Biomarkers for streamlining of Antibiotics in patients with severe infection.

Biomarkers for streamlining of Antibiotics in patients with severe infection. Philipp Schuetz, MD Feb, 2013 Email: Schuetzph@gmail.com

You see this patient in your ICU -3d: Cough, Dyspnoe, Sputum T: 38.8 C, basal RG s (?) 8-9h: 9h: Culture (Sputum, blood) Legionella Ag, Serology, PCR Laboratory values 1) Antibiotic Therapy needed? 2) If yes for how long

Fraction of total patients Possible harm of UNDER-TREATMENT 1 Survival Fraction Cumulative Effective Antimicrobial Initiation 0.8 0.6 0.4 0.2 0 Time from hypotension onset (hrs) Kumar A. et al., Crit Care Med 2006, 34:1286

Possible harm of OVER-TREATMENT r = 0.75 Albrich WC, Emerg Inf Dis 04

Biomarker guided therapy in the ICU Signs & Symptoms? - Temperature, BP - - SIRS criteria Imaging? Cultures? - Blood, Sputum, Tissue Laboratory? - Leukocytes / WBC - ESR, CRP, SAA - Neopterin, strem-1 Other? Condition Diabetes Hyperglycemia Hypotension Shock Infection Sepsis Biomarker Blood glucose Lactate / ScvO 2 Procalcitonin?! Treatment Insulin: Dose / type Fluid: Amount / rate Antibiotics Initiation / duration

Thyrocytes Thyroxine Hormokines Hormones expressed like Cytokines C-Cells Calcitonin Thyroid Leukocytes Perit. Macrophages Spleen Lung Liver Kidney Adrenals Brain Spine Stomach Pancreas Small Intestine Colon Heart Muscle Skin Adipose Tissue Testes Healthy Sepsis Inflammation Bacterial Interferons Toxins IL-1 viral Infection TNF Procalcitonin Müller B, et al. J Clin Endocrinol Metab 2001

Inflammatory Host Response Golgi apparatus ProCT Bacterial Infection (e.g.endotoxin) ProCT IL-1 TNF IFN "hormokine" CT-mRNA ALL Other Organs Constitutive Secretion viral Infection CT Golgi apparatus CT ProCT endocrine Linscheid P, et al Crit Care Med 04; 32: 1715-21 Endocrinology 03; 144: 5578-84 & 05; 146: 2699-708 CT-mRNA Regulated Secretion Thyroidal C-cells Thyroidal C-cell (camp, Mg, Gastrin)

Cytokines & Hormokines upon Infection TNFa IL6 PCT CRP ug/ml 5 4 Fatal Outcome 3 2 1 0 0 12 24 36 48 60 72 h Endotoxin iv adapted from Meisner M, J Lab Med 1999 Dandona P, et al. J Clin Endocrinol Metab 1994 Harbarth S, AJRCCM 2001 Becker KL, J Clin Endocrinol Metab 2004

30 Studien, 3244 patients pooled sensitivity: 0.77 (95%CI 0.72 0.81) pooled specificity 0.79 (95% CI 0.74 0.84) Lancet Infect Dis. 2013 Jan 31.

Medicine Murphy s Law Dynamic Continuum RTI Common Cold Bronchitis Pneumonia Sepsis Setting Primary Care Emergency Room Hospital ICU Prevalence EU 500Mio 50Mio 5Mio 0.05Mio Mortality <<1% <1-3% 5-20% 30-70% better to start antibiotic therapy & to hospitalize early!?

Proof-of-Concept RCTs Respiratory Tract Infection Standard Group (without PCT-result) Randomization PCT Group Treatment Based on Standard Guidelines Follow-up After 10-14 Days PCT (ng/ml) <0.1 0.1-0.25 0.25-0.5 >0.5 Antimicrobial Treatment NO! No Yes YES! Clinical and PCT Control After 6-24h

Antibiotic prescriptions (%) The ProResp-Study Antibiotic Use in LRTI 83% 44% 100 Standard group PCT group p = 0.03 p = 0.003 p < 0.001 p = 0.003 p < 0.001 80 60 40 20 0 CAP Bronchitis AECB Asthma Others Christ-Crain M et al, Lancet 04

PCT Rules out Mortality in High Risk Patients our main finding was that in patients with CAP, patients with a PCT 0.1 ng/ml had a low 30-day mortality rate, even in patients defined as high risk by established clinical risk prediction rules. Huang, Ann Emerg Med. 2008 Jul;52(1):48-58.e2.

