhibited MIC90 values that were more than four dilutions below the PK/PD resistance breakpoint.

Using the PK/PD breakpoints (Table 1) and proportions of non-typeable H. influenzae exhibiting the various MIC values (Tables 5 and 6), rates of susceptibility to the second-generation cephalosporins among non-typeable H. influenzae, both β-lactamase producers and non-producers, were variable. Susceptibility was low for two drugs; 0% and 6% for cefaclor and 10% and 42% for cefprozil, respectively. This contrasts with rates for cefuroxime of 78.3% and 95%, respectively.

Based on both CLSI breakpoints and PK/PD breakpoints, β-lactamase-non-producing non-typeable H. influenzae were all susceptible to high-dose amoxicillin with or without clavulanate, while 96% were susceptible to standard-dose amoxicillin. Addition of the β-lactamase inhibitor, clavulanate, protected amoxicillin so that all non-typeable H. influenzae were susceptible to high-dose amoxicillin/clavulanate (including all β-lactamase producers) while only 85% were susceptible to standard-dose amoxicillin/clavulanate.

No non-typeable H. influenzae were susceptible to azithromycin using the PK/PD breakpoint of 0.12 mg/L, while 85.5% of β-lactamase non-producers and 90% of producers would be considered susceptible at the CLSI breakpoint of 4.0 mg/L.

There was a sizeable difference in rates of susceptibility to trimethoprim/sulfamethoxazole; susceptibility of 60% in β-lactamase producers compared with 83.1% in β-lactamase non-producers.

The most prominent differences seen in the proportion considered susceptible using PK/PD breakpoints as opposed to CLSI breakpoints were azithromycin (0% versus 87.4%), cefaclor (3.5% versus 83.2%) and cefprozil (28.7% versus 83.2%). There was less difference between susceptibility using PK/PD versus CLSI breakpoints for cefuroxime (88.1% versus 99.3%), cefdinir (83.9% versus 100%) and amoxicillin/clavulanate standard dose (91.6% versus 100%) (Table 1). For other drugs, use of either breakpoint provided similar rates of susceptibility.

By PK/PD breakpoints, the rank of drug activity against non-typeable H. influenzae was highest for ceftriaxone and lowest for azithromycin (Table 10).

Table 10

Rank order of tested drugs against S. pneumoniae (n = 208), non-typeable H. influenzae (n = 143) or M. catarrhalis (n = 62), isolated between 2005 and 2007 from two paediatric medical centres in the Midwestern area of the USA

Non-typeable H. influenzae S. pneumoniae M. catarrhalis 
Ceftriaxone ceftriaxone HD amoxicillin/clavulanate 
Cefixime HD amoxicillin ± clavulanate cefixime 
HD amoxicillin/clavulanate clindamycin azithromycin 
SD amoxicillin/clavulanate SD amoxicillin ± clavulanate ceftriaxone 
Cefuroxime axetil cefuroxime axetil SD amoxicillin/clavulanate 
Cefdinir cefprozil cefdinir 
Trimethoprim/sulfamethoxazole cefdinir cefprozil 
HD amoxicillin cefixime cefuroxime axetil 
SD amoxicillin azithromycin HD amoxicillin 
Cefprozil trimethoprim/sulfamethoxazole cefaclor 
Cefaclor penicillin SD amoxicillin 
Azithromycin cefaclor  
Non-typeable H. influenzae S. pneumoniae M. catarrhalis 
Ceftriaxone ceftriaxone HD amoxicillin/clavulanate 
Cefixime HD amoxicillin ± clavulanate cefixime 
HD amoxicillin/clavulanate clindamycin azithromycin 
SD amoxicillin/clavulanate SD amoxicillin ± clavulanate ceftriaxone 
Cefuroxime axetil cefuroxime axetil SD amoxicillin/clavulanate 
Cefdinir cefprozil cefdinir 
Trimethoprim/sulfamethoxazole cefdinir cefprozil 
HD amoxicillin cefixime cefuroxime axetil 
SD amoxicillin azithromycin HD amoxicillin 
Cefprozil trimethoprim/sulfamethoxazole cefaclor 
Cefaclor penicillin SD amoxicillin 
Azithromycin cefaclor  

HD, high dose; SD, standard dose.

