**January 30, 2001**

**New Drug Application 50-755**

**Augmentin^TM^ (amoxicillin/clavulanate potassium)**

# 

SUMMARY OF CLINICAL/STATISTICAL REVIEW
[3](#summary-of-clinicalstatistical-review)

Introduction [3](#introduction)

Current Labeling for approved Augmentin formulations (Augmentin 7:1 and
Augmentin 4:1) for the treatment of acute otitis media
[3](#current-labeling-for-approved-augmentin-formulations-augmentin-71-and-augmentin-41-for-the-treatment-of-acute-otitis-media)

SmithKline Beecham's Proposed Labeling for Augmentin ES
[4](#smithkline-beechams-proposed-labeling-for-augmentin-es)

REGULATORY GUIDANCE DOCUMENTS [4](#regulatory-guidance-documents)

Clinical Efficacy Data for Augmentin ES (Augmentin 14:1) to treat AOM
due to penicillin resistant S. pneumoniae
[6](#clinical-efficacy-data-for-augmentin-es-augmentin-141-to-treat-aom-due-to-penicillin-resistant-s.-pneumoniae)

STUDY DESIGN SUMMARY [8](#study-design-summary)

Differences in the analysis between the FDA and the applicant
[9](#differences-in-the-analysis-between-the-fda-and-the-applicant)

RESULTS [10](#results)

Safety [14](#safety)

SUMMARY [15](#summary)

CLINICAL PHARMACOLOGY [16](#clinical-pharmacology)

SUMMARY OF RELEVANT HUMAN PHARMACOKINETICS/PHARMACODYNAMICS DATA
[16](#summary-of-relevant-human-pharmacokineticspharmacodynamics-data)

CONCLUSIONS [18](#conclusions)

MICROBIOLOGY [18](#microbiology)

In Vitro Activity [19](#in-vitro-activity)

Pharmacokinetic and Pharmacodynamic Studies
[23](#pharmacokinetic-and-pharmacodynamic-studies)

Efficacy Studies in Animal Models of Infection
[26](#efficacy-studies-in-animal-models-of-infection)

Efficacy Studies in Humans [27](#efficacy-studies-in-humans)

Discussions on Breakpoint Determination
[30](#discussions-on-breakpoint-determination)

References [33](#references)

ATTACHED ARTICLES [35](#attached-articles)

#  

# SUMMARY OF CLINICAL/STATISTICAL REVIEW

## Introduction

SB has submitted a new drug application to support the claim of efficacy
for Augmentin ES in the treatment of acute otitis media due to H.
*influenzae*, *Moraxella catarrhalis* and *Streptococcus pneumoniae,*
including penicillin resistant strains with penicillin MIC≥2 mcg/mL.

**I. Proposed new formulation:** Amoxicillin-clavulanate potassium
90/6.4mg/kg/day (14:1ratio of amoxicillin to clavulanate); 600mg/42.9mg
per 5mL oral suspension

**Proposed Trade Name**: Augmentin ES

### 

### II. SmithKline Beecham's Rationale for Augmentin ES 

SmithKline Beecham recognizes that *Streptococcus pneumoniae* is a
non-β-lactamase producing organism susceptible in most cases to
amoxicillin alone. Given empiric antibiotic selection, and the three
most likely pathogens in otitis media *(S. pneumoniae, Haemophilus
influenzae,* and *Moraxella catarrhalis*), development of a higher
strength *Augmentin* (14:1 ratio) to \"cover\" the more resistant *S.
pneumoniae,* as well as provide coverage against the two most likely
other pathogens (β-lactamase producers), in acute otitis media was
deemed appropriate.

**III. Intended Use**

*Augmentin*-ES is intended to be used for the empiric treatment of acute
otitis media in children where infection with either
beta-lactamase-producing strains of *H. influenzae* and *M. catarrhalis*
or *S. pneumoniae* of reduced susceptibility to penicillin (i.e., MIC≥2
mcg/mL) is suspected.

## Current Labeling for approved Augmentin formulations (Augmentin 7:1 and Augmentin 4:1) for the treatment of acute otitis media

**I. INDICATIONS AND USAGE**

Augmentin is indicated in the treatment of the following infections:

OTITIS MEDIA\--caused by beta-lactamase-producing strains of
*Haemophilus influenzae* *and Moraxella (Branhamella) catarrhalis*.

**II. DOSAGE AND ADMINISTRATION**

II. 

Patients aged 12 weeks (3 months) and older

  --------------------------- --------------------- ---------------------
  **INFECTIONS**              DOSING REGIMEN        

                              **q12h**              **q8h**

                              200 mg/5 mL or 400    125 mg/5 mL or 250
                              mg/ 5 mL oral         mg/ 5 mL oral
                              suspension            suspension

  Otitis media                45 mg/kg/day q12h\    40 mg/kg/day q8h\
                              (7:1 ratio of         (4:1 ratio of
                              amoxicillin to        amoxicillin to
                              clavulanate)          clavulanate)

  Duration of therapy studied                       
  and recommended for acute                         
  otitis media is 10 days.                          
  --------------------------- --------------------- ---------------------

The currently marketed 7:1 and 4:1 formulations are approved for the
treatment of acute otitis media due to β-lactamase-producing *H.
influenzae* and *Moraxella catarrhalis,* but not *S. pneumoniae.* The
proposed label aims to add *S. pneumoniae,* including penicillin
resistant strains of MIC [\>]{.underline}2μg/mL, and increase the dose
of Augmentin administered to patients with acute otitis media to
90mg/kg/day q12 hours (14:1 ratio), based on the amoxicillin component.

## SmithKline Beecham's Proposed Labeling for Augmentin ES

**I. INDICATIONS AND USAGE**

*"Augmentin ES* is indicated in the treatment of infections caused by
susceptible strains of the designated organisms in the conditions listed
below:

Acute Otitis Media---caused by β-lactamase-producing strains of *H.
influenzae or M. catarrhalis,* and *S. pneumoniae* (including
penicillin-resistant strains, MIC value for penicillin ≥2 µg/mL) when
suspected.

Bacteriological studies, to determine the causative organisms and their
susceptibility to *Augmentin ES*, should be performed if indicated.
Infections caused by *S. pneumoniae,* including penicillin-resistant
strains, are amenable to treatment with *Augmentin ES* due to its
amoxicillin content.

Therapy may be instituted prior to obtaining the results from
bacteriological and susceptibility studies to determine the causative
organisms and their susceptibility to *Augmentin ES* when there is
reason to believe the infection may involve any of the
β-lactamase-producing organisms listed above. Once the results are
known, therapy should be adjusted, if appropriate."

**II. DOSAGE AND ADMINISTRATION**

Pediatric patients aged 12 weeks (3 months) and older

The recommended dose of Augmentin ES is 90 mg/kg/day divided q12h, based
on the amoxicillin component.

## REGULATORY GUIDANCE DOCUMENTS

**I. The Points to Consider** **Document of the Division of
Anti-infective Drug Products**

Two trials are suggested for acute otitis media:

-   one clinical only study using rigid case definitions
    \-\--statistically adequate and well-controlled, multicenter,
    comparative study \-- to establish equivalence to an approved
    product; baseline tympanocentesis is not necessary but
    tympanocentesis is strongly encouraged for therapeutic failures

-   one open, microbiological/clinical study with tympanocentesis at
    study entry to establish microbiologic etiology, and post-therapy
    tympanocentesis of failures to determine bacterial persistence or
    superinfection

**II. The IDSA/FDA guidelines**

-   The preferred antimicrobial agent should have proven activity
    against *Haemophilus influenzae, Moraxella catarrhalis,* and *S.
    pneumoniae*.

-   All children who receive systemic antibacterial agents within the 7
    days before study entry for an illness other than AOM should be
    excluded.

-   Consider aspirates from those who fail therapy clinically at least
    72 hours after study drug initiation.

-   Expect effective agent to sterilize middle ear fluid (MEF) in \>80%
    of patients within 72 hours

-   After enrollment, observations should be made 3-5 days after the
    initiation of therapy and at least 2 and 4-6 weeks later.

-   Both ears should be aspirated for bacteriologic assessment in
    patients with bilateral AOM.

**III. Draft Guidance for Industry--Acute Otitis media\--Developing
Antimicrobial Drugs for Treatment July, 1998**

The clinical diagnosis of acute otitis media (AOM) must be based on:

1.  history and physical examination

2.  pneumatic otoscopy findings:

-   swollen bulging tympanic membrane (TM) which may be erythematous

-   loss of light reflex and tympanic membrane landmarks

-   abnormal TM mobility, and

3.  tympanometry or acoustic reflectometry

To be evaluable, a patient should receive within 80-120% of the
prescribed dose and dosing regimen. A patient who receives at least 72
hours of therapy and is not doing well may be considered a failure.
Tympanocentesis is recommended for patients judged to be failing
therapy.

For microbiological evaluability, the diagnosis of AOM must be based on
the results of tympanocentesis. Patients must have:

-   sample(s) from the affected ear(s)-samples from perforated TMs are
    acceptable if perforation is \<48 hours old

-   isolation of bacterial pathogen(s)

-   *in vitro* susceptibility testing of the isolate to the study and
    control drugs

The test of cure visit: 2-4 weeks after study entry

**Microbiologic Outcome**

For most patients, it is anticipated that microbiologic eradication will
be presumed from the clinical response at the test of cure (TOC) visit.
Negative culture results from tympanocentesis at the on therapy visit
should not be considered evidence of documented eradication. A negative
culture result may represent antimicrobial suppression.

