Prevention of Cdiff recurrence: Evidence from a Cdiff Antitoxin

Prevention of Cdiff recurrence: Evidence from a Cdiff Antitoxin Prof. Emilio Bouza Departament of Medicine. Hospital Gregorio Marañon and Complutense University. Madrid. Spain

Disclosures Last year Participation in meetings and advisory boards with: Astellas, MSD Research funds received from private and public origins Payment for conferences: Pfizer, MSD, BioMérieux, Singulex, Vircell

Index The burden of CDI and rcdi The population at risk. Prediction scores Bezlotoxumab. After the Modify I and II studies Bezlotoxumab in populations at high risk for recurrence Guidelines and Bezlotoxumab Bezlotoxumab indications in present real practice

The burden of recurrences (rcdi) 20-25% after the first episode Much more after the first one Recurrences increase 2.5 fold the rate of readmissions 4 fold the Length of hospital stay 33% higher mortality Lessa FC. N.Engl.J.Med. 2015; 372: 825-834 Sheitoyan-Pesant C. C.I.D. 2016; 62: 574-580 Olsen MA. C.M.I. 2015; 21: 164-170 Olsen MA. Am.J.Infect.Cont. 2015; 43: 318-322

rcdi impact (Kaiser Permente USA) No CDI CDI rcdi 4,334,214 24,122 4,174 Admissions in the following year 32% 38% 50% Mean d/admission 3.2 4.6 8.3 Mean ICU days 0.3 0.6 0.9 Mortality 1 y 6% 12% 16% Patients Kuntz JL. I.C.H.E. 2017; 38: 45-52

The burden of CDI and rcdi The population at risk. Prediction scores Bezlotoxumab. After the Modify I and II studies Bezlotoxumab in populations at high risk for recurrence Guidelines and Bezlotoxumab Bezlotoxumab indications in present real practice

rcdi: Risk Factors Advanced age Need to continue administering other Abx. Defective humoral immune response Severe underlying disease Continued use of PPIs Factors from the microorganism Kyne L. Lancet 2001; 357:189-193 Kym YG. J.Clin.Gastroenterol 2012; 46:397-400 Linsky A. Arch.Intern.Med. 2010; 170: 772-778 Nair S. Am.J.Gastroenterol. 93:1873-1876

Predictive scores of recurrence Comments Study Variables Included in Score Comments Hu et al. Gastroenterology 2009;136:120614. Age > 65 years Severe disease based on Horn index Additional antibiotic use Small sample size Score performed poorly in a prospective internal validation cohort (53.8% sensitive, 76.5% specific) Will require external validation to determine clinical utility. Miller et al. (ATLAS) BMC Infect Dis 2013;13:148. Age Treating with systemic antibiotics during CDI therapy Temperature Leukocyte count SCr Albumin level Useful for predicting severity and response to treatment, but found to be a poor predictor of recurrence. D agostino et al. Clin Infect Dis 2014;58:1386-93 Age > 75 years >10 unformed bowel movements in 24 hours. Scr > 1.2 mg/dl Prior episode of CDI CDI treatment received (vancomycin or fidaxomicin) Derived and validated from a large prospective dataset. Poorly predictive of recurrent CDI (C statistic 0.54) Modified from Daniels LM. Expert.Opin.Pharmacother. 2018; Sept 25:1-12

Predictive scores of recurrence Comments Study Variables Included in Score Comments Zilberberg et al. J Hosp Med 2014;9:418-23. Age Community onset CDI Prior hospitalization Fluoroquinolone use at onset of CDI Other high risk antibiotic use at onset of CDI Gastric acid suppression Derived from a large retrospective single center cohort study and crossvalidated in the same population. Performed poorly an external validation study (C statistic 0.59) [27] Viswesh et al. Am J Health Syst Pharm 2017;74:474-482. CDI present on admission Temperature > 37.8 C at admission Leukocyte count > 15,000 cells/mm3 Nosocomial CDI Abdominal distention Derived from a large retrospective single center cohort study and crossvalidated in the same population. Will require external validation to determine clinical utility. Modified from Daniels LM. Expert.Opin.Pharmacother. 2018; Sept 25:1-12

