Large Dosage Amoxicillin/Clavulanate, Compared With Azithromycin, for the Treatment of Bacterial Acute Otitis Media in Children

 
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    Large Dosage Amoxicillin/Clavulanate, Compared With
    Azithromycin, for the Treatment of Bacterial Acute Otitis
                       Media in Children
    Alejandro Hoberman, MD,* Ron Dagan, MD,† Eugene Leibovitz, MD,† Andres Rosenblut, MD,‡
     Candice E. Johnson, MD,§ Anne Huff, PhD,储 Rajesh Bandekar, PhD,储 and Brian Wynne, MD储

                                                                            Conclusion: Amoxicillin/clavulanate was clinically and bacterio-
Background: A large dosage pediatric formulation of amoxicillin/
                                                                            logically more effective than azithromycin among children with
clavulanate with an improved pharmacokinetic/pharmacodynamic
                                                                            bacterial AOM, including cases caused by penicillin-resistant S.
profile was developed to eradicate many penicillin-resistant strains        pneumoniae and ␤-lactamase-positive H. influenzae.
of Streptococcus pneumoniae and Haemophilus influenzae (includ-
ing ␤-lactamase-producing strains).                                         Key Words: extra-strength amoxicillin/clavulanate, azithromycin,
Methods: This randomized, investigator-blinded, multicenter trial           bacterial acute otitis media, clinical trial
examined treatment of bacterial acute otitis media (AOM) in chil-           (Pediatr Infect Dis J 2005;24: 525–532)
dren 6 –30 months of age with amoxicillin/clavulanate (90/6.4 mg/
kg/d in 2 divided doses for 10 days) versus azithromycin (10 mg/kg
for 1 day followed by 5 mg/kg/d for 4 days). Tympanocentesis was
performed at entry for bacteriologic assessment, at the on-therapy
visit (day 4 – 6) to determine bacterial eradication and at any time
before the end-of-therapy visit (day 12–14) if the child was catego-
                                                                            I n recent years, an important factor affecting the manage-
                                                                              ment of acute otitis media (AOM) has been the increasing
                                                                            development of antimicrobial resistance among the common
rized as experiencing clinical failure. Clinical assessments were           pathogens that cause AOM, particularly the worldwide prev-
performed at the on-therapy, end-of-therapy and follow-up (day              alence of drug-resistant Streptococcus pneumoniae. In 1985,
21–25) visits.                                                              ⬃90% of S. pneumoniae strains isolated from patients with
Results: We enrolled 730 children; AOM pathogens were isolated at           AOM were susceptible to penicillin (minimal inhibitory con-
baseline for 249 of the amoxicillin/clavulanate group and 245 of the        centration 关MIC兴 of ⱕ0.06 ␮g/mL); by 1997, the suscepti-
azithromycin group. For children with AOM pathogens at baseline,            bility of S. pneumoniae to penicillin had decreased to 43%.1
clinical success rates at the end-of-therapy visit were 90.5% for           Of greater concern has been the appearance of S. pneumoniae
amoxicillin/clavulanate versus 80.9% for azithromycin (P ⬍ 0.01),           isolates with resistance to multiple classes of antimicrobial
and those at the on-therapy and follow-up visits were 94.9% versus          agents, including macrolides. Among isolates of Haemophi-
88.0% and 80.3% versus 71.1%, respectively (all P ⬍ 0.05). At the           lus influenzae and Moraxella catarrhalis, ␤-lactamase pro-
on-therapy visit, pretherapy pathogens were eradicated for 94.2% of         duction rates have increased from 16% and 88% of strains
children receiving amoxicillin/clavulanate versus 70.3% of those            collected before 1985 to 44% and 96% of those collected in
receiving azithromycin (P ⬍ 0.001). Amoxicillin/clavulanate erad-           1997, respectively.1
icated 96.0% of S. pneumoniae (92.0% of fully penicillin-resistant                 A large dosage amoxicillin/clavulanate formulation
S. pneumoniae) and 89.7% of H. influenzae (85.7% 关6 of 7 cases兴 of          (90/6.4 mg/kg/d; Augmentin ES-600; GlaxoSmithKline,
␤-lactamase-positive H. influenzae). Corresponding rates for                Durham, NC) was approved in the United States for the
azithromycin were 80.4% (54.5%) for S. pneumoniae and 49.1%                 treatment of children with recurrent and persistent cases of
(100% 关1 of 1 case兴) for H. influenzae (all P ⬍ 0.01 for between-           AOM, particularly those for whom S. pneumoniae with penicil-
drug comparisons).                                                          lin MICs of ⱕ2 ␮g/mL or ␤-lactamase-positive H. influenzae or
                                                                            M. catarrhalis are suspected.2–5 Because this formulation and
                                                                            azithromycin are frequently prescribed for the treatment of
                                                                            children with this condition, we evaluated their bacteriologic and
Accepted for publication January 12, 2005.
From the *Children’s Hospital of Pittsburgh, Pittsburgh, PA; †Soroka Uni-
                                                                            clinical efficacy in a randomized clinical trial designed to dem-
   versity Medical Center and Ben Gurion University, Beer Sheva, Israel;    onstrate statistically significant differences in efficacy between
   ‡Hospital Santiago del Rio, Santiago, Chile; §Children’s Hospital and    treatment groups in children 6 –30 months of age.
   University of Colorado School of Medicine, Denver, CO; and 㛳Glaxo-
   SmithKline, Collegeville, PA.
Supported by GlaxoSmithKline.                                                                        METHODS
Address for reprints: Alejandro Hoberman, MD, Children’s Hospital of        Design. This randomized, investigator-blind, multicenter study
   Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213-2583. Fax 412-
   692-5807; E-mail hoberman@chp.edu.                                       was conducted in 34 centers in Bulgaria, Chile, the Dominican
Copyright © 2005 by Lippincott Williams & Wilkins                           Republic, Guatemala, Israel, Peru (1 center each), Romania (2
ISSN: 0891-3668/05/2406-0525                                                centers), Latvia (3 centers), Mexico (4 centers) and the United
DOI: 10.1097/01.inf.0000164794.50281.1a                                     States (19 centers) from April 2001 to November 2002. The