**Analysis**

Primary efficacy variable:

Pathogen eradication rate at the TOC visit for clinical/microbiologic
study

Clinical cure rate at the TOC visit for the clinical only study

**IV. Advisory Committee Recommendations on AOM (March 1997)**

-   larger microbiologic studies needed to show bacteriologic cure and
    assure that the drug has significant antimicrobial effect on the
    illness for which it is approved

-   number of patients evaluated in clinical microbiologic studies
    should be increased, with emphasis on those with
    penicillin-intermediate or penicillin-resistant organisms

-   patients who fail therapy should have tympanocentesis at the time of
    failure

**V. Advisory Committee Recommendations on AOM (July 1998)**

-   Drugs to be approved must show activity against the three major AOM
    pathogens

-   Documentation of bulging TM at study entry is important

-   Biphasic pneumatic otoscopy recommended to document AOM;
    electroacoustic reflectometry or tympanometry would be useful to
    demonstrate the presence of an effusion

-   TOC visit 2-4 weeks after entry into study

-   Drug resistant *S. pneumoniae* (DRSP) Working Group recommends that
    repeat tympanocentesis day 3-5 of study is critical measure of
    treatment efficacy and for approval; repeat tympanocentesis at day
    3-5 can be limited to treatment failures, and patients with
    resistant organism (e.g., non-susceptible pneumococci) at baseline

-   Inclusion of patients with acutely perforated TM acceptable \[for
    *Streptococcus pneumoniae* or group A Streptococcus (*Streptococcus
    pyogenes*) only (Reller) or for all AOM pathogens (Craig)\]

-   To better detect differences in clinical response, tighten inclusion
    criteria in clinical only study, and **enrich** the population with
    patients under 2 years of age

-   No consensus on the number of *Streptococcus pneumoniae* isolates
    needed

# 

## Clinical Efficacy Data for Augmentin ES (Augmentin 14:1) to treat AOM due to penicillin resistant S. pneumoniae

SmithKline Beecham submitted the results of 3 pivotal studies in this
application to support the proposed higher dose of Augmentin to treat
AOM.

The first of the pivotal studies is an open-label, single center
pharmacokinetic/ pharmacodynamic study (25000/446), conducted in 19
patients. Children were 3 months to 12 years of age and presented with
AOM. Middle ear fluid (MEF) and plasma concentrations of amoxicillin
were determined 1, 2, and 3 hours (six patients randomized to each
timepoint) after administration of a single oral dose of *Augmentin*
45/3.2 mg/kg, and the tolerability of the *Augmentin* 90/6.4 mg/kg/day
q12h for 10 days was evaluated. The aim of this study was to provide
evidence for the time over MIC (T\>MIC) as a surrogate for bacteriologic
efficacy. Results of the mean plasma concentrations of amoxicillin from
the this study were available for up to 3 hours only, and results from a
pharmacokinetic study with Augmentin 7:1 were used to predict the T\>MIC
profile for Augmentin 14:1.

The second pivotal trial is a clinical study with no tympanocentesis,
designed as a randomized, double blind, multicenter, comparative study
(25000/447) of Augmentin 90/6.4mg/kg/day (14:1 ratio) versus Augmentin
45/6.4mg/kg/day (7:1 ratio). Patients were randomized 1:1 to receive
treatment for 10 days. Four hundred and fifty three children, 3 months
to 12 years of age, were enrolled in the study. This patient population
was not enriched for penicillin resistant *S. pneumoniae*. Evaluations
were done 12-14 and 22-28 days after the initiation of therapy. No
bacteriologic data were collected.

The clinical cure rates at the follow-up visit, days 22-28, in the FDA
per protocol population were 82.8% and 78.3% for Augmentin 14:1 and
Augmentin 7:1, respectively (the difference was not statistically
significant). Estimates of the number of patients, if any, with AOM due
to penicillin resistant *S. pneumoniae* in this trial were not possible
without microbiologic data.

The third pivotal study (25000/536) is an open-label, non-comparative,
bacteriologic study conducted in patients with acute otitis media who
received Augmentin 14:1 for 10 days. Five hundred twenty one children
between the ages of 3 months and 48 months of age were enrolled in the
study. Enrichment of the study population with patients likely to have
PRSP was undertaken by recruiting young patients, recipients of previous
therapy for AOM, patients who had received otitis media prophylaxis,
siblings of patients with AOM, and day care attendees.

Tympanocentesis was done at baseline and repeated at the on-therapy
visit, days 4-6, in patients with *S. pneumoniae* at baseline. Patients
with other baseline pathogens could have had the repeat tympanocentesis
at the on-therapy visit (d4-6), or at the time they were declared a
clinical failure.

Study visits were conducted at baseline, on therapy, day 4-6, at the end
of therapy, day 12-15, and at the test of cure, day 25-28.

The briefing packet will focus on the PRSP results from the third
pivotal clinical/microbiologic trial (study 536). A summary of the study
design for this trial follows.

## STUDY DESIGN SUMMARY

+---------------------+------------------------------------------------+
| Study 25000/536     |                                                |
+---------------------+------------------------------------------------+
| Primary Objective   | > To obtain bacteriological efficacy data for  |
|                     | > *Augmentin*                                  |
|                     | >                                              |
|                     | > ES in the treatment of children with AOM due |
|                     | > to *S.*                                      |
|                     | >                                              |
|                     | > *pneumoniae* with penicillin MICs of ≥ 2.0   |
|                     | > mcg/mL                                       |
|                     | >                                              |
|                     | > To obtain bacteriological efficacy data for  |
|                     | > *Augmentin*                                  |
|                     | >                                              |
|                     | > ES in the treatment of children with AOM due |
|                     | > to *S.*                                      |
|                     | >                                              |
|                     | > *pneumoniae* with amoxicillin/clavulanic     |
|                     | > acid MICs of                                 |
|                     | >                                              |
|                     | > 4.0 mcg/mL.                                  |
+---------------------+------------------------------------------------+
| Secondary Objective | > Demonstration of the clinical efficacy of    |
|                     | > *Augmentin* ES                               |
|                     | >                                              |
|                     | > in patients infected with *S. pneumoniae*    |
|                     | > including                                    |
|                     | >                                              |
|                     | > isolates with amoxicillin/clavulanic acid    |
|                     | > MICs of 4.0                                  |
|                     | >                                              |
|                     | > mcg/mL and in patients infected with *S.     |
|                     | > pneumoniae*                                  |
|                     | >                                              |
|                     | > including isolates with penicillin MICs of ≥ |
|                     | > 2.0 mcg/mL.                                  |
|                     |                                                |
|                     | Assessment of the clinical and bacteriological |
|                     | efficacy of *Augmentin* ES in patients with    |
|                     | AOM due to any pathogen.                       |
+---------------------+------------------------------------------------+
| Study design        | Open label, non-comparative, multi-center      |
|                     | study                                          |
+---------------------+------------------------------------------------+
| Study dates         | 24 February, 1999 to November 5, 1999          |
+---------------------+------------------------------------------------+
| Patients Population | males and females; 3 months to 48 months       |
+---------------------+------------------------------------------------+
| Location            | US-21 sites; Foreign-4 sites                   |
+---------------------+------------------------------------------------+
| Study drug          | *Augmentin* 90/6.4 mg/kg/day every 12 hours    |
| dosing/duration     | for 10 days                                    |
+---------------------+------------------------------------------------+
| Inclusion Criteria  | a\. Purulent otorrhea of less than 24 hrs      |
|                     | duration                                       |
|                     |                                                |
|                     | **[OR]{.underline}**                           |
|                     |                                                |
|                     | b\. Middle ear effusion                        |
|                     |                                                |
|                     | Middle ear effusion is evidenced by at least   |
|                     | [two]{.underline} of the following:            |
|                     |                                                |
|                     | 1\. decreased or absent tympanic mobility      |
|                     | measured by pneumatic otoscopy,                |
|                     |                                                |
|                     | 2\. yellow or white discoloration of the       |
|                     | tympanic membrane, or                          |
|                     |                                                |
|                     | 3\. opacification of the tympanic membrane.    |
|                     |                                                |
|                     | **Plus**                                       |
|                     |                                                |
|                     | at least [one]{.underline} of the following    |
|                     | indicators of acute inflammation:              |
|                     |                                                |
|                     | 1.ear pain within 24 hours, including          |
|                     | [unaccustomed]{.underline} tugging or rubbing  |
|                     | of ear,                                        |
|                     |                                                |
|                     | 2.marked redness of the tympanic membrane, or  |
|                     |                                                |
|                     | 3.distinct fullness or bulging of the tympanic |
|                     | membrane.                                      |
+---------------------+------------------------------------------------+
| Exclusion Criteria  | spontaneous perforation of the tympanic        |
|                     | membrane and drainage for longer than          |
|                     | 24 hours;                                      |
|                     |                                                |
|                     | tympanoplastic tube(s) in place, or anatomic   |
|                     | abnormalities associated with prolonged middle |
|                     | ear effusion                                   |
+---------------------+------------------------------------------------+
| Evaluation visits   | Baseline                                       |
|                     |                                                |
|                     | On therapy visit days 4-6                      |
|                     |                                                |
|                     | Interim visit as needed                        |
|                     |                                                |
|                     | End of therapy day 12-15                       |
|                     |                                                |
|                     | Test of Cure day 25-28                         |
+---------------------+------------------------------------------------+
| Procedures          | -   Tympanocentesis at baseline, or if the     |
|                     |     membrane is ruptured with purulent         |
|                     |     effusion of less than 24 hours duration,   |
|                     |     direct culture may be obtained             |
|                     |                                                |
|                     | -   Second tympanocentesis:                    |
|                     |                                                |
|                     | All patients with *S. pneumoniae* (alone or    |
|                     | with other pathogens):                         |
|                     |                                                |
|                     | at day 4-6 preliminary visit.                  |
|                     |                                                |
|                     | All other patients:                            |
|                     |                                                |
|                     | **A:** for treatment failure only OR           |
|                     |                                                |
|                     | **B:** all patients at day 4-6.                |
+---------------------+------------------------------------------------+
| SB 1° Efficacy      | bacteriological response in patients with AOM  |
| Parameter           | due to *S. pneumoniae* with penicillin MICs ≥  |
|                     | 2 mcg/mL at the on therapy visit, day 4-6 of   |
|                     | treatment                                      |
+---------------------+------------------------------------------------+
| FDA 1° Efficacy     | Bacteriologic outcome at TOC was inferred from |
| parameter           | the clinical response at TOC (day 25-28)       |
+---------------------+------------------------------------------------+
| Secondary efficacy  | 1\) bacteriological response of other          |
| parameters          | pathogens to study medication at the           |
|                     | on-therapy visit (day 4-6), and presumed       |
|                     | bacteriological response of other pathogens to |
|                     | study medication at the test of cure visit     |
|                     | (day 25-28),                                   |
|                     |                                                |
|                     | 2\) clinical response (clinical cure or        |
|                     | clinical failure) at the end-of-treatment      |
|                     | visit (day 12-15), and                         |
|                     |                                                |
|                     | 3\) clinical response (clinical cure, clinical |
|                     | failure, or clinical recurrence) at the        |
|                     | test-of-cure visit (day 25-28).                |
+---------------------+------------------------------------------------+

In general, the Divisional definitions of outcome recommended in the
draft Guidance document for AOM were followed in the review of study
536. These differed from those of the applicant as outlined below.