S. pneumoniae (Tables 2, 3, 7 and 8)

Of the 208 pneumococcal isolates, 86 were penicillin-susceptible (41.3%), 60 were intermediately susceptible to penicillin (28.8%) and 62 were highly penicillin-resistant (29.8%) by 2007 CLSI breakpoints.

When evaluating all pneumococcal isolates by PK/PD breakpoints, ceftriaxone (95.2% susceptible), amoxicillin (89.4% susceptible to high dose and 73.5% susceptible to standard dose) and clindamycin (85% susceptible) were the most active drugs (Table 2). All but one oral cephalosporin had moderate activity (59.1% to 69.2% susceptible). Only 28.8% of isolates were susceptible to cefaclor. Azithromycin had similar overall anti-pneumococcal activity to the oral cephalosporins with 56.7% being susceptible by PK/PD breakpoint. Trimethoprim/sulfamethoxazole was active against half (50.5%) of all pneumococcal isolates (Table 7).

Serotype 19A comprised 42 (20.2%) of the 208 isolates. Of these 19A isolates, 19.4% were penicillin-susceptible, 19.4% were penicillin-intermediate strains and 61.2% were penicillin-resistant strains by 2007 CLSI breakpoints. Using PK/PD breakpoints, only one-third (33.3–36.1%) of serotype 19A isolates was susceptible to the oral cephalosporins, with the exception of cefaclor (8.3% susceptible) (Table 3). Similarly, 33% were susceptible to azithromycin and 25% were susceptible to trimethoprim/sulfamethoxazole by PK/PD breakpoints (Table 3). Of the 19A isolates, 67% were multidrug-resistant (resistant to more than two classes) by PD breakpoints. Most of the multidrug-resistant strains were highly resistant to all tested drugs except for ceftriaxone (86.1% susceptible) and clindamycin or high-dose amoxicillin (58.3% susceptible to each).

Comparing susceptibility rates of all S. pneumoniae serotypes using PK/PD breakpoints versus CLSI breakpoints (Table 2), divergence was notable for azithromycin (56.7% versus 62.7%), cefaclor (28.8% versus 47.1%) and ceftriaxone (95.2% versus 88.9%). Divergence of susceptibility rates comparing PK/PD with CLSI breakpoints for 19A serotypes (Table 3) was notable only for a higher rate of susceptibility to ceftriaxone by PK/PD (86.1% versus 66.7%).

Drug activity against all S. pneumoniae serotypes using PK/PD breakpoints was highest for ceftriaxone and lowest for cefaclor (Table 10). For 19A serotype isolates, it was ceftriaxone > clindamycin = high-dose amoxicillin > cefuroxime axetil > standard-dose amoxicillin = azithromycin = cefdinir = cefixime = cefprozil > trimethoprim/sulfamethoxazole > penicillin > cefaclor.

M. catarrhalis (Tables 4 and 9)

All but three of the 62 M. catarrhalis isolates produced β-lactamase. Because there is no CLSI breakpoint for cefixime versus M. catarrhalis, the BSAC breakpoint was considered as an alternative (Table 4). Cefixime, high-dose amoxicillin plus clavulanate and azithromycin exhibited the overall highest activity, having the lowest MIC ranges against M. catarrhalis and MIC90 lower than the PK/PD breakpoints. Cefprozil, cefuroxime, cefaclor, cefdinir and amoxicillin exhibited the least activity with the highest MIC ranges and MIC90 values greater than the PK/PD breakpoints. The MIC range for ceftriaxone fell between the other two groups and its MIC90 was at the PK/PD breakpoint.