The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005                                                                525
Hoberman et al                                         The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005

protocol was approved by national or local ethics committees or     infection and symptoms of inflammation after ⱖ72 hours of
the institutional review board for each center. Informed consent    therapy, such that additional antibiotic therapy was pre-
was obtained from parents before study entry.                       scribed for AOM, or if a valid assessment of the clinical
Subjects. Children 6 –30 months of age were eligible for            outcome could not be made. This group included children
inclusion in the study if they had AOM, based on the                who did not return for assessment at this visit. Similar criteria
presence of purulent otorrhea for ⬍24 hours or middle ear           were used for the on-therapy visit. At the follow-up visit,
effusion evidenced by at least 2 of the following tympanic          children were classified as experiencing clinical success if
membrane findings: (1) yellow or white discoloration, (2)           they demonstrated a persistent clinical cure and as experienc-
opacification or (3) decreased or absent mobility measured          ing clinical failure if they had a recurrence of AOM that
with pneumatic otoscopy. Evidence of middle ear effusion            required additional antibiotic therapy. This category of clin-
needed to be accompanied by ⱖ1 of the following signs of            ical failure also included children categorized as experiencing
inflammation: (1) ear pain (including unaccustomed tugging          clinical failure at the on-therapy or end-of-therapy visits and
of the ear), (2) marked erythema or (3) distinct fullness or        those who did not return for the assessment.
bulging of the tympanic membrane.5                                         Bacteriologic response at the on-therapy and end-of-
       Children were excluded from the study for the follow-        therapy visits was defined as success if there was eradication
ing reasons: weight of ⬎40 kg, otorrhea for ⬎24 hours,              of the initial AOM pathogen (with or without the presence of
presence of tympanostomy tubes or anatomic abnormalities            a new pathogen), as demonstrated with repeat tympanocen-
associated with prolonged middle ear effusion, serious un-          tesis, or a lack of middle ear fluid, as determined through
derlying disease, hypersensitivity to study medications or          either observation or tympanocentesis. Children were classi-
concomitant use of medications known to interact with the           fied as experiencing bacteriologic failure if the initial patho-
study drugs. We also excluded children who had received             gen persisted in the middle ear fluid at the on-therapy visit or
systemic antibiotic therapy within 72 hours, except when            before the end-of-therapy visit.
AOM developed while the patient was undergoing prophy-              Bacterial Isolation and Susceptibility Testing. Pathogens re-
lactic antimicrobial therapy for AOM.                               covered from middle ear fluid at local laboratories were sent
Interventions and Assessments. We randomized (1:1) eligible         to a central laboratory for confirmation of identification and
children to receive either amoxicillin/clavulanate (90/6.4 mg/      susceptibility testing. Determination of the penicillin, amoxi-
kg/d in 2 divided doses for 10 days) or azithromycin (10 mg/kg      cillin, amoxicillin/clavulanate, erythromycin and azithromy-
for 1 day, followed by 5 mg/kg/d for 4 days), and we conducted      cin MICs for the 4 protocol-defined AOM pathogens was
baseline (day 1), on-therapy (day 4 – 6), end-of-therapy (day       performed with broth microdilution methods, according
12–14) and follow-up (day 21–25) clinical assessments. Efficacy     to National Committee for Clinical Laboratory Standards
assessments were conducted for children with bacterial AOM.         (NCCLS) guidelines6 and guidelines of the plate manufac-
For bacteriologic assessments, we performed tympanocentesis         turer (Trek Diagnostics, Cleveland, OH). MIC results were
for all children with an intact tympanic membrane at the initial    interpreted according to NCCLS guidelines,7 and isolates
visit. For children with otorrhea for ⬍24 hours, direct sampling    were classified as susceptible, intermediate or resistant to
of otorrhea or tympanocentesis was performed. We considered         each drug. Because no NCCLS breakpoints for amoxicillin/
S. pneumoniae, H. influenzae, M. catarrhalis and Streptococcus      clavulanate (90/6.4 mg/kg/d) have been assigned, the break-
pyogenes AOM pathogens. A second sample of middle ear fluid         point for conventional formulations was used. Isolates of H.
was obtained at the on-therapy visit from children who (1) had      influenzae and M. catarrhalis were tested for ␤-lactamase
S. pneumoniae at baseline, (2) or had AOM pathogen(s) at            production with Cefinase disks (Becton Dickinson, Sparks,
baseline and either experienced clinical failure or withdrew from   MD), according to the manufacturer’s instructions.
the study before the end of therapy. Exceptions included a center   Statistical Analyses. We assumed overall clinical success
in Israel, where repeat tympanocentesis was performed at the        rates at the end of therapy of 86% for patients treated with
on-therapy visit for all children with AOM pathogens at base-       amoxicillin/clavulanate and 75% for patients treated with
line, and a center in the United States, where on-therapy tym-      azithromycin.8 Accordingly, a total of 203 children per treat-
panocentesis was performed only for children with non–              ment arm were required to detect a difference with 80%
penicillin-susceptible S. pneumoniae (MIC ⱖ 0.12 ␮g/mL) at          power at a significance level of 0.05. With the assumptions
baseline.                                                           that ⬃70% of all middle ear fluid sample cultures would yield
Outcomes. Compliance was assessed on the basis of medica-           a pathogen and 80% of children who had a pathogen would
tion diaries completed by the parents and comparisons of the        qualify for the per-protocol population, 203/(0.7 ⫻ 0.8)
amount of medication dispensed with that returned. Clinical         resulted in 363 children required per treatment arm. The
response at the end of therapy (day 12–14) among children           treatment difference and 95% confidence intervals (CIs) were
with bacterial AOM represented the primary efficacy end-            determined for the difference between treatment groups at
point for the study. Children were classified as experiencing       each endpoint. Fisher’s exact test or continuity-corrected ␹2
clinical success if they had lessening or complete resolution       test P values were calculated as appropriate.
of otoscopic signs of acute infection and symptoms of in-
flammation, with or without middle ear effusion, such that no
additional antibiotic therapy was needed for AOM. Children                                    RESULTS
were assigned a clinical response of failure if there was an        Subjects. We randomized 731 children to amoxicillin/clavu-
inability to resolve or improve the otoscopic signs of acute        lanate (368 children) or azithromycin (363 children). One child

