Hospital Infectious Disease: Hot Topics

Transcription

1 Hospital Infectious Disease: Hot Topics Briana Wenke, PharmD Pharmacist St. Francis Hospital, Federal Way Washington Disclosure No actual or potential conflict of interest in relation to this program/presentation I will be discussing off-label uses and/or investigational use of the following medications in my presentation: Rifaximin Cholestyramine Colestipol Tigecycline IVIG CDA1/CDB1 Actoxumab Bezlotoxumab LFF571 CB183,315 Objectives At the completion of this program, the participant will be able to: Select appropriate antibiotic therapy for hospital-acquired pneumonia based on the updated IDSA guidelines Explain how procalcitonin can be used to de-escalate and limit duration of antibiotic therapy for select disease states Describe treatment principles for Clostridium difficile based on patient characteristics 1

2 Topic #1: Updated IDSA Hospital-Acquired Pneumonia (HAP) and Ventilator-Acquired Pneumonia (VAP) Guidelines 2005 vs 2016 HAP/VAP Guidelines Main differences GRADE methodology Removal of healthcare-associated pneumonia (HCAP) Local antibiograms Shorter courses of therapy Other differences Procalcitonin Double-coverage for Pseudomonas Aeruginosa Not intended for immunosuppressed patients Why do we care? HAP/VAP among most common hospital-acquired infections (22%) 10% of ventilated patients diagnosed with VAP Negative patient outcomes: mortality All-cause mortality associated with VAP: 20-50% Meta-analysis: attributable mortality 13% Negative patient outcomes: length of stay Prolongs mechanical ventilation by days Prolongs hospitalization by days Cost ~$40,000 per patient 50% of HAP patients develop serious complications HAP in ICU patients: mortality rate approaches that of VAP 2

3 GRADE Methodology GRADE Methodology/Level of Evidence For the purposes of this presentation: Strong Recommendation (SR) Weak Recommendation (WR) High-quality evidence (H) Moderate-quality (M) Low-quality evidence (L) Very low-quality evidence (VL) Removal of Healthcare- Associated Pneumonia (HCAP) Contact with healthcare system MDRO Neither sensitive nor specific to identify at-risk patients Outcomes likely due to age/comorbidities Validated risk factors Underlying patient characteristics Likely will be included in updated CAP guidelines Spring

4 HCAP First defined in 2005 IDSA/ATS guidelines Consensus-derived criteria Low quality of evidence Not prospectively validated Co-chair of guideline committee publicly disavowed HCAP entity shortly after publication in 2005 Am J Resp Crit Care Med 2005;71: HCAP Strategy Original definition Hospitalized for > 2 days in past 90 days Resident of SNF or LTCF Home infusion therapy Wound care in past 30 days HD in past 30 days Family member with MDRO Recommended treatment Dual anti-pseudomonal coverage PLUS MRSA coverage Am J Resp Crit Care Med 2005;71: HCAP Strategy Cumulative antibiotic use associated with development of C. difficile infection HR 2.5 (95% CI ) for patients on 2 antibiotics HR 3.3 (95% CI ) for patients on 3-4 antibiotics Multicenter observational study demonstrated increased rate of overall 28 day mortality in patients with HCAP receiving triple antibiotic therapy as recommended by IDSA/ATS guidelines Clin Infect Dis 2011;53:42-8.; Lancet Infect Dis 2011;11(3):

5 Pathogens in HCAP 2014 meta analysis and systematic review (24 studies; n = 22,456 patients) Assessed frequency of MDRO in HCAP vs CAP groups MRSA, Enterobacteriacae, Pseudomonas Mortality and ICU admissions Clin Infect Dis 2014;58(3): Pathogens in HCAP No organisms met specified threshold for correlation (AUC 0.75) HCAP definition not sufficiently sensitive or specific to identify risk of MDRO Adjusted analysis found no difference in MDR rate Studies with high prevalence in HCAP also had high prevalence in CAP Clin Infect Dis 2014;58(3): Mortality in HCAP HCAP associated with increased mortality overall Less so when adjusted for higher mean age and # co-morbidities common in HCAP patients No mortality differences when excluding studies that mandated culture positive infection Clin Infect Dis 2014;58(3):

