A New Goldilocks Story

A Review of the CAP-IT Trial

Kendall Spicer, Pharm.D., PGY1 Pharmacy Resident
Objectives 2

• Understand the purpose of the CAP-IT trial

• Compare the differences between current guideline-directed
practices and interventions studies in the CAP-IT trial

• Analyze and correlate collected data

• Apply study findings to potential changes in clinical practice

Background 3

• 2011 IDSA guidelines for managing community-acquired pneumonia (CAP) in

children >3 months old
• Antibacterial therapy not routinely recommended for preschool-aged children
with acute respiratory disease (typically viral)
• First line: amoxicillin 90 mg/kg/day divided into 2 doses
• Alternative: Augmentin or +/- macrolide

• Duration: 10-day regimens are most studied and supported, but “shorter courses
may be just as effective”
• Per CDC recommendation, immunizations for S. pneumoniae and H. influenzae
type-b should be completed between 12 and 15 months of age
Background 4

SAFER Trial: Short-Course Antimicrobial Therapy for Pediatric

Community-Acquired Pneumonia
• Canadian, 2-center, randomized clinical trial
• Compared 5 vs. 10-day durations of high-dose amoxicillin
• Studied 281 patients and assessed clinical cure at days 14 and 21

• Results per protocol:

• 5-day therapy = 88.6% clinical cure
• 10-day therapy = 90.8% clinical cure
Study Design 5

• Purpose: determine efficacy of low-dose or shorter amoxicillin

regimens for pediatric CAP vs. high-dose or longer regimens
• Multicenter, randomized, blinded, placebo-controlled, 2x2
factorial, noninferiority trial
• Noninferiority margin: 8%

• Took place in the UK from 2017-2019

• Varied outpatient amoxicillin treatments after discharge from

emergency department, observation, and inpatient units
Sample Population 6

• Inclusion:
• Children >6 months of age
• Weighing 6-24 kg
• Amoxicillin monotherapy for CAP on discharge
• Clinical CAP:
• Reported cough within 96 hours,
• Reported or observed fever within 48 hours (38°C),
• Overt difficulty breathing
• Retractions, belly breathing, nasal flaring, crackles, focal findings, etc.
Sample Population 7

• Exclusion:
• Treatment with β-lactam for previous 48 hours or more
• Severe comorbidities/chronic illness
• Complicated pneumonia or sepsis
• Lack of focal findings for pneumonia
• Contraindication to amoxicillin

• Eligible: 2642
• Randomized: 824
• Analyzed: 814
Interventions 8

• Low-dose (LD) vs. high-dose (HD) Duration Variation

• LD = 35-50 mg/kg/day
3D 7D
• HD = 70-90 mg/kg/day
LD LD-3D LD-7D All LD

Variation
Dose
• Short course vs. long course
HD HD-3D HD-7D All HD
• Short = 3-day duration (3D)
• Long = 7-day duration (7D) All 3D All 7D

• Theoretically, consider HD-7D group to be “control”

Interventions 9

• Additional Procedure Items

• No requirement for specific radiologic/laboratory diagnostics (routine care)

• If possible, baseline nasopharyngeal swab was collected for S. pneumoniae

sampling; repeated at day 28

• Telephone follow-up at days 3, 7, 14, and 21; face-to-face at day 28

• Face-to-face follow-up if returned to the hospital

Results 10

• Primary endpoint: retreatment with antibiotics (outside the trial

protocol) for a respiratory tract infection within 28 days of
randomization
Duration Variation
• Subgroup analyses: 3D 7D
• Prior inpatient antibiotics vs. none
LD LD-3D LD-7D 12.6%

Variation
• Prior antibiotics 95% CI = 11.4 & 11.5 (both) (51/410)

Dose
• Severe vs. non-severe CAP
• Severe CAP 95% CI = 10 (dose only) HD HD-3D HD-7D 12.4%
(49/404)

12.5% 12.5%
(51/413) (49/401)
Results 11

• Secondary endpoints
• CAP severity (ordinal scale)
• Treatment-related adverse events
• Adherence to assigned regimen
• Presence of penicillin-resistant
S. pneumoniae at 28 days
Results 12

• Secondary endpoints
• CAP severity – composite Abnormal Duration Variation
Respiratory Rate 3D 7D
• Treatment-related adverse events
• Adherence to assigned regimen LD 66% 65% 65.9%

Variation
(138/208) (132/202) (270/410)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD 61% 68% 63.9%
(124/205) (134/199) (258/404)

63.4% 66.3%
(262/413) (266/401)
Results 13

• Secondary endpoints
• CAP severity – composite Abnormal Duration Variation
O2 Saturation 3D 7D
• Treatment-related adverse events
• Adherence to assigned regimen LD 3% 5% 4.4%

Variation
(7/208) (11/202) (18/410)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD 5% 7% 6.2%
(11/205) (14/199) (25/404)

4.4% 6.2%
(18/413) (25/401)
Results 14

• Secondary endpoints
• CAP severity – composite Duration Variation
Chest Retractions
• Treatment-related adverse events 3D 7D

• Adherence to assigned regimen LD 57% 60% 58.3%

Variation
(117/208) (122/202) (239/410)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD 60% 61% 60.4%
(122/205) (122/199) (244/404)