## Differences in the analysis between the FDA and the applicant

1.  **Definition of Primary Efficacy Endpoint**

#### The definition of the primary efficacy parameter differed between FDA and the applicant. The primary efficacy parameter was defined by the applicant as the bacteriological response (bacteriological success or bacteriological failure) in patients with AOM due to *S. pneumoniae* with penicillin MICs ≥2 mcg/mL at the on-therapy visit on Days 4, 5 or 6. 

#### Consistent with the FDA draft guidance document for AOM, the medical reviewer's primary efficacy parameter, that is, the primary bacteriologic outcome at TOC, was inferred from the clinical response at the TOC visit. 

2.  **Assessment of clinical outcome**

-   Four patients, who had a clinical presentation still consistent with
    acute otitis media at the time of assessment (at either the on
    therapy visit or at the test of cure visit), were assigned a
    clinical outcome of failure in the FDA analysis. These 4 patients
    were considered successes in the applicant's analysis.

-   The test of cure visit (days 25-28), not the end of therapy visit
    (days 12-15), was the key timepoint for the assessment of clinical
    outcome in the FDA analysis.

## 

## RESULTS

The results summarized in this briefing packet will be primarily those
from the clinical/bacteriologic study, study 536, with emphasis on the
clinical and bacteriologic outcomes in patients with acute otitis media
due to penicillin resistant *S. pneumoniae*.

The demographic characteristics of patients in the intent-to-treat (ITT)
population are summarized in table 1.

## 

**DEMOGRAPHICS**

  ---------------------------------- ------------- --------- -- -- ---------------
  Table 1 Demographic                                              
  Characteristics - ITT                                            
  PopulationDemographic                                            
  Characteristics - ITT Population                                 

  **Demographic Characteristics**    **Augmentin                   
                                     ES\                           
                                     N=521**                       

  **Gender, n (%)**                                                

  Male                               312           (59.9)          

  Female                             209           (40.1)          

  **Race, n (%)**                                                  

  Caucasian                          311           (59.7)          

  Black                              90            (17.3)          

  Oriental                           1             (0.2)           

  Other                              119           (22.8)          

  **Age (mos)**                                                    

  Mean (SD)                          18.59 (12.01)                 

  Median                             14.37                         

  Min-Max                            (3.1, 50.9)                   
  ---------------------------------- ------------- --------- -- -- ---------------

Approximately 60% of the patients were male and Caucasian, and the
median age was 14.4 months.

Table 2 summarizes the baseline characteristics of patients in various
study populations.

Penicillin resistant *S. pneumoniae* (alone or with other pathogens) was
isolated at baseline in 41 patients in the ITT population (n=359). Of
these 41 patients in the PRSP ITT population, 81% of patients had
received antibiotics in the previous 3 months, 46% attended day care,
almost 80% were under 18 months of age, and only 12.2% (5/41) presented
with purulent otorrhea. In the typical trials of AOM ("all comers"
trials), children who present with AOM and meet other selection criteria
are enrolled, and no specific criteria are applied to enrich the study
population. In addition, patients with prior exposure to anti-infective
drug products, and patients receiving antimicrobial prophylaxis for
recurrent otitis media are excluded from these AOM trials.

Table 2 BASELINE CHARACTERISTICS BY POPULATION

+------------------------+------+-------+------+-------+-------+-----+
| **Attribute**          | **IT |       | **   |       | **    |     |
|                        | T:** |       | ITT: |       | ITT:P |     |
|                        |      |       | SP** |       | RSP** |     |
|                        | **   |       |      |       |       |     |
|                        | Base |       |      |       |       |     |
|                        | line |       |      |       |       |     |
|                        | Pa   |       |      |       |       |     |
|                        | thog |       |      |       |       |     |
|                        | en** |       |      |       |       |     |
+------------------------+------+-------+------+-------+-------+-----+
|                        | Rate | N     | Rate | N     | Rate  | N   |
+------------------------+------+-------+------+-------+-------+-----+
| *S. pneumoniae*        | 0    | 15    | 1    | 15    | 1.000 | 41  |
| documented             | .437 | 7/359 | .000 | 7/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
| PRSP documented        | 0    | 4     | 0    | 4     | 1.000 | 41  |
|                        | .114 | 1/359 | .261 | 1/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
| \>1 pathogen           | 0    | 5     | 0    | 4     | 0.390 | 16  |
| documented             | .139 | 0/359 | .280 | 4/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
|                        |      |       |      |       |       |     |
+------------------------+------+-------+------+-------+-------+-----+
| Purulence              | 0    | 2     | 0    | 1     | 0.122 | 5   |
|                        | .072 | 6/359 | .089 | 4/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
| Abnormal mobility      | 0    | 33    | 0    | 14    | 0.949 | 37  |
|                        | .980 | 6/343 | .987 | 7/149 |       | /39 |
+------------------------+------+-------+------+-------+-------+-----+
| Abnormal color         | 0    | 35    | 0    | 15    | 0.974 | 38  |
|                        | .989 | 1/355 | .993 | 2/153 |       | /39 |
+------------------------+------+-------+------+-------+-------+-----+
| Abnormal opacity       | 0    | 34    | 0    | 15    | 0.949 | 37  |
|                        | .983 | 8/354 | .980 | 0/153 |       | /39 |
+------------------------+------+-------+------+-------+-------+-----+
| Abnormal position      | 0    | 33    | 0    | 14    | 0.923 | 36  |
|                        | .943 | 1/351 | .928 | 1/152 |       | /39 |
+------------------------+------+-------+------+-------+-------+-----+
| Otalgia                | 0    | 30    | 0    | 13    | 0.805 | 33  |
|                        | .848 | 1/355 | .840 | 1/156 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
| Redness                | 0    | 30    | 0    | 13    | 0.846 | 33  |
|                        | .868 | 8/355 | .863 | 2/153 |       | /39 |
+------------------------+------+-------+------+-------+-------+-----+
| Temperature \> 98.6°C  | 0    | 22    | 0    | 11    | 0.675 | 27  |
|                        | .666 | 5/338 | .730 | 1/152 |       | /40 |
+------------------------+------+-------+------+-------+-------+-----+
|                        |      |       |      |       |       |     |
+------------------------+------+-------+------+-------+-------+-----+
| USA centers            | 0    | 18    | 0    | 7     | 0.537 | 22  |
|                        | .526 | 9/359 | .484 | 6/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
| Male sex               | 0    | 21    | 0    | 8     | 0.561 | 23  |
|                        | .593 | 3/359 | .561 | 8/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+
| Antibiotics previous 3 | 0    | 15    | 0    | 6     | 0.808 | 21  |
| months                 | .530 | 1/285 | .521 | 3/121 |       | /26 |
+------------------------+------+-------+------+-------+-------+-----+
| Day care               | 0    | 11    | 0    | 4     | 0.462 | 12  |
|                        | .404 | 5/285 | .405 | 9/121 |       | /26 |
+------------------------+------+-------+------+-------+-------+-----+
| Age \> 18 months       | 0    | 12    | 0    | 5     | 0.220 | 9   |
|                        | .354 | 7/359 | .357 | 6/157 |       | /41 |
+------------------------+------+-------+------+-------+-------+-----+

SP=*S. pneumoniae*; PRSP=penicillin resistant *S. pneumoniae*

Patients in the PRSP ITT population were more likely to have received
prior antibiotics and the great majority was under 18 months of age.
Just less than half the patients were evaluated in 4 foreign sites, 3
Central American sites and 1 Israeli site.

#  

**Table 3 PRSP ITT Population**

Baseline Characteristic n/N (%)

USA center 22/41 (53.7)

Male sex 23/41 (56.1)

Antibiotics prior 3 months 21/26 (80.8)

Day care attendance 12/26 (46.2)

\> 18 months of age 9/41 (22.0)

### 

### Table 4 PRSP ITT Population

**Baseline Characteristic**

n/N (%)

Purulence 5/41 (12.2)

Abnormal mobility 37/39 (94.9)

Abnormal color 38/39 (97.4)

Abnormal opacity 37/39 (94.9)

Abnormal position 36/39 (92.3)

Otalgia 33/41 (80.5)

Redness 33/39 (84.6)

Temperature \> 98.6°C 27/40 (67.5)

**CLINICAL EFFICACY**

### 

### Table 5 FDA analysis of clinical outcome (cure) in overall PRSP populations

> 95% CI for

Population n/N (%) point estimate

FDA PP 14/34 (41.2) (24.6-59.3)

FDA PP plus patients withdrawn for AEs\* 14/37 (37.8) (22.5-55.2)

ITT (missing excluded) 15/38 (39.5) (24.0-56.6)

ITT (missing counted as failures) 15/41 (36.6) (22.1-53.1)

PP= per protocol

\*Three patients withdrawn for AEs are included

The clinical response rate in the FDA per protocol analysis was lower
than that in the sponsor's analysis, because of the 4 additional
clinical failures included by the reviewer.

### Table 6 FDA analysis of clinical outcome (cure) in PRSP populations, by penicillin MIC

> Pen MIC=2μg/mL Pen MIC=4μg/mL

Population n/N n/N

FDA PP 9/20 (45.0) 5/14 (35.7)

FDA PP plus patients withdrawn for AEs\* 9/21 (42.9) 5/16 (31.3)

ITT (missing excluded) 9/21 (42.9) 6/17 (35.3)

ITT (missing counted as failures) 9/23 (39.1) 6/18 (33.3)

PP= per protocol

\*Three patients withdrawn for AEs are included

Clinical response rates in patients with *S. pneumoniae* with penicillin
MIC=4μg/mL were lower than those for patients with MIC=2μg/mL.