6 HCAP Summary HCAP definition poor at determining who might have these pathogens Overtreat areas of low MDR prevalence Undertreat areas of high MDR prevalence Need to look at other risk factors Excess mortality of HCAP primarily attributable to age and comorbidities Clin Infect Dis 2014;58(3): HAP: Initial Treatment Coverage: Staphylococcus Aureus (SR,VL) MRSA -Prior IV abx -Unit: >20% MRSA -High risk for mortality (W, VL) -Vancomycin -Linezolid (S, VL) MSSA Empiric (W,VL) Pipericillin/tazobactam Cefepime Levofloxacin Imipenem Meropenem Proven -Oxacillin -Nafcillin -Cefazolin HAP: Initial Treatment Coverage: Pseudomonas aeruginosa/other gram negative bacilli (SR,VL) Double Coverage -IV abx < 90 days -High risk mortality (SR,VL) Antibiotic Selection Beta-lactams/Cephalosporins -Pipericillin/tazobactam -Cefepime -Ceftazidime -Structural lung disease Carbapenems/Fluoroquinolones/etc -Ciprofloxacin -Levofloxacin -Imipenem -Meropenem -Aminoglycosides -Aztreonam 6

7 HAP: Length of Therapy 7 day course (SR,VL) Clinical criteria + procalcitonin vs clinical criteria alone (WR,L) Control group in studies had abx durations of 9-15 days Unclear if procalcitonin useful for stopping antibiotics prior to 7 days Procalcitonin not recommended for use in determining when to initiate antibiotics Initial Treatment: VAP Coverage: Staphylococcus Aureus (SR,L) MRSA -Prior IV abx -Septic shock -ARDS -5+ days hospitalization -Unit: >10-20% MRSA (or?) -High risk for mortality (W, VL) -Vancomycin -Linezolid (S, H) MSSA Empiric (W,VL) Pipericillin/tazobactam Cefepime Levofloxacin Imipenem Meropenem Proven -Oxacillin -Nafcillin -Cefazolin Initial Treatment: VAP Coverage: Pseudomonas aeruginosa/other gram negative bacilli (SR,L) Double Coverage -Prior IV abx -Septic shock -ARDS -5+ days hospitalization -Unit: >10% GN resistance -High risk for mortality (WR,L) -Structural lung disease Antibiotic Selection Beta-lactams/Cephalosporins -Pipericillin/tazobactam -Cefepime -Ceftazidime Carbapenems/Fluoroquinolones/etc -Ciprofloxacin -Levofloxacin -Imipenem -Meropenem -Aminoglycosides -Aztreonam 7

8 VAP: Length of Therapy 7 day course (SR,M) Clinical status Radiographic findings Laboratory findings Clinical criteria + procalcitonin vs clinical criteria alone (WR,L) Control group in studies had abx durations of 9-15 days Unclear if procalcitonin useful for stopping abx prior to 7 days Procalcitonin not recommended for determining when to initiate antibiotics VAP: Risk Factors NOT Associated with MDRO Re-intubation Immunosuppression Chronic respiratory failure Tracheostomy Diabetes Mellitus Recent corticosteroids Addressed in several studies Inhaled Antibiotic Therapy Use: VAP -GNB ONLY susceptible to aminoglycosides/polymyxins (WR,VL) Use systemic + inhaled Adjunctive Not responding to systemic abx alone 8

9 Conclusion It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgement with respect to particular patients or special clinical situations. Topic #2: Procalcitonin What is it? Precursor to calcitonin Rapidly produced/released in response to endotoxicin/proinflammatory cytokines Detectable within 2-4 hours Peaks within 6-24 hours Inhibited by interferon-gamma FDA approval Lower respiratory tract infections Sepsis 9