Based on PK/PD breakpoints, the lowest susceptibility rates were seen for cefaclor and amoxicillin (<15%). Low susceptibility rates (37%) were seen for both cefprozil and cefuroxime. Cefdinir and standard-dose amoxicillin plus clavulanate had reasonable activity with 80.6% and 88.7% of isolates being susceptible. Cefixime and high-dose amoxicillin plus clavulanate were the most active with 100% of the isolates being susceptible. Ceftriaxone and azithromycin were close with 97% to 98% of organisms being susceptible (Table 4).

The largest divergence in susceptibility rates of M. catarrhalis isolates when comparing PK/PD with CLSI breakpoints occurred with the oral cephalosporins, cefaclor (6.5% versus 95.2%) and cefuroxime (37.1% versus 98.4%) (Table 4).

Drug activity against M. catarrhalis was highest for high-dose amoxicillin/clavulanate and lowest for standard-dose amoxicillin (Table 10).

Discussion

The emergence of antimicrobial resistance because of medical interventions that affect respiratory flora, whether in the form of new vaccines or antibiotic use, continues to affect clinical decisions on antibiotic choices for paediatric respiratory infections such as AOM or acute bacterial rhinosinusitis (ABRS). When the decision is made to use antibiotics for these illnesses, three respiratory pathogens, i.e. S. pneumoniae, non-typeable H. influenzae and M. catarrhalis, are the most common targets.

Introduction of the universal use of heptavalent conjugate pneumococcal vaccine in infants starting in 2000 was projected to, and at first seemed to, be associated with a decrease in antibiotic resistance in pneumococci because most of the resistance strains prior to 2000 were among the seven serotypes in the conjugate vaccine.17,18

Additional reduction in resistance among other respiratory pathogens was considered possible given the recent decrease in antibiotic utilization in the USA for paediatric patients.19,20 Further, another positive factor was the putative effect of guidelines for treatment of AOM, issued by the AAP in 2004, which offered observation (withholding antibiotics) as a reasonable option in selected AOM patients. Taken together, these factors were expected to reduce the need for broad-spectrum drugs for paediatric respiratory bacterial infections.

However, recent studies have shown that H. influenzae producing β-lactamase were more frequent in recurrent AOM than in the previous era.6,7 In addition, national surveillance has indicated that serotype 19A pneumococci are increasing in frequency probably due to serotype substitution as an effect of PCV7. Moreover, a sizeable proportion of 19A strains are multidrug-resistant with high levels of resistance to many oral drugs commonly used in paediatrics.21–25

Susceptibility results for pathogens isolated from 2005 to 2007 in two Midwestern sites in the USA, which we tested, indicate that there are still options with which to treat β-lactamase-producing H. influenzae. Third-generation cephalosporins (ceftriaxone and cefixime) and high-dose amoxicillin plus clavulanic acid were the most active. Cefuroxime axetil and cefdinir were the next most active.

In contrast, PCV7 cross-reactive serotypes within group 19 exhibited higher rates of resistance and at higher levels compared with non-19A pneumococci, a phenomenon not unlike that reported in the years up to 2005 when our study began.5,24,25 Parenteral ceftriaxone was the only drug tested with more than 80% activity against 19A strains. It was interesting to note that high-level resistance to multiple drug classes appeared to be more frequent among 19A isolates within the last 12 months of the study period.

Antibiotic resistance noted in M. catarrhalis from our two sites during the study did not appear to be notably different from those reported during the previous 10 years in larger national surveillance projects.26,27

Because the proportions of susceptible organisms vary dramatically for at least some drugs based on which breakpoints are used as thresholds, it is important to note that we focused on PK/PD breakpoints whenever possible. Because our pneumococcal isolates were obtained prior to changes in the CLSI breakpoints for penicillin in 2008, we used the 2007 breakpoints. This seemed reasonable also because the change in breakpoints was based on adult data involving pneumococcal pneumonia. It is unclear whether these breakpoints are applicable to paediatric infection sites such as AOM.