**BACTERIOLOGICAL EFFICACY-ON THERAPY**

Table 7 Day 4-6 on therapy bacteriologic success rates for *S.
pneumoniae* populations

Population ITT PP

n/N (%) n/N (%)

*S. pneumoniae* (all) 149/157 (94.3) 121/123 (98.4)

> *S. pneumoniae*

Penicillin MIC\<2μg/mL 103/109 (94.5) 84/84 (100)

*S. pneumoniae*

Penicillin MIC[\>]{.underline}2μg/mL 38/41 (92.7) 31/33 (93.9)

*S. pneumoniae*

Penicillin MIC=2μg/mL 22/23 (95.7) 19/19 (100)

*S. pneumoniae*

Penicillin MIC=4μg/mL 16/18 (88.9) 12/14 (85.7)

\*7 patients without penicillin MICs at baseline were excluded from the
analysis for the penicillin susceptible and penicillin resistant
populations.

##### BACTERIOLOGIC EFFICACY AT TOC

Bacteriologic eradication rates at the test of cure visit were presumed
from the clinical outcome at the test of cure (as seen in tables 5 and
6).

Two patients with penicillin resistant *S. pneumoniae* (penicillin
MIC=2μg/mL) and *H. influenzae* isolates at baseline had repeat
tympanocentesis at the time they were declared clinical failures. The
repeat tympanocentesis documented eradication of the penicillin
resistant *S. pneumoniae* and persistence of *H. influenzae*.

Although these patients remained clinical failures at the test of cure
assessment for the PRSP population, their bacteriologic outcome for PRSP
at the test of cure visit is that of bacteriologic eradication. As a
result, the presumed bacteriologic eradication rates in the overall PRSP
population at TOC changed from 36.6% to 41.5% in the ITT population and
from 41.2% to 47.1% in the per protocol population. Since both patients
had PRSP with penicillin MIC= 2μg/mL at baseline, only these results are
affected ( See table 8).

### Table 8 Presumed PRSP bacteriologic outcome at TOC 

  ------------------ --------------------------- ----------------- -----------------
                     Pen                         Pen MIC=2μg/mL    Pen MIC= 4μg/mL
                     MIC[\>]{.underline}2μg/mL                     

  Population         n/N (%)                     n/N (%)           n/N (%)

  FDA PP             16/34 (47.1)                11/20 (55.0)      5/14 (35.7)

  ITT (missing       17/41 (41.5)                11/23 (47.8)      6/18 (33.3)
  counted as                                                       
  failures)                                                        
  ------------------ --------------------------- ----------------- -----------------

### 

## Safety 

The following 3 tables summarize the safety results from third trial,
study 536. Of adverse events of the gastrointestinal system, diarrhea
was the most common reason for withdrawal of patients from the study.

  -------------------------------------- ----------------- ---------------
  **Table 9 Number (%) of Patients                         
  Reporting Adverse Experiences Leading                    
  to**                                                     

  **Withdrawal**                                           

                                         ***Augmentin*     
                                         ES**              

                                         **N=521**         

  **AE by Body System/Preferred Term**   **N**             **(%)**

  **Patients With At Least One AE**                        

  **Leading To Withdrawal\***            25                (4.8)

  **Gastrointestinal System**            18                (3.5)

  Diarrhea                               15                (2.9)

  Vomiting                               7                 (1.3)

  Abdominal Pain                         1                 (0.2)

  Melena                                 1                 (0.2)

  **Skin and Appendages**                4                 (0.8)

  Rash                                   2                 (0.4)

  Maculo-Papular Rash                    1                 (0.2)

  Urticaria                              1                 (0.2)

  Application Site                       2                 (0.4)

  Contact Dermatitis                     2                 (0.4)

  **Resistance Mechanism**               2                 (0.4)

  Infection                              1                 (0.2)

  Otitis Media                           1                 (0.2)

  **Body As A Whole**                    1                 (0.2)

  Fever                                  1                 (0.2)

  \*The number of patients within a body                   
  system are not additive since a                          
  patient can have more than one                           

  Withdrawal reason within a Body System                   
  -------------------------------------- ----------------- ---------------

Protocol defined diarrhea was reported by the applicant in 65 patients.
Five more patients who met the protocol definition of diarrhea were
identified and have been accounted for in table 10.

  --------------------------- ----------------- -----------------------------------
  **Table 10 Number (%) of                      
  Patients with                                 
  Protocol-Defined Diarrhea\*                   
  (PDD)**                                       

                              ***Augmentin***   **ES**

                              **N=521**         

                              **N**             **(%)**

  Patients with PDD                             

  Yes                         70                (13.4)

  No                          451               (86.6)
  --------------------------- ----------------- -----------------------------------

\*3 or more watery stools in a day, 2 watery stools on 2 consecutive
days or reported an adverse event of 'diarrhea'

  ---------------------------------------- ---------------- --------------
  **Table 11 Most Frequently Occurring                      
  (\>1% of Patients) Adverse Experiences--                  
  ITT Population**                                          

                                           ***Augmentin*    
                                           ES**             

                                           **N=521**        

  **Adverse Experience by Preferred Term** **N**            **(%)**

  Patients Reporting At Least One AE       193              (37.0)

  Vomiting                                 36               (6.9)

  Contact Dermatitis\*                     32               (6.1)

  Fever                                    32               (6.1)

  Otitis Media\*\*                         23               (4.4)

  Upper Respiratory Tract Infection        21               (4.0)

  Diarrhea                                 20               (3.8)

  Rhinitis                                 15               (2.9)

  Earache                                  1                (0.2)

  Rash                                     13               (2.5)

  Coughing                                 12               (2.3)

  Asthma                                   8                (1.5)

  Moniliasis                               8                (1.5)

  Nervousness                              7                (1.3)

  Conjunctivitis                           6                (1.2)

  Toothache                                6                (1.2)

  \* Consisted of reports of diaper rash                    

  \*\* Includes recurrence of otitis media                  
  between EOT and TOC for patients with                     
  baseline pathogen and recurrence                          

  or persistence of otitis media at final                   
  safety assessment for patients with no                    
  baseline pathogen; therefore, otitis                      

  media is not considered to be a                           
  potential side-effect of treatment with                   
  *Augmentin* ES.                                           

                                                            
  ---------------------------------------- ---------------- --------------

**Table 12 Safety Update from Studies with Augmentin ES**

Study No. enrolled withdrawn withdrawn serious AE

> for AE for diarrhea

### 536 149 11(7.3) 5 (3.4) 6 (4.0) 

### 541 56 5 (8.9) 4 (7.1) 0

### 555 \~100 2 (2.0) 2 (2.0) 3 (3.0)

### 574 8 0 0 0 

### Total \~313 18 (5.6) 11 (3.5) 9 (2.9)

## SUMMARY

SmithKline Beecham submitted 3 pivotal trials, a PK/PD study, a clinical
only trial, and a clinical/microbiology study, to support a claim of
efficacy of Augmentin ES for the treatment of AOM due to penicillin
resistant *S. pneumoniae.*

Since bacteriologic data were lacking, results from the clinical only
trial were not specific for the efficacy of Augmentin 14:1 for the
treatment of AOM due to PRSP.

Results from the clinical/microbiologic study were relied on for an
evaluation of the clinical and bacteriologic efficacy of Augmentin ES
for the treatment of AOM due to PRSP. Based on the FDA analysis, the
clinical cure rate in patients with AOM due to

PRSP at the TOC visit was 41.2% (95% CI of the point estimate:
24.6-59.3%). Patients with penicillin MIC=4μg/mL had worse clinical
outcomes at TOC than those with penicillin MIC= 2μg/mL. The results of
the bacteriologic outcome at the on therapy visit were consistently
better than those for the clinical outcome at the test of cure visit.
Penicillin resistant *S. pneumoniae* isolated at baseline was absent
from the culture at the on therapy visit in 93.9% of patients in the per
protocol population, but fewer than half of the patients were clinical
cures at the TOC visit (41.2%).

Without a comparative arm, or knowledge of the natural course of AOM due
to penicillin resistant *S. pneumoniae* in pediatric patients, it is
difficult to make a clear assessment of the study results for the
treatment of AOM due to penicillin resistant *S. pneumoniae.*

The Committee will be asked to discuss reasons for the differences
observed in the bacteriologic outcomes on therapy (day 4-6) and the
clinical cure rates at the TOC visit (day 25-28) in the population
enriched with young children and patients with recurrent disease.
Additional questions will be provided.

# CLINICAL PHARMACOLOGY 

## SUMMARY OF RELEVANT HUMAN PHARMACOKINETICS/PHARMACODYNAMICS DATA

The applicant referenced two pediatric pharmacokinetics studies to
support NDA 50-755 for Augmentin^®^ ES (amoxicillin/clavulanate
potassium) 14:1 suspension. Study 25000/382 was conducted with five
subjects aged one month to 12 years. The study was designed to evaluate
the steady state pharmacokinetics of amoxicillin and clavulanate
following oral administration of Augmentin^®^ 45/6.4 mg/Kg/day in
divided doses q12h for a total of 10 days. Blood samples were obtained
at pre-dose, hourly up to eight hours, and at 12 hours. Plasma
amoxicillin concentrations were measured, and then doubled to estimate
amoxicillin concentrations following the amoxicillin/clavulanate
potassium dose 90/6.4 mg/Kg/day in divided doses q12h. Following this
procedure the estimated amoxicillin concentrations were 18 mcg/mL, 20
mcg/mL, and 12 mcg/mL at 1, 2, and 3 hours post-dose, respectively. The
time above the minimum inhibitory concentration (T\>MIC) values were
calculated from the full estimated amoxicillin concentration-time
profiles. Using this approach the applicant reported a mean T\>MIC of
approximately 41% of the dosing interval for an amoxicillin MIC of 4
mcg/mL.

Study 25000/446 was conducted to determine the middle ear fluid (MEF)
and plasma concentrations of amoxicillin at 1, 2 and 3 hours after
administration of a single oral dose of Augmentin^®^ 45/3.2 mg/Kg to
patients being treated for acute otitis media. One MEF sample and one
blood sample was obtained from each of 17 patients aged three months to
12 years who completed the study. Each patient was selected to have an
MEF and blood sample taken at 1, 2, or 3 hours post--dose. Table 1 below
summarizes the amoxicllin concentrations.