526                                                                                            © 2005 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005                         Amoxicillin/Clavulanate for AOM

                                                                                          FIGURE 1. Flow diagram showing
                                                                                          progression of children through the
                                                                                          study and reasons for exclusion
                                                                                          from analyses. Two children receiv-
                                                                                          ing amoxicillin/clavulanate and 4
                                                                                          children receiving azithromycin
                                                                                          who were evaluated at the end-of-
                                                                                          therapy visit were not evaluated at
                                                                                          the on-therapy visit.

in the amoxicillin/clavulanate group did not receive study med-     at baseline, ie, 249 children in the amoxicillin/clavulanate
ication; therefore, 730 children were included in the safety        group and 245 in the azithromycin group. Nineteen (7.6%)
analysis. The flow of children in the study is shown in Figure 1.   children in the amoxicillin/clavulanate group and 38 (15.5%)
The 2 treatment groups were well matched with respect to            in the azithromycin group had ⬎1 pathogen. No differences
demographic characteristics and risk factors for AOM (Table 1).     between treatment groups were apparent in the distribution of
In general, children in both treatment groups were relatively       pathogens at baseline. Overall H. influenzae was the most
young (mean age, 15.1 and 15.2 months for the amoxicillin/          frequently isolated pathogen (121 of 249 关48.6%兴 children in
clavulanate and azithromycin groups, respectively); 87.6% of        the amoxicillin/clavulanate group and 124 of 245 关50.6%兴
children were ⱕ24 months of age. Approximately two-thirds of        children in the azithromycin group). This trend was observed
the children had siblings, one-third attended day-care centers,     in the United States, in Israel and overall. ␤-Lactamase
one-third had AOM and received systemic antimicrobial therapy       production was observed in 23.7% of H. influenzae isolates
in the 30 days before enrollment and one-third were exposed to      and 96.8% of M. catarrhalis isolates from the combined
tobacco smoke pollution at home.                                    amoxicillin/clavulanate and azithromycin treatment groups.
Bacteriologic Findings. Four hundred ninety-four (67.7%) of         Of S. pneumoniae isolates (111 of 249 关44.6%兴 children in the
the 730 children had ⱖ1 protocol-defined pathogen isolated          amoxicillin/clavulanate group and 118 of 245 关48.2%兴 chil-