Predictive scores of recurrence Comments Study Variables Included in Score Comments Escobar et al. Infect Control Hosp Epidemiol 2017;3:1196-1203 Comparison of 4 models Derived from a large multicenter retrospective cohort and internally validated in a separate cohort. None of the models performed well (C statistics 0.59 0.61). Reveles et al. Pharmacotherapy 2018;38:349-356 Prior 3rd or 4th generation cephalosporin use Prior proton pump inhibitor use Prior antidiarrheals Non-severe CDI Community onset CDI Large retrospective national cohort of veterans. Clinical prediction rule Cobo et al. Int J Antimicrob Agents 2018; 51:393398. Age Prior CDI in last year Positive direct toxin test Persistence of diarrhea on day 5 of treatment correlated strongly with recurrence (R2 = 0.94) in an internal validation cohort. Will require external validation to determine clinical utility. Derived from a retrospective multicenter cohort and validated in a separate cohort (including several of the same centers from derivation cohort). Moderately predictive for recurrent CDI Modified from Daniels LM. Expert.Opin.Pharmacother. 2018; Sept 25:1-12

Anticipating rcdi Database. Adult Veterans Administration total of 22,615 first-episode CDI October 1, 2002, and September 30, 2014 7,538 derivation cohort and 15,077 validation. Reveles et al. Pharmacotherapy 2018;38:349-356

Anticipating rcdi Points Variables Prior 3rd-4th G cephalosporins Prior PPIs Prior antidiarrheals Non severe presentation Community-onset 1 1 1 2 3 Low risk 0-2 points (R: 8.9%) Medium risk High risk 3-5 points (R: 20.2%) 6-8 points (R: 35%) Reveles et al. Pharmacotherapy 2018;38:349-356

CDI: the value of Ct Amplification before Ct 24 predicts a greater risk of poor evolution Reigadas E. Bouza E. J.Antimicrob.Chemother. 2016; 71: 1380-1385

Combined vs Clinical Prediction Rule POCDI Clinical Score COMBINED Score Microbiological + Clinical Reigadas E. Bouza E. J.Antimicrob.Chemother. 2016; 71: 1380-1385

CDI: Monoclonal antibodies antitoxin B MODIFY I and MODIFY II Studies 2.655 adult patients Oral standard of care Abx + Monoclonal Abx vs Placebo Randomized trials. EndPoint: Recurrence rate Wilcox MH. N.Engl.J.Med. 2017; 376: 305-317

Recurrence. mitt MODIFY I and MODIFY II Studies Randomized trials. EndPoint: Recurrence rate Wilcox M. N.Engl.J.Med. 2017; 376: 305-317

Adverse events Selected serious AE in Phase 3 trials (within 12 w of Infusion) Placebo ACT+BEZ BEZ alone 781 N (%) 777 N (%) 786 N (%) 255 (32.7) 212 (27.3) 231 (29.4) 7 (1) 17 (2.2) 17 (2.2) 12 (1.5) 10 (1.3) 16 (2) Abdominal pain 4 (0.5) 4 (0.5%) 7 (0.9) Respiratory failure 6 (0,8) 5 (0.6) 5 (0.6) Acute kidney injury 10 (1.3) 4 (0.5) 6 (0.8) MedMDA preferred term Subjects with > 1 AE Cardiac * failure Diarrhea Wilcox M. N.Engl.J.Med. 2017; 376: 305-317

Bezlotoxumab. Sub-analysis of Modify I and II Gender Hepatic impairment Race Renal impairment Ethnicity Severity Age (+/- 65 years) Co-morbidity Hypertoxigenic strains Gerding et al. ECCMID Amsterdam 2016

CDI: Monoclonal antibodies antitoxin B Results by Diagnostic method Reduction was more significant in patients detected by direct stool toxin (47%) than in those diagnosed by NAAT tests (25%) Wilcox M. N.Engl.J.Med. 2017; 376: 305-317

Prespecified subpopulations * * * * * * Gerding et al. ECCMID Amsterdam 2016

Bezlo in patients at risk of rcdi Modify I and II 1,554 pts (Bezlo and PBO) Pts with 1 or more pre-established risk factors (75%) - age 65 years, - history of CDI - compromised immunity - severe CDI - ribotype 027/078/244 Gerding D. Clin.Infect.Dis. 2018. 2018 Aug 16;67:649-656

Bezlo in patients at risk of rcdi Bezlotoxumab for prevention of recurrent C. difficile infection in patients at increased risk for recurrence Modify I and II 1,554 pts (Bezlo and PBO) 1,175 (75.6%) had > 1 Risk F. 36% 1 Risk Factor 27% 2 Risk Factors 12% 3 or more RFs rcdi 31 % with 1 Risk factor rcdi 46 % with 3 Risk factors Gerding D. Clin.Infect.Dis. 2018. 2018 Aug 16;67:649-656

Bezlo in patients at risk of rcdi Bezlotoxumab for prevention of recurrent C. difficile infection in patients at increased risk for recurrence Risk Factors Absolute Reduction Relative Reduction 1 14.2% 45.3% 2 14.2% 34.5% 3 24.8% 53.9% REDUCTION OF FMT S AND 30 D MORTALITY Gerding D. Clin.Infect.Dis. 2018. 2018 Aug 16;67:649-656