+-------------+-----------+-------------+-------------+-------------+
| **Time,     | **No.     | **Plasma**  | **MEF**     | **M         |
| hour**      | P         |             |             | EF/Plasma** |
|             | atients** | µg/mL       | µg/mL       |             |
+-------------+-----------+-------------+-------------+-------------+
| 1           | 5         | 7.7         | 5.0         | 0.8         |
|             |           |             |             |             |
|             |           | (1.5-14.0)  | (1.0-9.8)   | (0.4-1.7)   |
+-------------+-----------+-------------+-------------+-------------+
| 2           | 7         | 15.7        | 5.2         | 0.3         |
|             |           |             |             |             |
|             |           | (11.0-25.0) | (2.4-10.0)  | (0.2-0.5)   |
+-------------+-----------+-------------+-------------+-------------+
| 3           | 5         | 13.0        | 6.4         | 0.6         |
|             |           |             |             |             |
|             |           | (5.5-21.0)  | (4.4-8.3)   | (0.3-0.8)   |
+-------------+-----------+-------------+-------------+-------------+

**Table 1.** Study 25000/446 - Mean (Range) amoxicillin concentration in
plasma and middle ear fluid (MEF) and the mean ratio of MEF to plasma
(Range).

The applicant used mean plasma amoxicillin concentrations to predict the
rest of the 0-hour to 12-hour plasma amoxicillin concentration-time
profile by assuming 1.2 hours (estimate from Study 25000/382) for the
amoxicllin elimination half-life. The left panel of Figure 1 displays
measured concentrations, mean concentrations, and predicted mean
concentrations, as well as illustrates how the applicant determined
T\>MIC (4 mcg/mL) to be approximately 38% of the 12-hour dosing
interval.

The right panel of Figure 1 shows the measured MEF amoxicillin
concentrations and mean concentrations. No attempt was made to predict
mean MEF amoxicillin concentrations beyond the sampling times and
estimate T\>MIC in MEF.

![](media/image1.png){width="5.58125in" height="4.177777777777778in"}

**Figure 1. Left Panel** -- Individual plasma amoxicillin concentrations
obtained from 17 children aged 3 months to 12 years with acute otitis
media (Study 25000/446) and receiving 90/6.4 mg/Kg/day of amoxicillin
and clavulanate in divided doses q12h. In addition, the plot displays
mean plasma amoxicillin concentrations and predicted mean
concentrations. The plot also illustrates time above MIC (T\>MIC) for 4
mcg/mL of approximately 38% of the 12-hour dosing interval. **Right
Panel** -- Individual and mean middle ear fluid amoxicillin
concentrations obtained from the same children.

## CONCLUSIONS

The difference between mean amoxicillin concentrations in Study
25000/446 and the predicted mean amoxicillin concentrations in Study
25000/382 shows that the predicted concentrations are overestimated.
Therefore, the mean T\>MIC of 41% of the dosing interval is an
overestimate.

The mean plasma amoxicillin concentration-time profile in Study
25000/446 is the result of a combination of mean plasma concentrations
determined from the study and predicted concentrations based on the
estimated half-life of 1.2 hours from Study 25000/382. The estimate for
T\>MIC of 38% of the dosing interval is a single value based on the
composite concentration-time profile. No estimate of variation was
provided for predicted mean amoxicillin concentrations. Consequently, no
assessment of variation was provided for the estimated T\>MIC value.
Therefore, the significance of the T\>MIC estimate is unclear.

The MEF amoxicillin concentration-time profile and T\>MIC cannot be
determined from Study 25000/446.

# MICROBIOLOGY

The focus of this section of the briefing document concerns Sponsor's
proposal for new in vitro susceptibility interpretive criteria for
Augmentin ES (14:1) and Augmentin (7:1). In vitro susceptibility testing
is performed to assess the potential efficacy of an antimicrobial in the
treatment of a pathogen isolated from a specified site of infection.
Association of established susceptibility breakpoints with clinical
outcome is critical in that the value selected usually predicts a
successful clinical outcome in the majority of cases.

**The sponsor proposes the following interpretive criteria for in vitro
susceptibility testing of *S. pneumoniae* against Augmentin^®^** ES.

  ------------------------------- ---------------------------------------
  [MIC (µg/mL)]{.underline}       [Interpretation]{.underline}

  [\<]{.underline} 4/2            Susceptible (S)

  [\>]{.underline} 8/4            Resistant (R)
  ------------------------------- ---------------------------------------

In order to establish appropriate breakpoints, the sponsor has submitted
the following preclinical and clinical data:

1.  In vitro antimicrobial activity and MIC frequency distribution of
    Augmentin^®^ versus *S. pneumoniae*. These data help describe the
    relationship between isolates from surveillance data versus isolates
    obtained from clinical trial. The data also identify the less
    susceptible *S. pneumoniae* population.

2.  Pharmacokinetic and pharmacodynamic studies that describe serum
    concentration of Augmentin^®^ and Augmentin^®^ ES during the dosing
    interval and the relationship of these values to the susceptibility
    pattern of *S. pneumoniae.*

3.  In vivo animal study to determine the efficacy of Augmentin^®^ ES in
    experimental respiratory tract infections caused by *S. pneumoniae*.

4.  Clinical efficacy data using Augmentin^®^ ES in an open-label study
    that describe the association of the MIC of the pathogen isolated
    during the clinical investigation with clinical outcome of the
    patient at the test of cure. These data should help further describe
    the predictive value of the proposed breakpoints.

## In Vitro Activity

**In vitro activity against *S. pneumoniae***

The in vitro susceptibility data presented in the sponsor's submission
are generated from the Alexander Project 1997 -- 1998, the International
Surveillance Study (ISS); the Clinical Microbiology Institute (CMI), and
the Consultants in Anti-Infectives Surveillance and Testing (CAST). In
this briefing package only the data for *S. pneumoniae* are presented.

One of the currently marketed Augmentin formulations contains amox/clav
at a ratio of 7:1. Based on pharmacokinetic/pharmacodynamic, in vitro,
in vivo and clinical data, a request by the sponsor for susceptibility
breakpoint of ≤ 2 μg/mL is currently pending with the Agency. Thus, for
the purposes of comparison, the in vitro data in this briefing package
are presented using both the breakpoints of ≤ 2 μg/mL (for the 7:1
ratio), and the ≤ 4 μg/mL breakpoints (for the 14:1 ratio).

Table 1 demonstrates the activity of amoxicillin/clavulanic acid
(amox/clav) against penicillin-susceptible, intermediate and resistant
isolates of *S. pneumoniae.* Using ≤ 2.0 μg/mL as susceptible breakpoint
for amox/clav, the percentage of penicillin-resistant isolates that
would be categorized as susceptible to amox/clav ranges from 65% to 80%
depending on the data set used. Using the proposed breakpoint for the
14:1 formulation (≤ 4.0 μg/mL), the percentage of penicillin-resistant
isolates that would be categorized as susceptible to amox/clav ranges
from 80% - 96%.

**Frequency distribution of *S. pneumoniae***

Frequency distribution histograms (Figures 1-4) showing the percentage
and number of isolates by MIC are generated from the Alexander Project
1997-1998 and the International Surveillance Study. The amox/clav MICs
are expressed in terms of the amoxicillin component. A vertical line in
each histogram indicates the sponsor-proposed susceptibility breakpoint
of 4.0 μg/mL. Similar histograms for penicillin MIC against *S.
pneumoniae* (not shone here) demonstrate that amoxicillin and penicillin
MICs are basically similar and only vary by one tube dilution. Of
special importance is the population with amoxicillin MICs of
[\>]{.underline} 2.0 μg/mL (the breakpoint for penicillin resistance).
Figures 1-4 demonstrate that the MIC distributions are very similar in
both studies for the US and the global isolates. Of note is that bimodal
population distribution is separated by the 0.5 μg/mL MIC (the currently
FDA-approved susceptible MIC breakpoint for both amoxicillin and
amox/clav).

**Table 1:** Activity of amox/clava against *S. pneumoniae* isolated in
the US categorized by penicillin susceptibility.

<table>
<colgroup>
<col style="width: 12%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 3%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4">Penicillin-Susceptible</td>
<td colspan="4">Penicillin-Intermediate</td>
<td colspan="4">Penicillin-Resistant</td>
</tr>
<tr class="even">
<td></td>
<td>N</td>
<td><p>Amx/Cla</p>
<p>MIC<sub>90</sub></p></td>
<td>%Susc. @ ≤ 2 μg/mL<sup>a</sup></td>
<td>%Susc. @ ≤ 4 μg/mL<strong><sup>b</sup></strong></td>
<td>N</td>
<td><p>Amx/Cla</p>
<p>MIC<sub>90</sub></p></td>
<td>%Susc. @ ≤2 μg/mL<sup>a</sup></td>
<td>%Susc. @ ≤4 μg/mL<strong><sup>b</sup></strong></td>
<td>N</td>
<td><p>Amx/Cla</p>
<p>MIC<sub>90</sub></p></td>
<td>%Susc. @ ≤2 μg/mL<sup>a</sup></td>
<td>%Susc. @ ≤4 μg/mL<strong><sup>b</sup></strong></td>
</tr>
<tr class="odd">
<td>Alexander 1997</td>
<td>82</td>
<td>0.03</td>
<td>100</td>
<td>100</td>
<td>19</td>
<td>1</td>
<td>100</td>
<td>100</td>
<td>23</td>
<td>4</td>
<td>65.2</td>
<td>95.7</td>
</tr>
<tr class="even">
<td>CAST</td>
<td>354</td>
<td>≤0.25</td>
<td>100</td>
<td>100</td>
<td>87</td>
<td>1</td>
<td>100</td>
<td>100</td>
<td>111</td>
<td>4</td>
<td>80.2</td>
<td>92.8</td>
</tr>
<tr class="odd">
<td>Alexander 1998</td>
<td>787</td>
<td>0.03</td>
<td>100</td>
<td>100</td>
<td>217</td>
<td>1</td>
<td>100</td>
<td>100</td>
<td>452</td>
<td>8</td>
<td>64.6</td>
<td>79.9</td>
</tr>
<tr class="even">
<td>International surveillance study</td>
<td>186</td>
<td>0.03</td>
<td>100</td>
<td>100</td>
<td>65</td>
<td>1</td>
<td>100</td>
<td>100</td>
<td>96</td>
<td>8</td>
<td>79.2</td>
<td>86.5</td>
</tr>
</tbody>
</table>