© 2005 Lippincott Williams & Wilkins                                                                                        527
Hoberman et al                                                     The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005

             TABLE 1. Demographic Characteristics and Risk Factors for AOM at Baseline for Children
             With Bacterial AOM (per Protocol) and All Children

                                                                          Evaluable Children With
                                                                                                                      All Children
                                                                         Bacterial AOM (per Protocol)
                     Characteristic/Risk Factor for AOM
                                                                             A/C                 AZI             A/C               AZI
                                                                          (N ⫽ 200)           (N ⫽ 204)       (N ⫽ 367)         (N ⫽ 363)

                 Gender (male)                                            110 (55.0)*         129 (63.2)      196 (53.4)        217 (59.8)
                 Race
                   White                                                   87 (43.5)           93 (45.6)      176 (48.0)        179 (49.3)
                   Black                                                   21 (10.5)           16 (7.8)        41 (11.2)         31 (8.5)
                   Other†                                                  92 (46.0)           95 (46.6)      150 (40.9)        153 (42.1)
                 Age (mo)
                   Mean ⫾ SD                                              15.1 ⫾ 6.6          15.2 ⫾ 6.6      15.3 ⫾ 6.8       14.9 ⫾ 6.5
                   Range                                                      6 –32               6 –32           6 –32            5–36
                   ⱕ24 mo                                                 173 (86.5)          181 (88.7)      317 (86.4)       325 (89.5)
                 Weight (kg)
                   Mean ⫾ SD                                             10.32 ⫾ 2.18        10.29 ⫾ 2.16    10.35 ⫾ 2.30     10.22 ⫾ 2.31
                   Range                                                    6.6 –17.5           5.9 –17.7       6.6 –29.0        5.4 –29.5
                 Siblings                                                 136 (68.0)          137 (67.2)      227 (61.9)       243 (66.9)
                 Attends day care                                          64 (32.0)           75 (36.8)      127 (34.6)       137 (37.7)
                 Systemic antimicrobial therapy within 30 d                62 (31.0)           56 (27.5)      109 (29.7)       109 (30.0)
                 Smoking in household                                      73 (36.5)           84 (41.2)      137 (37.3)       146 (40.2)
                 Currently breast-feeding                                  49 (24.5)           51 (25.0)       71 (19.3)        74 (20.4)
                 Previously breast-fed                                    156 (78.0)          161 (78.9)      276 (75.2)       277 (76.3)
                 AOM within 30 d                                           62 (31.0)           55 (27.0)      120 (32.7)       113 (31.1)
               *Numbers in parentheses, percent.
                †
                  Mostly Hispanic, a few Native American and 1 Middle Eastern.
               A/C indicates amoxicillin/clavulanate; AZI, azithromycin.