Major differences in proportions of susceptible organisms were noted between PK/PD breakpoints and CLSI breakpoints mostly for azithromycin and cefaclor. There remains controversy over the appropriate PK/PD breakpoints for cefixime. The putative breakpoint based on early PK data from the mid-1990s was 0.5 mg/L. Later, other standards were suggested and 1.0 mg/L seemed acceptable, particularly in the BSAC guideline. This report uses the 1.0 mg/L breakpoint.

The most active drugs across the board against all isolates in this study were ceftriaxone and high-dose amoxicillin plus clavulanic acid. Against Gram-negative organisms, cefixime was highly active, and high-dose amoxicillin plus clavulanic acid was quite similar to ceftriaxone. Cefaclor, cefprozil and azithromycin as well as trimethoprim/sulfamethoxazole were the drugs with the least overall activity, particularly when cefaclor and cefprozil were tested against β-lactamase-producing organisms, and azithromycin when considered for any H. influenzae.

The recent reduction in isolates among the seven serotypes found in PCV7 has had an unplanned effect: serotype substitution with 19A. The high-level multidrug resistance among more than half the 19A in our study should further raise questions in clinicians’ minds concerning the optimum choice of therapy when the decision has been made to use antibiotics to treat recurrent/persistent AOM or ABRS. This is due to the fact that we expect 19A strains of pneumococci and β-lactamase-producing non-typeable H. influenzae to be enriched among children with recurrent AOM and ABRS.

A weakness in our study is the fact that cultures are usually obtained in paediatrics in the setting of serious or recurrent/persistent infections. Therefore, our and other surveillance data are likely to be skewed toward isolates obtained from patients with recent antibiotic use or other risk factors for antibiotic resistance.6,7 Therefore, these data should be considered in that context and may not apply to patients who have infrequent antibiotic exposure or infrequent AOM. It is therefore unclear whether children with intermittent or infrequent AOM or ABRS have similar proportions of resistant organisms in the form of β-lactamase-producing non-typeable H. influenzae or multidrug-resistant pneumococci because there is a paucity of data on isolates from such patients in the PCV7 era. For these patients, high-dose amoxicillin likely remains the drug of choice.

However, our findings should raise concern among clinicians treating more serious paediatric respiratory infections such as acute mastoiditis, pneumonia or empyema. If 19A pneumococci continue to make up as much as 20% of pneumococcal isolates, and they continue to exhibit nearly 15% rates of ceftriaxone MICs >4 mg/L and nearly 33% rates of clindamycin MICs >0.5 mg/L, empirical clindamycin plus ceftriaxone may soon become unacceptable as empirical therapy. Fluoroquinolones and linezolid were the only oral drugs to provide high rates of susceptibility for 19A isolates in prior studies. These are not routinely used or recommended for common paediatric respiratory infections. However, a fluoroquinolone, or linezolid or vancomycin plus a third-generation cephalosporin may be a better choice in more serious presentations.

Finally, our data should be added to other data as an impetus to accelerate the approval and release of the extended PCV that contains 19A as one of the serotypes. Until such approval, it may be reasonable to consider temporary off-label use of the non-conjugate 23-valent polysaccharide vaccine (containing 19A) in children ≥2 years of age with history of or risks for recurrent respiratory tract/invasive infections due to S. pneumoniae, despite the lower affinity and shorter duration of antibody response that it induces.

Funding

Funded in part by a grant from Lupin Pharmaceuticals Inc. and Harrison Summer Scholar Funds.

Transparency declarations

C. J. H. receives grant support from Cubist Pharmaceuticals, Lupin Pharmaceuticals Inc. and Johnson & Johnson Pharmaceuticals. The other authors do not have any commercial or other associations that might pose a conflict of interest (pharmaceutical stock ownership, consultancy).

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