^a^ Susceptible at ≤ 2/1 μg/mL for amox/clav, tested as a 2:1 ratio

^b^ Susceptible at ≤ 4/2 μg/mL for amox/clav, tested as a 2:1 ratio

**Figure 1.** Frequency distribution of amox/clav MICs for *S.
pneumoniae* from the Alexander Project 1997-1998 - US (N=1,580)

![](media/image2.wmf)

**Figure 2.** Frequency distribution of amox/clav MICs for *S.
pneumoniae* from the Alexander Project 1997-1998 - all geographic
regions (N=6,048)

![](media/image3.wmf){width="6.403472222222222in"
height="3.8979166666666667in"}

**Figure 3.** Frequency distribution of amox/clav MICs for *S.
pneumoniae* from the International Surveillance Study - US (N=347)

![](media/image4.wmf){width="6.403472222222222in"
height="3.2777777777777777in"}

Figure 4. **Frequency distribution of amox/clav MICs for *S. pneumoniae*
from the International Surveillance Study - all geographic regions
(N=2,672)**

![](media/image5.wmf){width="6.298611111111111in"
height="3.6569444444444446in"}

## Pharmacokinetic and Pharmacodynamic Studies

**Animal Studies**

The efficacy of amoxicillin and amox/clav was compared in a neutropenic
murine thigh infection model using strains of *S. pneumoniae* of
differing susceptibilities to the study drugs. A correlation between
therapeutic efficacy and the duration of time that serum levels of
amoxicillin exceeded the MIC was described. Acceptable efficacy was
observed if levels exceeded the MIC for at least 30% of the dosing
interval.

In a separate study, a neutropenic mouse pneumonia model was also used
to assess the activity of amoxicillin against six strains of *S.
pneumoniae* with MICs ranging from 0.01 to 4.0 μg/mL. In this study,
when time above MIC (T\>MIC) exceeded 40%, the decrease in bacterial
numbers was maximal (≥4 log10 cfu) and efficacy correlated directly with
T\>MIC, irrespective of the dosing interval. However, there was no
significant decrease in bacterial numbers at T\>MIC of 25% or less of
the dosing period.

Both these studies indicate that **in animals,** the pharmacodynamic
parameter correlating with favorable outcome is the percent of time
during the dosing interval that the amox/clav concentration remains
above the MIC of the infecting organism.

**Human Studies**

The applicant submitted two pharmacokinetic studies in pediatric
subjects. It is of importance to note that the mean T\>MIC value
described below for study 25000/382 **is based upon extrapolated plasma
concentrations.** The applicant believes that this extrapolation is
reasonable given that the pharmacokinetics of amoxicillin are linear.

**Study 25000/382** was designed to evaluate the steady state
pharmacokinetic profiles of amoxicillin and clavulanate in children aged
one month to 12 years after receiving *Augmentin* 45/6.4 mg/kg/day (7:1
ratio) in divided doses q12h, or 40/10 mg/kg/day (4:1 ratio) in divided
doses q8h for a total of 10 days. In the study, **five subjects** were
administered *Augmentin* at **45/6.4 mg/kg/day in divided doses q12h**.
On the pharmacokinetic assessment day (no earlier than 48 hours after
therapy was begun, and no later than nine days after start of therapy),
blood samples were drawn at pre-dose, hourly up to eight hours, and at
12 h after the dose. In order to estimate the pharmacokinetics and
T\>MIC of amoxicillin that might be achieved had the subjects given
45/6.4 mg/kg/day q12h actually received double the amoxicillin dose,
i.e. 90/6.4 mg/kg/day in divided doses q 12h, their individual plasma
concentration-time data were doubled on the basis of the known
pharmacokinetic linearity of amoxicillin. The extrapolated mean data is
presented in Figure 5. The corresponding T\>MIC values were then
calculated from the new **extrapolated** individual plasma concentration
vs. time profiles. Using this approach, it is **estimated** that a dose
of 90 mg/kg/day q12h may result in a **T\>MIC of approximately 41% (4.9
h/ 12 h) of a dosing interval, when an amoxicillin MIC of 4 μg/mL is
used in the calculation.** This is within the T\>MIC range of 30% or
more that was reported for observed killing of penicillin-intermediate
and penicillin-resistant *S. pneumoniae*.

**Figure 5.** **Extrapolated** mean plasma concentration vs. time
profile of amoxicillin in children receiving 90/6.4 mg/kg/day of
amoxicillin/clavulanate in divided doses q12h, derived from the mean
plasma concentration profile of amoxicillin obtained in 5 children
receiving 45/6.4 mg/kg/day of amoxicillin/clavulanate in divided doses
q12h

![](media/image6.wmf){width="6.197916666666667in"
height="4.272222222222222in"}

In the second pediatric PK/PD study, **25000/446**, **17 subjects** 3
months to 12 years of age, diagnosed with acute otitis media, were
administered Augmentin **90/6.4 mg/kg/day in divided doses q12h** **for
10 days.** Included in this study, was the collection of a single blood
specimen from each child for determination of amoxicillin concentration
at one, two or three hours after dosing. The plasma concentration versus
time profiles did not extend beyond 3 hours. Plasma concentrations of
amoxicillin appeared to peak at 2 hours. From these data, it is possible
to predict by **extrapolation** the rest of the profile **by assuming**
an amoxicillin elimination half-life of 1.2 h (the mean value obtained
in study 25000/382). This is illustrated with mean data in Figure 6.
Using this approach, the **T\>MIC for an amoxicillin MIC of 4 μg/mL is
approximately 38% (4.7 h/12 h)**.

**Figure 6.** Mean plasma concentration vs. time profile of amoxicillin
in 19 children receiving 90/6.4 mg/kg/day of amoxicillin/clavulanate in
divided doses q12h

![](media/image7.wmf){width="6.4in" height="3.8222222222222224in"}

\* = Actual data; later points are extrapolated assuming a T~1/2~ of 1.2
h

## Efficacy Studies in Animal Models of Infection

Efficacy of the proposed 14:1 dose of amox/clav (90 /6.4 mg/kg/day, in
two divided doses q12h) against experimental respiratory tract
infections (RTI) caused by *S. pneumoniae* exhibiting decreased
susceptibility to amoxicillin was investigated. Amox/clav was
administered to simulate concentrations obtained in pediatric patients
following administration of either 22.5/3.2 mg/kg amox/clav (7:1) bid or
45/3.2 mg/kg amox/clav (14:1) bid. Amox/clav at both dosing regimens
**reduced** the number of viable bacteria in the lungs of animals
infected with strain N1387 (amoxicillin **MIC = 2.0 μg/mL**)
significantly (p\<0.01) compared with control animals (Table 2).
However, amox/clav, at either dose, **did not reduce** the number of the
viable bacteria in the lungs of animals infected with strain RS1
(amoxicillin **MIC = 8.0 μg/mL**) compared with control animals.
Finally, the 45/3.2 mg/kg dose was more effective than the lower dose
(22.5/3.2 mg/kg) against *S.* *pneumoniae* strains with an amoxicillin
MIC = 4.0 μg/mL (p\<0.01).

**Table 2. Activity of amox/clav (14:1 dose) against
penicillin-resistant *S.* *pneumoniae* in the rat RTI model**

+-------+-----------------+------------+---------------+-------------+
|       |                 | **log10    |               |             |
|       |                 | c          |               |             |
|       |                 | fu/lungs** |               |             |
+-------+-----------------+------------+---------------+-------------+
| **Str | **Amoxicillin** | **Non      | **            | **Am        |
| ain** |                 | -treated** | Amox./Clav.** | ox./Clav.** |
|       | **MIC**         |            |               |             |
|       |                 | *          | **(22.5/3.2   | **(45/3.2   |
|       | **(μg/mL)**     | *Control** | mg/kg)**      | mg/kg)**    |
|       |                 |            |               |             |
|       |                 | **(NTC)**  | **(bid)**     | **(bid)**   |
+-------+-----------------+------------+---------------+-------------+
| N1387 | 2               | 6.97±0.30  | 4.37±0.93\*   | 2.          |
|       |                 |            |               | 62±0.85\*\* |
+-------+-----------------+------------+---------------+-------------+
| 14319 | 4               | 6.80±0.62  | 6.26±0.47     | 4.          |
|       |                 |            |               | 28±0.82\*\* |
+-------+-----------------+------------+---------------+-------------+
| 4     | 4               | 7.11±0.45  | 6.14±0.6\*    | 3.          |
| 10101 |                 |            |               | 91±0.81\*\* |
+-------+-----------------+------------+---------------+-------------+
| RS1   | 8               | 6.03±0.61  | 6.11±0.73     | 5.94±0.72   |
+-------+-----------------+------------+---------------+-------------+

\*Significantly different from NTC (p\<0.01)

\*\*Significantly different from NTC and amoxicillin (22.5 mg/kg;
p\<0.01)

## Efficacy Studies in Humans

The efficacy of Augmentin ES (amox/clav 14:1) in the treatment of
resistant pathogens in AOM centers on a pediatric study 25000/536,
titled: \"An open-label study to demonstrate bacteriologic efficacy of
Augmentin ES in the treatment of AOM due to *S. pneumoniae*.\" The
purpose of this study was to enroll pediatric patients, 3 to 48 months
of age, with AOM due to PRSP and amox/clav MICs of 4.0 μg/mL, and to
demonstrate efficacy and safety of amox/clav at doses of 90/6.4
mg/kg/day.

Tympanocentesis was performed at baseline and repeated at the on-therapy
visit (day 4-6) in patients from whom *S. pneumoniae* had been isolated,
and also in clinical failures, regardless of the initial pathogen
isolated. Additionally, a few investigators repeated tympanocentesis in
all enrollees (who grew a pathogen on initial tympanocentesis) at the
on-therapy visit, day 4-6.