10 Current Thresholds Sepsis/Septic Shock < 0.05 Normal reference value < 0.5 Local bacterial infection possible; low risk > 0.5 and < 2 System infection possible; moderate risk > 2 and < 10 Systemic infection likely; high risk > 10 Severe bacterial sepsis or septic shock Intensive Care Med Suppl 2:S Example Algorithm CHI Franciscan Health ASP Committee Last Revision Date May 2014 Current Thresholds-Lower Respiratory Tract Infection Lower Respiratory Tract Infections < 0.1 Absence of infection > 0.1 and < 0.25 Bacterial infection unlikely > 0.25 and < 0.5 Bacterial infection possible > 0.5 Presence of bacterial infection Expert Rev Anti Infect Ther, (5):

11 Example Algorithm CHI Franciscan Health ASP Committee Last Revision Date May 2014 Limitations False elevations Newborns (>72 hours) Trauma, surgery, cardiac shock, burns Treatment with agents that stimulate cytokines Malaria/fungal infections Acute graft vs host disease Medullary thyroid tumors Small cell lung cancer Renal insufficiency (AKI, CKD, ESRD) Missed infections Organisms that lack a cell wall Mycoplasma Chlamydophila Expert Rev Anti Infect Ther, (5): Procalcitonin in Renal Insufficiency Acute Kidney Injury (AKI) Chronic Kidney Disease (CKD) End Stage Renal Disease (ESRD) 11

12 Acute Kidney Injury (AKI) Nakamura Y, et al. Single center retrospective study 393 patients Diagnostic accuracy of procalcitonin significantly lower in AKI than in non-aki Heredia-Rodriguez, et al. Case-control study (cardiac surgery patients) 440 patients (SIRS, severe sepsis, septic shock) SCr > 2, median procalcitonin levels similar between infected/non-infected patients J Infect Chemother 2015 Apr;21(4):257-63, J Crit Care : Chronic Kidney Disease Serum procalcitonin levels are significantly higher in CKD patients without a history of dialysis or infection compared with healthy individuals On average: 36% CKD without infection have procalcitonin > % CKD with infection have procalcitonin >0.5 Contou D, et al. Observational, prospective single center study 135 CKD patients Procalcitonin > 0.85 strong independent predictor of infection J Infect (2):105-15, Clin Infec Dis (12): End Stage Renal Disease Adult patients on chronic HD without infection have average procalcitonin baselines ranging from 0.26 to 1.0 ng/ml prior to starting the dialysis session Higher in infected ESRD vs non-infected ESRD Level did not correlate with severity of infection Levels drop significantly after renal replacement therapy (RRT) High-permeability of procalcitonin through dialysis filter Magnitude of drop in levels depends on method of RRT Most significant for patients on HD Measure levels before dialysis; may be falsely low for up to 48 hours Optimal threshold Lee et al: 0.75 ng/ml (sensitivity 76.2%, specificity 80%) Clin Infec Dis (12):1761-7, Korean J Intern Med 30(2):

13 Example Algorithm CHI Franciscan Health ASP Committee Last Revision Date May 2014 General Principles Any threshold increase will increase sensitivity but decrease specificity Unnecessary antibiotics Use other test results, clinical signs and symptoms, and sound judgment Topic #3: Clostridium Difficile 13

14 Refresher: Guidelines (ACG vs IDSA/SHEA) Mild/moderate ACG: metronidazole PO x 10 days IDSA/SHEA: metronidazole PO x days Severe ACG: vanco or fidaxomicin x 10 days IDSA/SHEA: vanco x days Severe, complicated ACG: vanco + metronidazole IV + vanco PR + vanco intra-colon IDSA/SHEA: vanco + metronidazole IV Infect Control Hos Epidemiol (5): , Am J Gastroenterol 2013;108: Recurrences First recurrence (ACG/IDSA/SHEA) Same agent Stratified by disease severity Second recurrence (or more) (ACG/IDSA/SHEA) Vancomycin (pulse/taper) NO metronidazole Fecal transplant (ACG only) Infect Control Hos Epidemiol (5): , Am J Gastroenterol 2013;108: Hines VA Score Prospective observation by Fujitani et al. Strongest correlation between Hines VA Index and prediction of severe CDI Severe CDI: score of >3 Variables Hines VA Index Fever (> 38⁰C) 1 Ileus 1 SBP < 100 mmhg 1 Leukocytosis WBC < 15,000/mm 3 WBC 15,000/mm 3 but < 30,000/mm 3 WBC 30,000/mm 3 Points CT scan findings (thickened colonic wall, colonic dilation, ascites) None One Two or more Infect Control Hosp Epidemiol 2011;32(3):