57.9% 60.8%
(239/413) (244/401)
Results 15

• Secondary endpoints
• CAP severity – composite Duration Variation
Severe CAP
• Treatment-related adverse events 3D 7D

• Adherence to assigned regimen LD LD-3D LD-7D 43.9%

Variation
(180/410)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD HD-3D HD-7D 46.5%
(188/404)

42.9% 47.6%
(177/413) (191/401)
Results 16

• Secondary endpoints
• CAP severity – composite Retreatment in Duration Variation
Severe CAP 3D 7D
• Treatment-related adverse events
• Adherence to assigned regimen LD LD-3D LD-7D 17.3%

Variation
(31/180)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD HD-3D HD-7D 13.5%
(25/188)

16% 14.8%
(28/177) (28/191)
Results
• Secondary endpoints
• CAP severity (ordinal scale)
• Treatment-related adverse events
• Adherence to assigned regimen
• Presence of penicillin-resistant
S. pneumoniae at 28 days
17
Most Common:
• Diarrhea – 345 (41-45% across groups)
• Rash – 193 (22-27% across groups)
• No deaths occurred
Results 18

• Secondary endpoints
• CAP severity (ordinal scale)
• Treatment-related adverse events
• Found significant difference between
• Adherence to assigned regimen 3D and 7D groups
• Presence of penicillin-resistant • 3D group had higher adherence rates
S. pneumoniae at 28 days
Results 19

• Secondary endpoints
• CAP severity (ordinal scale) Penicillin Duration Variation
Nonsusceptibility 3D 7D
• Treatment-related adverse events
• Adherence to assigned regimen LD 21% 16% 18%

Variation
(7/34) (5/32) (12/66)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD 23% 6% 14%
(7/31) (2/32) (9/63)
• Samples available: 437 (53.7%)
22% 11%
• With S. pneumo.: 129 (29.5%) (14/65) (7/64)
Results 20

• Secondary endpoints
• CAP severity (ordinal scale) Amoxicillin Duration Variation
Nonsusceptibility 3D 7D
• Treatment-related adverse events
• Adherence to assigned regimen LD 3% 3% 3%

Variation
(1/34) (1/32) (2/66)

Dose
• Presence of penicillin-resistant
S. pneumoniae at 28 days HD 3% 3% 3%
(1/31) (1/32) (2/63)
• Samples available: 437 (53.7%)
3% 3%
• With S. pneumo.: 129 (29.5%) (2/65) (2/64)
Study Assessment 21

• Population:
• Median age ~2.5 years old, CAP treatment not routinely recommended
• Median weight correlates appropriately
• Easily objective signs of clinical CAP
• Most participants were appropriately vaccinated
• Appropriate to not require routine radiologic/diagnostic testing, not
generally recommended in pediatrics
• No glaring differences or skews in baseline characteristics
• May have received up to 48 hours of antibiotic therapy prior to study
• Skew for duration analysis?
Study Assessment 22

• Interventions:
• Doses assigned in mL’s, not
mg’s, based on bracketed
weight
• D1-D3: same brand used with
different strengths
• D4-D7: different brand than
previously with matching
placebo
• Appropriate procedure to
disguise the duration switch
and maintain blinding
Data Assessment 23

• Sample required for 90% power: 800 patients

• Primary analysis included 814 patients
• True primary endpoint data only available for 789 patients, data
for all others included up to loss of follow-up
• No imputation performed

• Noninferiority margin: 8%, more conservative than IDSA

recommendation of 10%
Data Assessment 24

• In dose variation arm, noninferiority failed in 2 subgroups:

• Prior inpatient antibiotics
• Sever CAP

• In duration variation arm, noninferiority failed in 1 subgroup:

• Prior inpatient antibiotics

• Sensitivity analysis performed for retreatment after first 3 days:

• 3D: 90.2% (46/51) of retreatments were after 3 days
• 7D: 85.7% (42/49) of retreatments were after 3 days
Clinical Application 25

Did we find the dose & duration that is “just right”?

• Observed possible noninferiority between high/low-dose and
long/short-course treatment arms in terms of retreatment
• Dose/duration reductions likely not appropriate in highly
symptomatic (severe) patients
• Longer, high-dose regimens may prevent development of resistant
pathogen colonization

Answer: NO
References 26

• Bielicki JA, Stöhr W, Barratt S, et al. Effect of Amoxicillin Dose and Treatment Duration on the Need
for Antibiotic Re-treatment in Children with Community-Acquired Pneumonia: The CAP-IT
Randomized Clinical Trial. JAMA. 2021;326(17):1713-1724. PMID: 34726708
• Bradley JS, Byington CL, Shah SS, et al. Executive Summary: The Management of Community-
Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice
Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of
America. Clinical Infectious Diseases. 2011;53(7):617-630.
• Pernica JM, Herman S, Kam AJ, et al. Short-Course Antimicrobial Therapy for Pediatric Community-
Acquired Pneumonia: The SAFER Randomized Clinical Trial. JAMA Pediatrics. 2021;175(5):475-482.
PMID: 33686625
A New Goldilocks Story
A Review of the CAP-IT Trial
Kendall Spicer, Pharm.D., PGY1 Pharmacy Resident