Patients were monitored clinically with an on-therapy visit (day 4-6),
returned for an end-of-treatment visit (day 12-15), and at the
test-of-cure visit (day 25-28). An interim visit was mandated within 24
hours for all patients who contacted the study site to report lack of
clinical improvement or clinical worsening.

> A total of 521 patients were randomized and received at least one dose
> of Augmentin ES. Of the 521 patients, 359 (69%) had a bacterial
> pathogen identified on initial tympanocentesis. Of 157 *S. pneumoniae*
> isolated at initial tympanocentesis, 41 (26%) were resistant to
> penicillin, with MIC of ≥ 2.0 μg/mL, while a total of 9 isolates had
> an amox/clav MIC of ≥ 4.0 μg/mL.
>
> The *S. pneumoniae* and bacteriological response (Table 3) listed by
> MIC to amox/clav follows:

**Table 3.** **Bacteriological Response** by Baseline *S. pneumoniae*
Susceptibility to amox/clav (**PP** and **ITT** Bacteriology
*S. pneumoniae* Alone or With Other Pathogens Population) -
**On-Therapy**

  ----------------------------- ----------------- --------- ------------- -----------
                                **Augmentin ES**                          

                                **PP                                      
                                Bacteriological                           
                                Population**                              

                                **Success**                 **Failure**   

  **Bacteriological Response**  **n/N**           **(%)**   **n/N**       **(%)**

  *S. pneumoniae* alone or with                                           
  other pathogens\                                                        
  amox/clav MIC (μg/mL)                                                   

  0.016\*                       2/2               (100.0)   0             

  0.03 \*\*                     62/62             (100.0)   0             

  0.06                          8/8               (100.0)   0             

  0.12                          4/4               (100.0)   0             

  0.25                          10/10             (100.0)   0             

  0.5                           2/2               (100.0)   0             

  1                             3/3               (100.0)   0             

  2                             22/23             (95.7)    1/23          (4.3)

  4                             3/3               (100.0)   0             

  8                             3/4               (75.0)    1/4           (25.0)

                                **ITT                                     
                                Bacteriological                           
                                Population**                              

                                **Success**                 **Failure**   

  **Bacteriological Response**  **n/N**           **(%)**   **n/N**       **(%)**

  *S. pneumoniae* alone or with                                           
  other pathogens\                                                        
  amox/clav MIC (μg/mL)                                                   

  0.016\*                       2/2               (100.0)   0             

  0.03\*\*                      76/80             (95.0)    4/80          (5.0)

  0.06                          11/12             (91.7)    1/12          (8.3)

  0.12                          5/5               (100.0)   0             

  0.25                          12/13             (92.3)    1/13          (7.7)

  0.5                           2/2               (100.0)   0             

  1                             3/3               (100.0)   0             

  2                             27/29             (93.1)    2/29          (6.9)

  4                             3/3               (100.0)   0             

  8                             5/6               (83.3)    1/6           (16.7)
  ----------------------------- ----------------- --------- ------------- -----------

> \* Includes MICs reported as 0.016 and 0.023
>
> \*\* Includes MICs reported as 0.03 and 0.032
>
> **Note:** 7 patients have missing penicillin and/or amox/clav MICs.
> They are counted as missing when displayed by MIC and are not part of
> the pen [\>]{.underline} 2 or \< 2 populations nor the amox/clav \< 4,
> = 4, \> 4 populations.
>
> The bacteriological response **on therapy** in Table 3 show that
> Augmentin ES had high eradication rates against *S. pneumoniae* with
> amox/clav MICs [\<]{.underline} 4.0 μg/mL. Bacteriological success
> rates for Augmentin ES against *S. pneumoniae* were essentially the
> same for both the PP and ITT populations at the on therapy visit.
>
> Tables 4 and 5 demonstrate the clinical outcome of patients at
> Test-Of-Cure (TOC), which is the efficacy end-point used by the FDA to
> assess efficacy.

**Table 4.** **Clinical Response** by Baseline *S. pneumoniae*
Susceptibility to amox/clav (**PP** Clinical Population at **Test of
Cure**)

  ------------------------------------- ------------- --------- ------------- ---------
                                        **Augmentin                           
                                        ES**                                  

                                        **PP Clinical                         
                                        Response                              
                                        TOC**                                 

                                        **Success**             **Failure**   

                                        **n/N**       **(%)**   **n/N**       **(%)**

  *S. pneumoniae* alone or with other                                         
  pathogens\                                                                  
  amox/clav MIC (μg/mL)                                                       

  0.016                                 1/1           (100.0)   0             

  0.03\*                                58/73         (79.5)    15/73         (20.5)

  0.06                                  8/11          (72.7)    3/11          (27.3)

  0.12                                  4/5           (80.0)    1/5           (20.0)

  0.25                                  7/9           (77.8)    2/9           (22.2)

  0.5                                   2/2           (100.0)   0/2           

  1                                     1/2           (50.0)    1/2           (50.0)

  2                                     14/24         (58.3)    10/24         (41.7)

  4                                     2/3           (66.7)    1/3           (33.3)

  8                                     1/5           (20.0)    4/5           (80.0)
  ------------------------------------- ------------- --------- ------------- ---------

> Note: 3 patients in this population were missing amox/clav MICs.
>
> \*Includes MICs reported as 0.03 and 0.032

**Table 5.** **Clinical Response** at Test of Cure for *S. pneumoniae*
by amox/clav MICs (**PP** Clinical Population at **Test of Cure**)

+---------------------------+-------+-----+-------+----+------+-----+
|                           | *     |     |       |    |      |     |
|                           | *Augm |     |       |    |      |     |
|                           | entin |     |       |    |      |     |
|                           | ES**  |     |       |    |      |     |
|                           |       |     |       |    |      |     |
|                           | **PP  |     |       |    |      |     |
|                           | Cli   |     |       |    |      |     |
|                           | nical |     |       |    |      |     |
|                           | Res   |     |       |    |      |     |
|                           | ponse |     |       |    |      |     |
|                           | TOC** |     |       |    |      |     |
+===========================+=======+=====+=======+====+======+=====+
|                           |       |     |       |    |      |     |
+---------------------------+-------+-----+-------+----+------+-----+
| **Clinical Response at\   | *S.   |     | *S.   |    | *S.  |     |
| Test of Cure**            | p     |     | p     |    | pne  |     |
|                           | neumo |     | neumo |    | umon |     |
|                           | niae* |     | niae* |    | iae* |     |
|                           | (     |     | with  |    | with |     |
|                           | alone |     | amox  |    | amox |     |
|                           | /with |     | [+]{. |    | [+]  |     |
|                           | other |     | under |    | {.un |     |
|                           | patho |     | line} |    | derl |     |
|                           | gens) |     | clav\ |    | ine} |     |
|                           |       |     | MICs  |    | c    |     |
|                           |       |     | [     |    | lav\ |     |
|                           |       |     | \<]{. |    | MICs |     |
|                           |       |     | under |    | \>   |     |
|                           |       |     | line} |    | 4.0  |     |
|                           |       |     | 4.0   |    | μ    |     |
|                           |       |     | μg/mL |    | g/mL |     |
+---------------------------+-------+-----+-------+----+------+-----+
|                           | **    | **  | **    | *  | **n  | **  |
|                           | n/N** | %** | n/N** | *% | /N** | %** |
|                           |       |     |       | ** |      |     |
+---------------------------+-------+-----+-------+----+------+-----+
| Success, n (%)            | 10    | (73 | 9     | (7 | 1/5  | (20 |
|                           | 1/138 | .2) | 7/130 | 4. |      | .0) |
|                           |       |     |       | 6) |      |     |
+---------------------------+-------+-----+-------+----+------+-----+
| Failure, n (%)            | 3     | (26 | 3     | (2 | 4/5  | (80 |
|                           | 7/138 | .8) | 3/130 | 5. |      | .0) |
|                           |       |     |       | 4) |      |     |
+---------------------------+-------+-----+-------+----+------+-----+

> Note: 3 patients in this population were missing amox [+]{.underline}
> clav MICs.

Of note in table 4 is that for *S. pneumoniae* isolates with amox/clav
MICs of [\<]{.underline} 2.0 μg/mL the clinical success rate is 74%
(96/130). This clinical success rate drops to 38% (3/8) for isolates
with MICs of [\>]{.underline} 4.0 μg/mL. In table 5, the clinical
success rate drops even further to 20% when the isolates have MICs of \>
4.0 μg/mL.

Finally, bacteriological versus clinical response rates for *S.
pneumoniae* are compared to evaluate whether Augmentin ES is efficacious
in treatment of AOM caused by PRSP, the primary objective of the Study
25000/536. Table 6 presents bacteriological response with clinical
response in the treatment of AOM due to PRSP and *S. pneumoniae*
isolates with amox/clav MICs of [\>]{.underline} 4 μg/mL.

**Table 6.** Bacteriological Response On-Therapy vs. Clinical Response
at Test of Cure for *S. pneumoniae* (PP Bacteriological *S. pneumoniae*
Alone or With Other Pathogens Population)

  -------------------------------------- ------------- -------- --------- ------------- -------- --------- --------
                                         **Clinical                                                        
                                         Response**                                                        

                                         **Success**                      **Failure**                      

  **Bacteriological Response**           **n**                  **(%)**   **n**                  **(%)**   

  *S. pneumoniae* alone/with other                                                                         
  pathogens, **penicillin MICs ≥                                                                           
  2.0 **μ**g/mL**                                                                                          

  Success                                16/30                  (53.3)    12/30                  (40.0)    

  Failure                                1/30                   (3.3)     0                                

  *S. pneumoniae* alone/with other                                                                         
  pathogens, **penicillin MICs \<                                                                          
  2.0 **μ**g/mL**                                                                                          

  Success                                68/84                  (81.0)    15/84                  (17.9)    

  Failure                                1/84                   (1.2)     0                                

  *S. pneumoniae* alone/with other                                                                         
  pathogens, **amox/clav MICs                                                                              
  [\<]{.underline} 2.0 μg/mL**                                                                             

  Success                                83/111        (74.8)                           26/111             (23.4)

  Failure                                2/111         (1.8)                            0                  

  *S. pneumoniae* alone/with other                                                                         
  pathogens, **amox/clav MICs =                                                                            
  4.0 μg/mL**                                                                                              

  Success                                2/3                    (66.7)    1/3                    (33.3)    

  Failure                                0                                0                                

  *S. pneumoniae* alone/with other                                                                         
  pathogens, **amox/clav MICs                                                                              
  \>4.0 μg/mL**                                                                                            

  Success                                1/3                    (33.3)    1/3                    (33.3)    

  Failure                                0                                1/3                    (33.3)    
  -------------------------------------- ------------- -------- --------- ------------- -------- --------- --------

The data presented in Table 6 indicate that the success rate for
treatment of AOM due to PRSP at TOC is 53%. The corresponding rate for
PSSP, however, is much higher at 81 %. For PRSP, the rate of clinical
failures at the TOC (40.0%, Table 6), is in sharp contrast to the
bacteriological response on therapy.