15 Metronidazole Dose: 500 mg PO/IV TID PO for mild/moderate IV for severe/severe complicated Higher levels in unformed stool Cumulative neurotoxicity May have less impact on microbiome/colonization resistance Resistance reported in some strains Clin Infect Dis 2012 (55);S71-S76, J Infect Dis (10): Vancomycin Dose: 125 mg PO QID or 500 mg PO QID High concentration in stool Recurrence rates of ~20% Pulse and taper 125mg PO QID x days 125mg PO BID x 7 days 125 mg QD x 7 days 125 mg PO Q 2-3 days x 8 weeks Clin Infect Dis 2012 (55);S71-S76, Infect Control Hos Epidemiol (5): New/Adjunctive/Alternative Agents Fidaxomicin Rifaximin Nitazoxanide Cholestyramine/Colestipol Tigecycline IVIG Fecal Microbiota Transplant Monoclonal Antibodies New Drug Developments Protective Agents 15

16 Fidaxomicin FDA approval Two large, double-blind, randomized, non-inferiority trials Possible reduction of recurrences Post-hoc exploratory ITT time-to-event meta-analysis of combined data Dose: 200 mg BID Chaser : 200 mg BID x 10 days AFTER vancomycin Not absorbed More effective in patients on concomitant antibiotics? Two phase III trials Cure rate: 90% fidaxomicin vs 79.4% for vanco Relapse rate: 16.9% for fidaxomicin vs 29.2% for vanco Cost Open Forum Infec Dis (2):69, Clin Infec Dis (2): , Clin Infect Dis (5):440-7 Rifaximin Dose: 400mg TID Alternative for metronidazole-unresponsive Prospective pilot trials Chaser 400mg BID x 14 days Patients with multiple recurrences/previous treatment strategies failed Not absorbed Somewhat flora sparing Resistance issues Clin Infect Dis (6):846-8, Therap Adv Gastroenterol (4): Nitazoxanide Dose: 500mg PO BID or 250mg PO QID Similar response rates to metronidazole/vancomycin Small studies Efficacy in patients who failed treatment with metronidazole Clin Infect Dis (1):152, J Antimicrob Chemother (4):

17 Cholestyramine/Colestipol Adjunctive treatment only Toxin binding Also binds vancomyin Clin Infect Dis 2012 (55);S71-S76 Tigecycline Dose 50mg IV Q12H 100mg IV LD then 500mg IV Q12H Broad-spectrum Patients w/ severe, intractable CDI for whom previous standard treatment failed Limited case reports Adjunct to standard treatment Limitations/drawbacks: Resistance Cost Increased mortality w/ use (recent FDA warning) Clin Infect Dis 2012 (55);S71-S76, Infect Dis Ther (2): IVIG MOA: binding/neutralization of toxin by IgG anti-toxin A antibodies Dose: mg/kg x 1-6 days Recurrent/refractory primarily More effective: colon-restricted, low APACHE 2 score Age > 60 Albumin < 2.5 WBC > 15 Temp > 38.3 Zar Criteria (IVIG for 2-4) Pseudomembranous colitis on colonoscopy ICU patient J Glob Infect Dis (2):