The ProHOSP - Study A novel Concept to optimize Allocation of Health Care Resources

Differential effects of PCT - Guidance Depending on type and severity of LRTI Schuetz P, ProHOSP, n=1359, JAMA, 2009

Safety of PCT Guided Antibiotic Stewardship SAE n=234 (17.2%) SAE n=168 (18.1%) Schuetz P, ProHOSP, n=1359, JAMA, 2009

How about Safety of Control Patients? Risk of Drug related Adverse Events increases with duration of AB Therapy adjusted OR: 1.08 (95%CI 1.05-1.10) 42% increase in AB side effects in ProHOSP control patients (28.1% vs 19.8%, p<0.001) Schuetz P, ProHOSP, n=1359, JAMA, 2009 Schuetz P, Virulence, 2009

PCT for Antibiotic Stewardship in the ICU?

Prognostic value of PCT in sepsis Survivors Deceased SIRS Harbarth et al. AJRCCM 2001

Similar to high risk patients for PE don t waste time! Patient Admitted to the ICU with Systemic Inflammatory Response Syndrome (SIRS) Clinical Evaluation Measurement of Procalcitonin Microbiological Workup No Life Threatening Disease, Not Immuno-Compromised Life Threatening Disease, High Suspicion of Bacterial Infection No Identification Identification of Organism Consider Initial Empiric Antibiotic Therapy Evaluation of Procalcitonin Cut off Range <0.25 >0.25-0.5 >0.5-1.0 >1.0 Exclusion of Contamination NO AB! No AB AB Yes AB YES! Reevaluation of the Clinical Course and Procalcitonin After 6-24 h, 48h, 72h No Infectious Cause of Fever Infection PCT not decreasing Patient Deteriorating Consider Surgery Drainage, Removal of Foreign Body or Obstruction Stop Antibiotics Schuetz P, Curr Opin Crit Care, 07

The PRORATA Study: Multicenter, ICU, Sepsis n = 621 Antibiotic Duration Outcome 23% more antibiotic free days alive Bouadma, Lancet 2010

The PRORATA Study Subgroups Antibiotic Duration Outcome Bouadma, Lancet 2010

PCT has pitfalls as a marker of infections Cut-off range depends on clinical setting PCT does not replace the doctor ( pretest-probability!) Co-Morbidities? Setting? Site & Extent of Infection? Assay? False positives & negative values occur pos: Surgery, cardiac shock, cytokine storm, neg: early, localised, subacute Single PCT measurement is of limited value Course & prognosis of disease? Withhold antibiotic therapy? Christ-Crain M, Muller B, Swiss Med Wkly 05; 135: 451-60

Procalcitonin to Diagnose Postoperative Infection after Cardiac Surgery 100 patients, 16 with infection postoperatively White blood count Procalcitonin AUC of procalcitonin: 0.88 [0.71 0.95]) Jebali, 2007, Anesthesiology

PCT to guide duration of AB therapy in surgical ICU patients: a randomized controlled trial PCT concentrations during follow up Choice and Duration of Antibiotic therapy 110 Surgical ICU patients with suspicion of sepsis Stopp AB if clinical signs improved and PCT <1 ng/ml or the PCT value was >1 ng/ml, but had dropped to 25 to 35% of the initial value over three days. Similar outcomes (SOFA & mortality) Conclusion: Monitoring of PCT is a helpful tool for guiding AB treatment in surgical intensive care patients. Hochreiter et all, CC 2009

14 randomised-controlled Trials, 4221 Patients with acute Respiratory Infections

The effect of PCT guidance is dependent on acuity of patients Schuetz P, Clinical Infectious Disease, 2012

Safety of PCT Protocols: Results from an IPD Metaanalysis 0.76 (0.61, 0.95) Schuetz P, CID 2012

Recent Guidelines recommend PCT as an adjunctive tool in discriminating true infection from other inflammatory processes causing acute fever IDSA guidelines, 2008 Recently, biomarkers have been described as useful tools to safely reduce antibiotic treatment duration. Biomarkers can guide treatment duration by the application of predefined stopping rules for antibiotics. It has been shown that such rules work even in most severe cases, including pneumonia with septic shock, and even if clinicians are allowed to overrule the predefined stopping rule Woodhead, Clin Microbiol Infect 2011; 17(Suppl. 6): E1 E59 We suggest the use of low procalcitonin to assist the clinician in the discontinuation of empiric antibiotics when no evidence of infection is found (grade 2C) Surviving Sepsis Campaign Guidelines, Dellinger P, CCM, 2013

How about Choice of therapy?