The data presented in Tables 6 are limited for evaluation of patients
who had *S. pneumoniae* with amox/clav MICs of [\>]{.underline} 4.0
μg/mL because there are only six patients/isolates at the TOC.
Nevertheless, the same trend as for PRSP is observed since the clinical
and microbiological success rate is at 50% (3/6) for these isolates. The
number of *S. pneumoniae* isolates with amox/clav MICs of
[\<]{.underline} 2.0 μg/mL is sufficient, and the efficacy rate for
treatment of AOM due to these isolates at TOC is 75%.

## Discussions on Breakpoint Determination

The susceptible breakpoint for in vitro susceptibility testing is
established using all the previously noted information so that
predictions of treatment success could be made with high degree of
assurance (\>80%) for the use of a given antimicrobial agent in a
clinical setting.

The MIC~90~ for PISP isolates against amox/clav is 1.0 μg/mL (Table 1).
This means that if a susceptible breakpoint of [\<]{.underline} 1.0
μg/mL is established for amox/clav, all the PSSP and PISP isolates would
be categorized as susceptible to amox/clav. The available clinical data
at TOC indicates that if patients with such isolates are treated with
amox/clav, the clinical success rate is 79% (Table 4).

Depending on the study (Table 1), the PRSP (MIC [\>]{.underline}2.0
μg/mL) isolates have MIC~90~s of 4.0-8.0 μg/mL against amox/clav. If one
establishes a susceptible breakpoint of [\<]{.underline} 2.0 μg/mL for
amox/clav then 65% to 80% (Table 1) of the PRSP isolated would be
categorized as amox/clav susceptible. The clinical data indicate that
clinical success rate is only 58% (Table 4) for patients with *S.
pneumoniae* isolates that have MICs of 2.0 μg/mL. However, if one
combines the clinical data to include any isolate that has MICs of
[\<]{.underline} 2.0 μg/mL the clinical success rate is 75% (Table 4).

Finally, if one establishes a susceptible breakpoint of [\<]{.underline}
4.0 μg/mL for amox/clav, 80 % to 96% (Table 1) of the PRSP isolated
would be categorized as amox/clav susceptible. The clinical data at TOC
contains only three patients with isolates having MICs of 4.0 μg/mL. The
clinical success rate for these patients is 67%. If one would combine
the clinical data to include all the isolates that have MICs of
[\<]{.underline} 4.0 μg/mL the clinical success rate would be 75% (Table
4).

The frequency distribution histograms for the US and global clinical
isolates recovered from clinical study 536 (Figures 7 & 8) are very
similar to the frequency distribution histograms from the in vitro
studies presented in Figures 1-4 earlier in this document. The two *S.
pneumoniae* populations in the bimodal distribution seem to be separated
by the current FDA approved breakpoint of 0.5 μg/mL for amoxicillin and
amox/clav. PRSP isolates are included in the population with MICs
[\>]{.underline} 2.0 μg/mL.

If one chooses the susceptible breakpoint for amox/clav at MIC of 1.0
μg/mL, the two populations would still be adequately separated and none
of the PRSP would be categorized as amox/clav susceptible.

If one selects the susceptible breakpoint at 2.0 μg/mL, the two
populations would no longer be distinct and some of PRSP would be
categorized as amox/clav susceptible.

Finally, if one selects the susceptible breakpoint at 4.0 μg/mL, the two
populations would be considered as one and all the PRSP isolates would
be categorized as amox/clav susceptible.

Figure 7. **Frequency distribution of amox./clav. MICs for *S.
pneumoniae* from Study 536-US (N=75)**

![](media/image8.wmf){width="5.9006944444444445in"
height="3.217361111111111in"}

Figure 8. **Frequency distribution of amox/clav MICs for *S. pneumoniae*
from Study 536 - all geographic regions (N=155)**

![](media/image9.wmf){width="5.530555555555556in" height="3.09375in"}

The pharmacodynamic studies in the neutropenic murine thigh model
suggest a relationship between therapeutic efficacy and the duration of
time that the serum levels of amoxicillin exceeded the MIC. Good
efficacy was observed if levels exceeded the MIC for at least 30% of the
dosing interval. Similar results were obtained when the neutropenic
murine pneumonia model was used. In this study, when T \> MIC exceeded
40%, the decrease in bacterial counts was maximal and efficacy
correlated directly with T \> MIC irrespective of the dosing interval.

The extrapolated results from pharmacokinetic and pharmacodynamic
studies in humans seem to indicate that Augmentin^®^ ES concentration
would remain above MIC of 4.0 μg/mL 38- 41% of the dosing interval.
Using the same extrapolated data, one is able to calculate the time
above MIC of 2.0 μg/mL to be at 50-51% of the dosing interval. One must
ask whether the pharmacodynamic hypothesis presented by the applicant
can be validated by the clinical trial.

The clinical study that would have been the proof of concept resulted in
8 patients at TOC with PRSP isolates that had amox/clav MICs of
[\>]{.underline} 4.0 μg/mL, five of whom were clinical failures,
resulting in a clinical success rate of only 38% (3/8, Table 4). If one
includes the isolates that had MICs of 2.0 μg/mL the clinical success
rate for patients with these isolates (MICs [\>]{.underline} 2.0 μg/mL)
is 53% (17/32, Table 4). This is consistent with the in vitro data where
one could predict that PRSP isolates would not be successfully treated
with amox/clav (Table 1). It is also consistent with the efficacy
studies in experimental animal respiratory tract infections where the
bacterial eradication rates decreased substantially when the MIC of the
infecting isolate was greater than 2.0 μg/mL.

The successful clinical response rate for patients with *S. pneumoniae*
isolates with amox/clav MICs of \<2 μg/mL (i.e. [\<]{.underline} 1.0
μg/mL) is 79% (81/103, Table 4). If one chooses MIC of [\<]{.underline}
1.0 μg/mL as the susceptible breakpoint for amox/clav against *S.
pneumoniae*, the in vitro susceptibility test would be able to predict a
clinical success about 80% of the time. If one chooses MIC of
[\<]{.underline} 2.0 μg/mL as the susceptible breakpoint for amox/clav
against *S. pneumoniae*, the in vitro susceptibility test would be able
to predict clinical success about 75% of the time. It general, the
susceptible breakpoints are set so that successful clinical outcome is
predicted \>80% of the time.

In summary, when one takes into consideration all the evidence provided
by the in vitro susceptibility data, the animal and human the PK/PD
data, the animal efficacy data, and the clinical outcomes from the
tympanocentesis trial, the susceptible breakpoint seems to fall on 1.0
μg/mL. At a breakpoint of 1.0 μg/mL, the T\>MIC would certainly be
closer to 60% of the dosing interval, clinical success is 79% and the
bimodal population is clearly separated. If one chooses the MIC of 1.0
μg/mL for the susceptible breakpoint, then MICs of 2.0 and 4.0 μg/mL
would be the obvious intermediate and resistant breakpoints,
respectively. If one chooses the MIC of 2.0 μg/mL for the susceptible
breakpoint then MICs of 4.0 and 8.0 μg/mL would be the obvious
intermediate and resistant breakpoints, respectively.

## References

1.  Amoxicillin/clavulanic acid in vitro activity against RTI pathogens
    from the 1997/1998 Alexander Project. C. Jakielaszek. 23 March,
    2000.

2.  Thornsberry, C., M.E. Jones, M.L.Hickey, Y. Mauriz, J. Kahn, and D.
    Sahm. 1999. Resistance surveillance of *Streptococcus pneumoniae*,
    *Haemophilus influenzae* and *Moraxella catarrhalis* isolated in the
    United States, 1997‑1998. J Antimicrob Chemother, 44, 749‑759.

3.  International surveillance study: Augmentin report. Bouchillon,
    S., S. Farooqui. 9 March, 2000.

4.  In vitro activity of gemifloxacin (SB‑265805) against contemporary
    clinical bacterial isolates from eleven North American medical
    centers, and assessment of disk test interpretive criteria. P.
    Fuchs, A. Barry and S. Brown. 24 June 1999.

5.  In vitro Activity of Penicillin, Amoxicillin and
    Amoxicillin1clavulanic acid Against Recent (1999) Clinical Isolates
    of *Streptococcus pneumoniae* from the United States: Consultants in
    Anti­Infectives Surveillance and Testing, Inc. Butler, D., and C.
    Stewart. 21 March, 2000.

6.  Jacobs, M.R., S. BaJaksouzian, A. Zilles, G. Lin, G. Pankuch and
    P.C. Appelbaum. 1998. An analysis of 1997 *Haemophilus influenzae*
    and *Streptococcus pneumoniae* MIC results utilizing
    pharmacokinctic/pharmacodynainic breakpoints. Poster 195. 36th
    Annual Meeting of the Infectious Disease Society of America, Denver,
    Colorado.

7.  Jacobs, M.R., S. Bajaksouzian, G. Lin, A. Zilles, G. Pankuch and
    P.C. Appelbaum. 1999. Susceptibility of *Streptococcus pneumoniae*,
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    agents: results of a 1998 US outpatient surveillance study.
    Poster 61. 39th Interscience Conference on Antimicrobial Agents and
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8.  A parallel group study to estimate the steady state pharmacokinetics
    of amoxicillin and clavulanate in pediatric patients in the age
    range 1 month to 12 years administered Augmentin 45/6.4 mg/kg (twice
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