Critical Appraisal Seminar

10/13

Discontinuing Beta-lactam Treatment After

3 Days for Patients with
Community-acquired Pneumonia in
Non-critical Care Wards
Dinh A;Ropers J;Duran C;Davido B;Deconinck L;Matt M;Senard O;Lagrange A;Makhloufi S;Mellon G;de Lastours V;Bouchand F;Mathieu E;Kahn
JE;Rouveix E;Grenet J;Dumoulin J;Chinet T;Pépin M;Delcey V;Diamantis S;Benhamou D;Vitrat V;Dombret MC;Renaud B;Perronne C;
“Discontinuing β-Lactam Treatment after 3 Days for Patients with Community-Acquired Pneumonia in Non-Critical Care Wards (PTC): A
Double-Blind, Randomised, Placebo-Controlled, Non-Inferiority Trial.” Lancet (London, England), U.S. National Library of Medicine,
https://pubmed.ncbi.nlm.nih.gov/33773631/.

Kyle Starkus
PGY1 Resident
Ascension St. Vincent Evansville
Background and Objective
• Background
• There is benefit in treating an infection with the shortest effective duration antibiotic
regimen to prevent resistance, adverse events, and related costs
• Standard practice in the European guidelines is to treat community acquired
pneumonia (CAP) with 7-10 days.

• Objective
• Assess the efficacy of 3 days of antibiotic treatment vs 5 days of additional
beta-lactam monotherapy when treating moderately severe community acquired
pneumonia

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Study Design

• A double-blind, randomized, placebo-controlled, non-inferiority trial

• Multi-center
• 16 different hospitals in France
• Study was supported by a grant from the French Ministry of Health and
sponsored by the DRCI of Versailles
• Direction de La Recherche Clinique et de L’Innovation
• Members from this department were involved in monitoring and planning the study

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 Study Design
• N = 310
• Inclusion criteria
• 18 years or older
• Moderately severe CAP
• treated with beta-lactam monotherapy or parenteral 3rd gen cephalosporin
• Clinical response at 72 hours of treatment
• Apyrexia, HR <100 BPM, RR <24, normal mental status, SBP > 90 mmHg
• Exclusion criteria
• Signs of severe or complicated CAP
• Abscess, pleural effusion, serious chronic respiratory infection
• Known immunosuppression
• Healthcare-associated pneumonia or suspicion of aspiration pneumonia
• Concurrent infection necessitating additional antibiotic treatment
• Suspected or confirmed legionellosis

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Study Design

• After 72 hours of beta-lactam treatment, eligible patients were randomized

1:1 using a web-based system and stratified by site and Pneumonia Severity
Index
• Prepared study medication packages of amoxicillin plus clavulanate or
placebo that were indistinguishable from each other. Packages were given
randomization number to blind all participants and healthcare providers
• No criteria for unmasking was detailed in the study
• Analysis of the primary outcome was performed using both intention to treat
and per-protocol

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Study Design

• Study Procedures

• Study group treatment-- Placebo tablets taken 3 times daily for an additional 5 days.
Designed to be indistinguishable in packaging, color, taste, and appearance.
• Pneumonia symptoms and adherence assessed at days 0, 3, 8, 15, and 30
• Primary outcome of cure assessed at day 15

• Control group treatment-- Amoxicillin-Clavulanate 1000mg/125mg tablet taken three

times daily for an additional 5 days (total duration 8 days)
• Pneumonia symptoms and adherence assessed at days 0, 3, 8, 15, and 30
• Primary outcome of cure assessed at day 15

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Study Design

• Endpoints and Measurements

• Primary endpoint - cure 15 days after first antibiotic intake

• Defined by apyrexia, resolution or improvement of respiratory symptoms, and no additional
antibiotic treatment for any cause
• Independent, blinded, adjudication committee reviewed the data extracted
• Each record was jointly reviewed by two physicians and formal meeting was held if consensus
was not met

• Major secondary endpoint - Adverse events related to therapy

• Recorded at prespecified meetings on days 3, 8, 15, and 30
• Most commonly: Diarrhoea

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Study Design

• Statistical Analysis
• 310 patients to provide 80% to show non-inferiority
• Allowance for 10% non-inferiority
• Confidence interval was set at 95%
• For the primary outcome the categorical data was presented as proportions
• For the secondary outcome Chi-squared test was used

• How dropouts were handled

• Analysis was performed using both intention to treat and per-protocol for the primary outcome
• Intention to treat analysis was performed using ‘worst-case scenario’
• This was not addressed for secondary outcomes

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Results
Placebo Group (n=152)
• Age - 72.5 years old
• 43% female
• 57% male
• 22% with comorbidities
• 31 (20%) with COPD
• CAP score at day 0- 44.4
Beta-Lactam Group (n=151
• Age - 74.0 years old
• 38% female
• 62% male
• 26% with comorbidities
• 40 (26%) with COPD
• CAP score at day 0- 46.2
Results

• Primary Endpoint Result-- in the ITT analysis, on day 15, 117/152 (77%) in
placebo group and 102/151 (68%) in the beta-lactam group were determined
to have been cured (95% CI -0.38-20.04)