Can PCT differentiate viral from bacterial CAP? n=103 with Influenza CAP, 46.6% with bacterial coinfection PCT cut-off of 0.8: Sens: 91%, Spec: 68%, NPV 91% AUC 0.90 (95% CI 0.74 1.00) Cuquemelle et al, ICM 2011

How about Costs?

Is Procalcitonin testing Cost-effective? Cost: around 24 USD per measurement Heyland KH et al, CCM 2011

What doesn t work?

Therapy Escalation based on PCT levels? Jensen et al.; PASS Study; CCM 2011

but Antibiotics cause side effects! 50% surgical patients (we know that PCT increases in these patients!) Who is to blame: PCT or the intervention or the algorithm? Algorithm used very small PCT changes (variability?)

Crit Care Med. 2012 Aug;40(8):2304-9.

Procalcitonin: What is the Evidence?

How do we treat patients in clincial practice? PCT guided therapy with the new Biomarker-APP

Now available in the APP Stores PCT ProADM Biomarker

Selection

Enter new patient / risk score calculation CURB-65

Risk score calculation - PSI

Recommendation

Follow-up 48h

Follow-up Recommendation - History

References

Questions? Schuetzph@gmail.com (First Update is planned soon)

Conclusions: Biomarker guided antibiotic duration is a rational approach to prevent antibiotic overconsumption in the ICU setting Procalcitonin seems to be a reliable marker to assist clinicians in the decision to stopp antibiotics This concept has been validated in 14 RCTs including >4500 patients Antibiotic reduction of 30-70% depending on the setting Reduction in antibitoic related side effects No evidence for recurrent infection / adverse outcomes No evidence for Therapy escalation based on PCT Residual limitations include Few US data, high rate of non-compliance False positives & negative values occur ( 10%) Single PCT measurement of limited value Future RCTs need to validate this promising concept DOWNLOAD THE «BIOMARKER» APP IT`S FREE!!!

Thank you, that s all folks! Any Questions? Schuetzph@gmail.com

Disclosure slide Support for speaking engagements was provided by BioMerieux Inc. Brahms/Thermofisher

Prognostic YES! But can it change Outcomes?

% Survival in Hamsters Procalcitonin Hormokine -Mediator in Sepsis E.coli E.coli + hproct E.coli + ProCT-Ab ip E.coli + prophyl. ProCT-Ab 100 80 60 %Survival in Hamsters 40 20 0 0h 12h 24h 36h 48h 60h 72h Nylen ES, et. al. Crit Care Med 1998, adapted

ProCT-Immunoneutralization in mammals Crit Care Med 02; 30:2313-21 & J Endotox Res 03; 9: 1-8

What motivates YOU stopping antibiotics? We said 8 days Patient is stable Patient has no more fever Patient goes home Patient develops a rash Patient sits on toilet with diarrhea Renal function is deteriorating The fellow (attending) is changing Cultures came back negative pick your choice or add another J. Pugin

Antibiotic stewardship in primary Care? 1 Endpoint: Sickdays 40 P<0.01 40% 30 30% 8.6 vs 8.7 d = 0.2 (-0.4-0.9)* * Intention to treat 100 75 50 25 0 20 10 0 2 Endpoint: Overall Antibiotic use Antibiotic Prescription (%) Sickdays Diarrhea (%) 7 6 5-72% - 77% 4 3 2 1 0 20% 10% 0% Antibiotic Exposure Control ProCT Briel M, Schuetz P et al, Arch Int Med

Antibiotic duration (days) The ProCAP Study Antibiotic Duration Antibiotic Prescriptoin (%) 20 19 17 15 13 12 10 8 6 4 2 p < 0.001 100 90 80 70 60 50 40 30 20 Standard group ProCT group Standard group ProCT group 10 0 AB started > 4d > 6d > 8d > 10d > 14d > 21d Shorter AB-Courses Fewer Resistances! But don t we have Guidelines in CAP to individually guide AB-Therapy? Christ-Crain M et al, Am J Respir Crit Care Med 2006

Recommendations for Future use / studies: Moderate Risk Situations (ED/CAP) Schuetz P, Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171:(15):1322-31.

A Biomarker should embedded in pragmatic, setting-specific, prospectively validated safe and effective clinical algorithms Respiratory tract infections Intensive Care Unit Schuetz P et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. Jama. 2009;302:(10):1059-66. Bouadma L et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375:(9713):463-74

Recommendations for Future use / studies: ICU / High risk Situations Schuetz P, Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171:(15):1322-31.

What is Procalcitonin (PCT)?

Procalcitonin: Hype or Hope? Ever gave a talk on Procalcitonin?