Relationship Between Microbiological Eradication and Clinical Outcome With Antibiotic Treatment in

Nosocomial Pneumonia, Complicated Urinary Tract Infection, and Complicated Intra-abdominal Infection

J.P. Jansen1, T. Kauf2, S. Eapen3, G. Medic4, M. Kollef5

1Redwood Outcomes, San Francisco, CA, USA; 2Cubist Pharmaceuticals, Lexington, MA, USA; 3Redwood Outcomes, Vancouver, BC, Canada; 4MAPI Consultancy, Houten, Utrecht, Netherlands;

5Barnes Jewish Hospital, St Louis, MO, USA

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Figure 1. Individual Study Results and Meta‑analysis of Treatment Effects Regarding Microbiological Eradication and Clinical Response Expressed as Log Odds Ratios for NP. (Note result by Verna et al., not presented)

Individual study results are represented with bubbles with their size proportional to the precision in eradication estimates. The ellipse reflects the joint uncertainty distribution of the 2 treatment effects obtained with the meta-analysis indicating the strength of their relation.OR = odds ratio.

This study was funded by Cubist Pharmaceuticals. Presented at the ISPOR 17th Annual European Congress 8-12 November 2014, Amsterdam, The Netherlands

Poster # PIN2

Jeroen P. JansenRedwood Outcomes1714 Stockton Street

San Francisco, CA, USA 94133Tel: +1 781 460 8861

Email: jjansen@redwoodoutcomes.com

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Figure 2. Individual Study Results and Meta‑analysis of Treatment Effects Regarding Microbiological Eradication and Clinical Cure Expressed as Log Odds Ratios for NP

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Figure 3. Individual Study Results and Meta‑analysis of Treatment Effects Regarding Microbiological Eradication and Mortality (All‑cause & In‑hospital) Expressed as Log Odds Ratios for NP

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Figure 4. Individual Study Results and Meta‑analysis of Treatment Effects Regarding Microbiological Eradication and All‑cause Mortality Expressed as Log Odds Ratios for cIAIs

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Figure 5. Individual Study Results and Meta‑analysis of Treatment Effects Regarding Microbiological Eradication and Clinical Response Expressed as Log Odds Ratios for cUTIs

RESULTS (con’t)BACKGROUND■■ Infections caused by Gram-negative bacteria, including nosocomial pneumonia (NP), complicated urinary tract infections (cUTI), and complicated intra-abdominal infections (cIAI), have been increasing.1-4

■■ Gram-negative bacteria are highly adaptive pathogens that develop resistance at an increasing rate thereby compromising treatment outcomes of these infections.

■■ To understand the value of a new antibiotic treatment, it is of interest to understand the relationship between microbiological eradication and clinical outcomes with antibiotic treatment.

■■ Although microbiological eradication is on the presumed causal path from antibiotic susceptibility to clinical success, other factors impact clinical success rates as well.

RESULTS (con’t)cIAI

■■ Twenty-two trials provided information on both microbiological eradication and all-cause mortality.

■■ Given the variation across trials, no clear relationship between treatment effects was observed (Figure 4); the correlation coefficient was 0.26 (95% CI, –0.56, 0.60).

cUTI■■ Six trials provided information on both microbiological eradication and clinical response, but no clear correlation between treatment effects was observed (–0.22; 95% CI, –0.79, 0.57; Figure 5).

■■ Given the limited data (5 trials ) there was no clear pattern between treatment effects in terms of eradication and clinical cure. An outlier study resulted in a counterintuitive correlation coefficient, but was not considered statistically significant.

OBJECTIVE■■ To assess the relationship between microbiological eradication and clinical outcomes with antibiotic treatment for NP, cIAI, and cUTI in an adult patient population based on randomized controlled trial (RCT) evidence.

REFERENCES1. American Thoracic Society; Infectious Diseases Society of

America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

2. DeFrances CJ, et al. National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat 13. 2007;165:1-209.

3. Solomkin JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133-164.

4. Food and Drug Administration. Draft Guidance for Industry on Complicated Urinary Tract Infections: Developing Drugs for Treatment; 77 Federal Register 11133; February 24, 2012.

5. Riley RD, et al. An alternative model for bivariate random-effects meta-analysis when the within-study correlations are unknown. Biostatistics. 2008;9:172-186.