dren in the azithromycin group), 48.5%, 11.4% and 20.5%                                 Children were classified as experiencing bacteriologic failure
were nonsusceptible to penicillin, amoxicillin and azithromy-                           if the initial pathogen persisted in the middle ear fluid at the
cin, respectively. Of penicillin-susceptible and -intermediate                          on-therapy visit or before the end-of-therapy visit.
S. pneumoniae, 4.7% and 17.1%, respectively, were resistant                                    Among the 183 children categorized as experiencing
to azithromycin. Of penicillin-resistant S. pneumoniae                                  bacteriologic success at day 4 – 6, 24.8% (25 of 101 children)
(PRSP) (⬎1.0 ␮g/mL) isolates, 52.2% were also resistant to                              in the amoxicillin/clavulanate group and 25.6% (21 of 82
azithromycin.                                                                           children) in the azithromycin group were so categorized
Bacteriologic Efficacy. Determination of bacteriologic re-                              because of the absence of middle ear effusion, whereas 75.2%
sponses was limited to children from whom pathogens were                                (76 of 101 children) in the amoxicillin/clavulanate group and
isolated at baseline and for whom the study protocols at the                            74.4% (61 of 82 children) in the azithromycin group were so
various study sites called for repeat tympanocentesis on day                            categorized on the basis of bacteriologic findings for middle
4 – 6. As described previously, repeat tympanocentesis was to                           ear fluid specimens. Among the children for whom bacteri-
be performed for children who in baseline tympanocentesis                               ologic responses were determined, amoxicillin/clavulanate,
assessments had the following: (1) in Israel, any of the 4                              compared with azithromycin, demonstrated significantly
AOM pathogens isolated; (2) at all other sites except Chil-                             higher rates of eradication of AOM pathogens (101 of 108
dren’s Hospital of Pittsburgh, any S. pneumoniae isolated;                              cases 关93.5%兴 versus 82 of 127 cases 关64.6%兴; P ⬍ 0.001), of
(3) at Children’s Hospital of Pittsburgh, any nonsusceptible S.                         S. pneumoniae (72 of 75 cases 关96.0%兴 versus 74 of 92 cases
pneumoniae isolated. In addition, repeat tympanocentesis was                            关80.4%兴; P ⬍ 0.01) and of H. influenzae (29 of 30 cases
performed at all sites in the event of clinical failure occurring                       关96.7%兴 versus 18 of 34 cases 关52.9%兴; P ⬍ 0.001). More
before the end-of-therapy visit (day 12–14). However, when                              pronounced differences between treatment groups, again fa-
repeat tympanocentesis was performed because of clinical                                voring amoxicillin/clavulanate, were noted in the eradication
failure, rather than because the child met the aforementioned                           of PRSP (23 of 25 cases 关92.0%兴 versus 12 of 22 cases
criteria at the various sites, results were not included in                             关54.5%兴; P ⬍ 0.05) and of azithromycin-resistant S. pneu-
bacteriologic efficacy analyses, to preclude bias that would                            moniae (14 of 15 cases 关93.3%兴 versus 6 of 18 cases 关33.3%兴;
result from the inclusion only of children who experienced                              P ⬍ 0.05). Rates of eradication of S. pneumoniae and H.
clinical failure (see below). Therefore, given the particular                           influenzae according to children’s treatment groups and
design of this study, S. pneumoniae was the pathogen for                                amoxicillin/clavulanate MICs are presented in Table 2. Of
which bacteriologic results were most frequently available.                             S. pneumoniae isolates with amoxicillin/clavulanate MICs
Bacteriologic response at the on-therapy and end-of-therapy                             of ⬍2 ␮g/mL, amoxicillin/clavulanate eradicated 98.0% (51
visits was defined as success if there was eradication of the                           of 52 isolates) and azithromycin eradicated 87.5% (63 of 72
initial AOM pathogen (with or without the presence of a new                             isolates) (P ⬍ 0.05). Of S. pneumoniae isolates with amoxi-
pathogen), as demonstrated with repeat tympanocentesis, or                              cillin/clavulanate MICs of 2 ␮g/mL, amoxicillin/clavulanate
the absence of middle ear fluid in otoscopic examinations.                              eradicated 92.3% (12 of 13 isolates) and azithromycin erad-

528                                                                                                                © 2005 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005                                                 Amoxicillin/Clavulanate for AOM