C. difficile: Renal Impairment From the Modify database Out of 1,554 patients 430 had Chronic Renal Failure (28%). GOOD response to monoclonal antibodies Abs.1266. Yoav Golan. IDWeek. San Diego Oct. 2017

Bezlotoxumab and the abx to treat CDI Oral presentation Bezlotoxumab equally effective irrespective of the antimicrobial used for primary treatment Abs 838. Duberkke ER. IDWeek. N.Orleans. IDSA. Oct.2016

Bezlotoxumab: Hypertoxigenic strains Abs 2114. Jonhson S. IDWeek. N.Orleans. IDSA. Oct.2016 Patients infected with hypertoxigenic strains such as RT 027, RT 176 y RT 198 or those that require prolongation of antibiotic treatment also responded well in the MODIFY I and II database cases Abs 2115. Mullane K. IDWeek. N.Orleans. IDSA. Oct.2016

C. difficile: Hematologic patients Impact of bezlotoxumab on outcomes associated with Clostridium difficile infection in MODIFY I/II participants with haematologic malignancy Sub-analysis of the MODIFY I/II trials showed that BEZ reduced the rate of rcdi compared with PBO in participants with haematologic malignancy as a comorbid condition. Cornerly O. Abs.0358. ECCMID.Madrid. April 2018

Bezlo: IBD Kelly CP. Gastroenterology 2018 Oct;155(4):1270-1271 Data collected from the MODIFY database Individuals with IBD were eligible to participate 2559 mitt participants Bezlotoxumab Placebo Diff. % (95% CI) IBD 44 (1.7%) 28/1554 16/1005 Diarrhoea ICC 15/28 (53.6%) 13/16 (81.6%) -27.2 (-51.1 to 2.3) rcdi Primary. 4/15 (26.7 %) 7/13 (53.8 %) -27.2 (-57.9 to 9.6) rcdi Second. 7/27 (25.9%) 7/15 (46.7%) -20.7 (-48.9 to 8.9)

New US Guidelines 35 major chapters 53 reccommendations No discussion on Bezlotoxumab McDonald LC. Clin.Infect.Dis. 2018; 66(7): e1-e48

Potential indications for Bezlotoxumab use: A potential score Low prediction 1 point Midle prediction 2 points High prediction 3 points Age > 65 y. Other episodes in the previous year Immunodeficiency Malignancy Severe Inflammatory Bowel Disease Low Ct amplification Hypertoxigenic strains Hospital Indicated but impossible to perform a FMT Clear indication: 3 or more points Other conditions with high risk. Liver chirrosis Bouza E. Personal Opinion. Oct. 2018

Summary

1.- Recurrent CDI occurs in a high proportion of patients after a First Episode of CDI. 2.- rcdi increase the rate of readmissions, the LOS and it is associated with a higher mortality. 3.- Several host risk factors increase the risk of recurrence after the first episode, including age>65 y, immunodeficiency, the need to continue with systemic antimicrobials,..

4.- Prediction scores based only on host risk factors have a limited sensitivity and specificity to discriminate the population at risk. 5.-Factors related to the microorganism should be probably added to those scores: Toxin load, situation of the intestinal microbiota, 6.- Bezlotoxumab is a monoclonal antibody active against Toxin B of C. difficile. 7.- Combined with SOC antibiotics, significantly decreased recurrent episodes after a single IV injection.

8.- The effect of Bezlotoxumab holds for populations at special risk, including hematologic patients, the elderly, those with prior episodes, those severely ill, and those with hypertoxigenic strains. 9.- Bezlotoxumab is well tolerated in different populations and do not require adjustments in renal or liver failure. 10.- Bezlotoxumab is indicated in patients at high risk for recurrent episodes but that population should be more precisely selected according to local conditions.

Hot Topics in Infectious Diseases (HTIDE) International Conference 25 26 October 2018 Mestre, Italy Q&A/Closing Remarks

Hot Topics in Infectious Diseases (HTIDE) International Conference 25 26 October 2018 Mestre, Italy This information is provided as a service to the medical profession and represents the opinions of the speakers, not necessarily those of Merck & Co., Inc., Kenilworth, NJ, USA, or its affiliates. Due to individual countries regulatory requirements, approved indications and uses of products may vary. Before prescribing any products, please consult the local Prescribing Information available from the manufacturer(s). Full Prescribing Information is available on request.

Hot Topics in Infectious Diseases (HTIDE) International Conference 25 26 October 2018 Mestre, Italy Thursday, 25 October 2018 Mestre, Italy Chair: Francesco Menichetti (Italy)