6. Buyse M, et al. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics. 2000;1:49-67.

7. Daniels MJ, Hughes MD. Meta-analysis for the evaluation of potential surrogate markers. Stat Med. 1997;16:1965-1982.

8. Molenberghs G, et al. Statistical challenges in the evaluation of surrogate endpoints in randomized trials. Control Clin Trials. 2002;23:607-625.

METHODS■■ Relevant studies were identified by a systematic literature review and the relationships of interest were assessed by means of a meta-analysis.

Evidence Base■■ In December 2013 a systematic literature search was performed

■■ MEDLINE, EMBASE, and the Cochrane Central Register of Clinical Trials were searched.

■■ Selection criteria: – Population: Adult patients with NP, cUTI, and cIAI.

Gram-negative bacteria needed to be present in (a fraction of) the studied population.

– Interventions: Any antibiotic treatment that included coverage of Gram-negative bacteria.

– Outcomes: Any measure of microbiological eradication as reported in the study; any measure of clinical outcome as reported in the study including clinical cure and mortality (in-hospital or all-cause).

– Study Design: RCTs. – Other: Papers published in English; 2000 to

December 2013.

Analysis■■ The following sets of bivariate meta-analyses were performed.5

■■ NP population – Log odds ratio of eradication with log odds ratio of

clinical response. – Log odds ratio of eradication with log odds ratio of

clinical cure. – Log odds ratio of eradication with log odds ratio of

mortality.■■ cIAI population

– Log odds ratio of eradication with log odds ratio of mortality.

– Note: Generally, patients with cIAI are not re-cultured after their abdomen is closed. Results are typically reported as “presumed eradication” as patients are clinically cured and cultures are not able to be obtained. As such, we did not estimate relationships between eradication and clinical response/cure for this population.

■■ cUTI population – Log odds ratio of eradication with log odds ratio of

clinical response. – Log odds ratio of eradication with log odds ratio of

clinical cure. – Note: Given the small mortality rate among cUTI

patients, no analysis was performed for the relationship between eradication and mortality.

DISCUSSION■■ Although the methodology to evaluate surrogacy for this study can be considered standard,6-8 there are limitations to the evidence base.

– Within-trial contrasts for clinical outcomes and eradication were frequently small without significant differences. Simply due to chance, the directions of treatment effects for the clinical outcome and eradication may be opposite within trials.

– There is some variation across trials in terms of definitions of clinical outcomes, timing of assessment, age, and comorbidity, which may have acted as effect modifiers thereby resulting in heterogeneous treatment effects regarding clinical outcomes given certain eradication effects.

– The between-trial variation in treatment effects for both eradication and clinical outcomes is limited.

– The number of trials that report both treatment effects in terms of microbiological eradication and clinical outcomes identified with the literature search is limited.

■■ Hence, it is not surprising that the estimated trial-level associations between eradication and clinical outcomes are uncertain and even show estimates in unexpected directions.

RESULTSNP

■■ Based on 9 trials reporting information on both microbiological eradication and clinical response no clear correlation was observed (Figure 1).

■■ The meta-analysis of 9 trials reporting both eradication and clinical cure showed a positive correlation regarding treatment effects (0.69; 95% CI, 0.01, 0.93; Figure 2).

■■ Based on 12 trials providing information on both eradication and mortality a correlation coefficient of –0.53 (95% CI, –0.59, 0.51) was estimated, and considered uncertain and not statistically important (Figure 3).

ACKNOWLEDGMENTSEditorial and layout support for this poster was provided by PAREXEL and funded by Cubist Pharmaceuticals.

CONCLUSIONS■■ A relationship between treatment effects in terms

of eradication and clinical cure was identified for NP, but not for clinical response or mortality.

■■ For cIAI and cUTI, the relationship between microbiologic eradication and clinical outcomes is unclear.

■■ Uncertain within-trial comparisons and limited between-trial variability of the available studies can be considered key factors explaining the uncertain trial-level associations between eradication and clinical outcomes obtained with the meta-analysis.

■■ Analysis of patient level data is recommended to understand the strength of the relationship between microbiological eradication and clinical outcomes associated with antibiotic treatment.

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