TABLE 2. Eradication of Streptococcus pneumoniae and
                                                                                           experiencing clinical failure was noted among those treated
Haemophilus influenzae According to Amoxicillin/
                                                                                           with azithromycin, compared with those treated with amoxi-
Clavulanate MIC and Treatment Group
                                                                                           cillin/clavulanate.
                                                                                           Clinical Efficacy. Among evaluable children with AOM
                       No. of Isolates Eradicated/Total No. of Isolates*                   pathogens at baseline, clinical responses at the end-of-therapy
   A/C MIC              S. pneumoniae                           H. influenzae
                                                                                           visit (primary efficacy endpoint) were significantly greater for
   (␮g/mL)                 (n ⫽ 167)                              (n ⫽ 94)                 amoxicillin/clavulanate than for azithromycin, ie, 90.5% and
                      A/C              AZI                    A/C               AZI
                                                                                           80.9%, respectively (treatment difference, 9.62; 95% CI
                                                                                           2.37–16.87; P ⬍ 0.01) (Table 4). Significantly greater clinical
    ⱕ0.015           2/2               4/4                                                 success rates favoring amoxicillin/clavulanate were also
     0.03           31/32             40/43
     0.06            3/3               4/5                                                 noted at the on-therapy visit (treatment difference, 6.95; 95%
     0.12            6/6               3/6                                                 CI 1.01–12.89) and at the follow-up visit (treatment differ-
     0.25
     0.5
                     3/3
                     4/4
                                       9/10
                                       1/2
                                                            2/2
                                                           18/20
                                                                                1/2
                                                                               19/37
                                                                                           ence, 9.26; 95% CI 0.19 –18.33) (P ⬍ 0.05 for each compar-
     1               2/2               2/2                 11/13                3/10       ison) (Table 4). For children with H. influenzae isolated at
     2              12/13              5/9                  3/3                 4/4        baseline, marked differences between treatment groups, fa-
     4               6/7               5/9                  1/1                 0/1
     8               2/2               1/2                                      0/1        voring amoxicillin/clavulanate, were apparent in clinical suc-
    16               1/1                                                                   cess rates at the end-of-therapy visit (day 12–14) (Table 5). A
    32
   ⬎32
                                                                                           trend for greater clinical efficacy with amoxicillin/clavulanate
    Total        72/75 (96)†      74/92 (80.4)          35/39 (89.7)        27/55 (49.1)   among children with PRSP and azithromycin-resistant S.
  *Results are provided for individual pathogens rather than for individual patients; ⬎1   pneumoniae strains was noted, although differences between
pathogen was isolated for 43 children.
   †
                                                                                           treatment groups did not reach statistical significance (Table
     Numbers in parentheses, percent.
   A/C indicates amoxicillin/clavulanate; AZI, azithromycin.
                                                                                           5). When all children with bacterial AOM were included,
                                                                                           differences between treatment groups did not reach statistical
                                                                                           significance (Table 4). Among children for whom no AOM
icated 55.6% (5 of 9 isolates) (P ⫽ 0.16). Of S. pneumoniae                                pathogens were isolated at baseline, clinical success rates did
isolates with amoxicillin/clavulanate MICs of ⱖ4 ␮g/mL,                                    not differ significantly between the 2 treatment groups, either
amoxicillin/clavulanate eradicated 90.0% (9 of 10 isolates),                               at the end-of-therapy visit on day 12–14 (81.4% 关96 of 118
including 2 of 2 isolates with MICs of 8 ␮g/mL and 1 isolate                               children兴 in both groups) or at the follow-up visit on day
with an MIC of 16 ␮g/mL, and azithromycin eradicated                                       21–25 (68.6% 关81 of 118 children兴 in the amoxicillin/clavu-
54.5% (6 of 11 isolates) (P ⫽ 0.15).                                                       lanate group versus 76.3% 关90 of 118 children兴 in the azithro-
       Results of repeat tympanocentesis performed when                                    mycin group).
children were categorized as experiencing clinical failure at                              Relationship Between Bacterial Eradication at the On-
any time up to day 12–14 (end-of-therapy visit) are presented                              Therapy Visit and Clinical Outcomes at the End-of-
in Table 3. A greater proportion of children categorized as                                Therapy Visit. Among children from whom S. pneumoniae
                                                                                           and/or H. influenzae were recovered at baseline and who
                                                                                           experienced bacteriologic failure at the on-therapy visit (ie,
TABLE 3. Bacteriologic Outcomes for Children                                               cultures remained positive), clinical failure at the end-of-
Categorized as Experiencing Clinical Failure Before                                        therapy visit occurred for 5 of 7 children (71.4%) treated with
the End-of-Therapy Visit (Day 12–14)                                                       amoxicillin/clavulanate and 20 of 49 children (40.8%) treated
                                                                                           with azithromycin. Bacteriologic success at the on-therapy
                                                 A/C*                       AZI            visit was associated with clinical success at the end-of-
            Pathogen(s)
                                          n               %            n           %       therapy visit for 96 of 105 children (91.4%) treated with
                                                                                           amoxicillin/clavulanate and 80 of 89 children (89.9%) treated
   Clinical failure                    19/200             9.5       39/204         19.1
                                                                                           with azithromycin. These relationships were similar for chil-
   All pathogens
     Eradication                          12             70.6           8          26.7
                                                                                           dren from whom PRSP was recovered at baseline. Therefore,
     Persistence                           5             29.4          22          73.3    clinical failure at the end-of-therapy visit and bacteriologic
     Total                                17            100            30         100      failure at the on-therapy visit occurred for 1 of 2 children
   Streptococcus pneumoniae                                                                (50%) treated with amoxicillin/clavulanate and 5 of 12 chil-
     Eradication                             7           77.8           5          45.5
     Persistence                             2           22.2           6          54.5    dren (42%) treated with azithromycin; clinical success at the
     Total                                   9          100            11         100      end-of-therapy visit and bacteriologic success at the on-
   Haemophilus influenzae                                                                  therapy visit occurred for 20 of 22 children (90.9%) treated
    Eradication                              3           50.0           2          11.1
    Persistence                              3           50.0          16          88.9
                                                                                           with amoxicillin/clavulanate and 10 of 10 children (100%)
    Total                                    6          100            18         100      treated with azithromycin.
   Moraxella catarrhalis                                                                   Treatment Compliance. Rates of compliance with study med-
    Eradication                              2          100            1          100      ications were high in both treatment groups (amoxicillin/
    Total                                    2          100            1          100
                                                                                           clavulanate, 85.8%; azithromycin, 91.3%). Clinical success
  *Two children in the amoxicillin/clavulanate group and 9 children in the azithromycin
group did not undergo repeat tympanocentesis.
                                                                                           rates at the end of therapy for children who were noncom-
   A/C indicates amoxicillin/clavulanate; AZI, azithromycin.                               pliant with study medication were 38.5% (20 of 52 children)