• Major Secondary Endpoint Result-- 22/152 (14%) in the placebo group vs

29/151 (19%) in the beta-lactam group reported adverse events linked to
treatment (p=0.29)

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Results

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Results

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Evaluation

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Study Design Assessment

• While the research question is useful in that evaluating shorter durations of

antibiotics plays a major role in antimicrobial resistance, it is limited by the
divergence of treatment practices in Europe and the US
• The study design experimental, utilizing a double-blind, randomized, placebo
controlled trial which can be used to determine causation as opposed to
association
• The clinical outcomes of cure by 15 days and adverse drug events were
clinically significant.
• Composite outcome used to determine cure of CAP were appropriate, including
apyrexia, resolution or improvement of clinical signs or symptoms (coughing
frequency or severity, sputum production, dyspnoea, crackles) and no
additional antibiotic treatment

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Selection Bias

• The studied population aligned with the patient characteristics seen at our hospital
• Average age was ~73 years old
• Included comorbid conditions
• Included relatively equivocal male/female patients
• Lack of external validity due to study population in only France

• The did meet power through the use of intention to treat statistics
• Determined 310 patients required for 80% power
• 310 patients were stratified - but some were lost to follow-up

• Study groups were not randomized on all relevant patient characteristics

• For example: 20% with COPD in placebo while 26% COPD in treatment

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Performance Bias
• The use of amoxicillin-clavulanate 1000mg/125mg TID for an additional 5 days was
an appropriate comparator based on European guidelines
• External validity and our ability to extrapolate findings to our patient population diminished due to
different standards of treatment (both agents and durations)

• Adherence was measured by placing duration of therapy in blister packs and having
patients present the pack for assessment at the 15 day point
• >90% adherence in the treatment group

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 Measurement and Attrition Bias
• Internal validity is compromised by not reporting culture data or the uniformed use of
chest X-rays / ultrasounds
• One group may have had a significant amount of resistant pathogens
• Lack of uniformity of CXR and US utilization to diagnosis CAP
• Improved internal validity by using the validated pneumonia severity index and
stratifying groups based on baseline score
• Internal validity is compromised due to the unavoidable professional judgement aspect
when diagnosing CAP
• Improved internal validity by using ‘worse case scenario’ in the intention to treat
statistical analysis
• For the placebo group - any patient lost to follow up was counted as a treatment failure
• For the beta-lactam group - any patient lost to follow up was counted as a treatment cure
• This would create the most rigorous circumstances to demonstrate non-inferiority

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Clinical Usefulness
• The primary outcome of cure at 15 days is clinically meaningful, and
surrogate measurements of cure, including apyrexia and resolution of clinical
symptoms, were relevant as feasible markers
• Beware of endpoints that consist of laboratory measures, etc. Unless strongly validated,
which is rare, they cannot be used to assume clinical outcomes.
• The non-inferiority was set at 10%, and a 9.42% difference in favor of
prolonged therapy was shown
• Although this demonstrates non-inferiority as defined, differences in baseline
characteristics tended to skew toward placebo favorable results and may have been
enough to demonstrate inferiority of placebo

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 Evidence Grade and Conclusion
• Evidence Grade (select grade and delete others)
• A—Useful
• Outstanding in design, methodology, execution, and reporting. Meets standards for clinical
meaningfulness and patient/prescriber acceptance. Clinical decisions can be made with reasonable
certitude. Rare.
• B—Possibly Useful
• Well-designed and executed, meets most “A” requirements
• Potentially strong and probably useful but with some threats to validity identified
• B-U—Possible to Uncertain Usefulness
• Possibly useful but sufficient uncertainty to not reach Grade B, but does not warrant Grade U
• U—Uncertain Validity and/or Usefulness
• Most studies. Caution is urged regarding use in making healthcare decisions. Sufficient uncertainty
about accuracy of estimates of effect to comfortably draw conclusions from the research and apply the
results.
• In the context of IDSA/ATS guidelines and standard practice in the US, shorter 5 day
durations (and 3 day azithromycin) are common practice. This trial perhaps
demonstrates the possibility of even greater reductions in duration of CAP treatment
with equivocal outcomes - and further studies are warranted.

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Questions?

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Citations
Dinh A;Ropers J;Duran C;Davido B;Deconinck L;Matt M;Senard O;Lagrange A;Makhloufi S;Mellon G;de Lastours V;Bouchand F;Mathieu E;Kahn JE;Rouveix E;Grenet
J;Dumoulin J;Chinet T;Pépin M;Delcey V;Diamantis S;Benhamou D;Vitrat V;Dombret MC;Renaud B;Perronne C; “Discontinuing β-Lactam Treatment after 3 Days for
Patients with Community-Acquired Pneumonia in Non-Critical Care Wards (PTC): A Double-Blind, Randomised, Placebo-Controlled, Non-Inferiority Trial.” Lancet (London,
England), U.S. National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/33773631/.

Joshua P. Metlay, Grant W. Waterer. “Diagnosis and Treatment of Adults with Community-Acquired Pneumonia. an Official Clinical Practice Guideline of the American
Thoracic Society and Infectious Diseases Society of America.” IDSA Home, https://www.idsociety.org/practice-guideline/community-acquired-pneumonia-cap-in-adults/.

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