© 2005 Lippincott Williams & Wilkins                                                                                                                  529
Hoberman et al                                                          The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005

        TABLE 4. Clinical Efficacy of Amoxicillin/Clavulanate and Azithromycin According to Study Visit

                                                                                                                               Treatment
                              Population                                  A/C (%)                 AZI (%)                                                   P
                                                                                                                               Difference

             Evaluable children with bacterial AOM
               On-therapy visit (d 4 – 6)                              94.9 (188/198)*        88.0 (176/200)*           6.95 (1.01–12.89)†                 ⬍0.05
               End-of-therapy visit (d 12–14)                          90.5 (181/200)         80.9 (165/204)            9.62 (2.37–16.87)                  ⬍0.01
               Follow-up visit (d 21–25)                               80.3 (155/193)         71.1 (135/190)            9.26 (0.19 –18.33)                 ⬍0.05
             All children with bacterial AOM
               On-therapy visit (d 4 – 6)                              89.6 (223/249)         83.3 (204/245)            6.29 (⫺0.13 to 12.72)               NS
               End-of-therapy visit (d 12–14)                          80.7 (201/249)         73.5 (180/245)            7.25 (⫺0.54 to 15.05)               NS
               Follow-up visit (d 21–25)                               68.3 (170/249)         62.0 (152/245)             623 (⫺2.56 to 15.02)               NS
          *Numbers in parentheses, n/N.
           †
             Numbers in parentheses, 95% CI.
          A/C indicates amoxicillin/clavulanate; AZI, azithromycin; NS, not significant.

        TABLE 5. Clinical Efficacy of Amoxicillin/Clavulanate and Azithromycin at the End-of-Therapy Visit
        (Day 12–14) Among Children With Haemophilus influenzae or Streptococcus pneumoniae Isolated at
        Baseline

                                                         Clinical Efficacy (%)
                      Pathogen                                                                    P            Treatment Difference                  95% CI
                                                       A/C                     AZI

            H. influenzae                         91.6 (87/95)*            73.7 (70/95)        ⬍0.01                    17.9                        6.37–29.42
            S. pneumoniae                         89.8 (79/88)             86.0 (86/100)        0.57                     3.8                       ⫺6.59 –14.13
              Penicillin-resistant                92.0 (23/25)             78.3 (18/23)         0.24                    13.7                      ⫺10.37–37.84
              Azithromycin-resistant              88.2 (15/17)             70.0 (14/20)         0.25                    18.2                      ⫺12.46 – 48.93
          *Numbers in parentheses, n/N.
           A/C indicates amoxicillin/clavulanate; AZI, azithromycin.

and 40.6% (13 of 32 children) for children randomized to
                                                                                           TABLE 6. Adverse Events and Withdrawals From the
amoxicillin/clavulanate and azithromycin, respectively.
                                                                                           Study According to Treatment Group
Safety. Adverse events and withdrawals from the study ac-
cording to treatment group are shown in Table 6.                                                                                     A/C                 AZI
                                                                                                   Safety Outcome                 (N ⫽ 367)           (N ⫽ 363)              P
                            DISCUSSION                                                                                            n         %         n          %
       Among children with AOM, an antimicrobial agent
                                                                                             Adverse events
with relatively low antibacterial efficacy may result in similar                              At least 1 adverse event           139      37.9       128      35.3       NS
clinical outcomes, compared with those that result from using                                 Fever                               38      10.4        37      10.2       NS
                                                                                              Diarrhea                            21       5.7        13       3.6       NS
an antimicrobial agent with high antibacterial efficacy.9,10
                                                                                             Withdrawal from the
However, rates of bacterial eradication are helpful in discrim-                                  study
inating among agents. Accordingly, there is a growing accep-                                  Adverse event                       21        5.7        7         1.9   ⬍0.05
tance of the need to take pharmacokinetic/pharmacodynamic                                     Insufficient therapeutic            13        3.5       35         9.6   ⬍0.01
                                                                                                 effect
measures into consideration when choosing antimicrobial                                       Protocol violation                  35       9.5        21       5.8       NS
therapy for children with AOM. The best predictors of effi-                                   Lost to follow-up                   21       5.7        13       3.6       NS
cacy are the time during which an antimicrobial agent main-                                   Other                                6       1.6        13       3.6       NS
                                                                                              Overall                             96      26.2        89      24.5       NS
tains serum concentrations above the MIC of the pathogen for
␤-lactam antimicrobial agents and the ratio of the area under                               A/C indicates amoxicillin/clavulanate; AZI, azithromycin; NS, not significant.

the concentration-time curve to the MIC for macrolide/aza-
lide antimicrobial agents.11–13 For amoxicillin, a serum con-
centration greater than the MIC for 40 –50% of the dosing                                  strains and most H. influenzae strains would not be eradicated
interval is predictive of 80 – 85% bacterial eradication in                                at a rate higher than that observed without antibiotics.
AOM.11 Amoxicillin/clavulanate (90 and 6.4 mg/kg/d of the                                         Previous studies among children with AOM showed a
amoxicillin and clavulanate components, respectively) was                                  clear relationship between early (day 4 –5) eradication of
developed to sustain amoxicillin/clavulanate concentrations                                infecting pathogens from the middle ear fluid and positive
in middle ear fluid at levels that would predict eradication of                            clinical outcomes.14,15 The results of the current study are
PRSP with amoxicillin/clavulanate MICs of ⱕ4 ␮g/mL.                                        consistent with previous reports. There was a strong correla-
Applying the area under the concentration-time curve/MIC                                   tion between early bacteriologic success at the on-therapy
model, the prediction for azithromycin, at the dosage used in                              visit (day 4 – 6) and clinical success at the end-of-therapy visit
this study, would be that macrolide-resistant S. pneumoniae                                (day 12–14) in the combined treatment groups for both S.

530                                                                                                                            © 2005 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005                               Amoxicillin/Clavulanate for AOM

pneumoniae (126 of 137 children, 92.0%) and H. influenzae         design; (2) a low rate of bacterial AOM at baseline (55%); (3)
(50 of 57 children, 87.7%), whereas the corresponding values      fewer children (⬃65%) ⬍24 months of age, ie, those most
for children without bacterial eradication were considerably      likely to experience treatment failure;15 (4) use of day 28 –32
lower (65.4% and 46.7% for S. pneumoniae and H. influen-          visit results as the primary outcome; and (5) performance of
zae, respectively). Viewed alternatively, our data indicate       repeat tympanocentesis for only 7 of 64 children categorized
that, for AOM caused by either S. pneumoniae or H. influ-         as experiencing clinical failure (mostly at one study site).
enzae, failure to eradicate pathogens from the middle ear fluid   Despite these limitations and differences in study design,
within 4 – 6 days increased the risk of clinical failure by       outcomes for children with AOM caused by H. influenzae
4.3-fold (for S. pneumoniae, 35.6% versus 8.0%; for H.            (azithromycin, 67%; amoxicillin/clavulanate, 81%; 95% CI
influenzae, 53.3% versus 12.3%), confirming the experience        of the difference, ⫺34.7% to ⫺6.8%) were similar to those
of others that antimicrobial agents with greater bacteriologic    reported previously8 and to those in our study.
efficacy result in higher clinical cure rates at the end of              We conclude that amoxicillin/clavulanate was effective
treatment. However, it must be noted that many children for       in eradicating AOM pathogens and that this led to high
whom cultures remained positive at day 4 – 6 eventually           clinical cure rates. Amoxicillin/clavulanate was significantly
experienced cures.                                                more effective than azithromycin bacteriologically and clin-
       As in other clinical trials, H. influenzae was a fre-      ically. The relatively high bacteriologic and clinical efficacy
quently isolated pathogen.2,8,16 Azithromycin failed to erad-     of amoxicillin/clavulanate, together with its excellent safety
icate H. influenzae for 47.0% of children, a finding consistent   profile, makes it a preferred antimicrobial choice for the
with both the previously reported low bacteriologic efficacy      treatment of children with recurrent or persistent AOM,
of azithromycin against this pathogen and the pharmacoki-         particularly those at risk for infection with nonsusceptible
netic/pharmacodynamic model.8,17,18 Peric et al19 recently        S. pneumoniae and/or ␤-lactamase-positive H. influenzae or
demonstrated that most H. influenzae strains have an intrinsic    M. catarrhalis.
macrolide-efflux mechanism, which is not overcome by dos-
age increases within tolerable limits.20 Therefore, despite the                       ACKNOWLEDGMENTS
in vitro findings that most H. influenzae strains are suscepti-         We acknowledge the contributions of Richard Morales
ble to azithromycin (according to the NCCLS definition of         and Tracy Henrick, GlaxoSmithKline Biometrics and Data
having a MIC of ⬍8 ␮g/mL), the results of clinical studies        Science Group, and John Breton, GlaxoSmithKline Clinical
with bacteriologic outcomes demonstrate that almost all H.        Research, for their contributions to the conduct of the study
influenzae isolates are, in fact, resistant to azithromycin, at   and the development of the manuscript. We also thank Jack L.
least with the concentrations and dynamics achieved with the      Paradise, MD, and Ellen R. Wald, MD, for their advice on
currently recommended dosages.                                    the study design and for their careful review of the manu-
       Children ⬍2 years of age are more likely than older        script.
children to have AOM caused by resistant pathogens, such as
PRSP, and accordingly are more likely to experience clinical                                   REFERENCES
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© 2005 Lippincott Williams & Wilkins                                                                                                       531
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