18 Fecal Microbiota Transplant 2013 ACG guidelines: 3+ recurrences 90-93% cure rates reported Am J Gastroenterol 2013;108: , Clin Infec Dis (10): Monoclonal Antibodies Targeted against toxins A and B Reduced relapse rates Treated w/ mabs + metronidazole/vanco CDA1 and CDB1: 7% relapse vs 25% Randomized, double-blind, placebo-controlled Actoxumab + Bezlotoxumab Phase III clinical trials Efficacy in preventing recurrent disease N Engl J Med : New Drug Developments LFF571 Semisynthetic thiopeptide Narrow-spectrum (flora sparing) High fecal concentrations Phase II trials (current) Efficacy/safety in patients w/ moderate CDI CB Cyclic lipopeptide Great in-vitro activity against c.diff than vancomycin or metronidazole Limited activity against intestinal flora Phase II trials Lower relapse rates compared to vancomycin Phase III trials (current) Efficacy compared to vancomycin Antimicrob Agents Chemother (11): , Antimicrob Agents Chemother (3):

19 Protective Agents Doxycycline Cohort study: ceftriaxone vs ceftriaxone/doxycycline 27% reduced risk Metronidazole Linezolid Retrospective study: major heart surgery patients Treated w/ linezolid = less development of CDI Appendix Probiotics Ann Pharmacother (6):772-6, Int J Antimicrob Agents : , Clin Gastroenterol Hepatol (12): References Kalil A, Metersky M, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Disease Society of America and the American Thoracic Society. Clinical Infectious Diseases 2016:63, 1-51 Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Resp Crit Care Med 2005;71: Stevens V, et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011;53:42-8. Chalmers JD, et al. Healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis. Clin Infect Dis 2014;58(3): Brunkhorst FM, Wegscheider K, Forycki ZF, Brunckhorst R. Procalcitonin for the early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Medicine (Suppl2):S Schuetz P, Albrich W, Christ-crain M, et al. Procalcitonin for guidance of antibiotic therapy. Expert Review of Antimicrobial Infection Therapy (5): Nakamura Y, Murai A, Mizanuma M, et al. Potential use of procalcitonin as a biomarker for bacterial sepsis in patients with or without acute kidney injury. Journal of Infection and Chemotherapy (4): Heredia-Rodriguez M, Bustamante-Munguira J, Fierro I, et al. Procalcitonin cannot be used as a biomarker of infection in heart surgery patients with acute kidney injury. Journal of Critical Care : Contou D, d Ythurbide G, Messika J, et al. Description and predictive factors of infection in patients with chronic kidney disease admitted to the critical care unit. Journal of Infection (2): Grace E. and Turner M. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clinical Infectious Disease (12): Lee WS, Kang DW, Back JH, et al. Cutoff value of serum procalcitonin as a diagnostic biomarker of infection in end-stage renal disease patients. Korean Journal of Internal Medicine (2): Surawicz CM, Brandt LJ, Binion DJ, et al. Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108: Fujitani S, George WL, Murthy AR. Comparison of clinical severity score indices for Clostridium difficile infection. Infect Control Hosp Epidemiol 2011;32(3): Venugopal, A. Current state of clostridium difficile treatment options. Clinical Infectious Disease 2015(55):S71-S76 Lewis BB, Buffie CG, Carter RA, et al. Loss of microbiota-mediated colonization resistance to clostridium difficile infection with oral vancomycin compared with metronidazole. Journal of Infectious Diseases (10): Soriano MM, Danziger LH, Gerding DN, et.al. Novel fidaxomicin treatment regimens for patients with multiple clostridium difficile infection recurrences that are refractory to standard therapies. Open Forum Infectious Disease (2):69 Johnson, S. Fidaxomicin chaser regimen following vancomycin for patients with multiple clostridium difficile recurrences. Clinical Infectious Disease (2): Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clinical Infectious Disease (5): Johnson S, Schriever C, Galang M, et al. Interruption of recurrent clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clinical Infectious Disease (6):846-8 References Continued Basu P, Dinani A, Rayapudi K, et al. Rifaximin therapy for metronidazole-unresponsive clostridium difficile infection: a prospective pilot trial. Therapeutic Advances in Gastroenterology (4): Britt N, Steed M, Potter M, et al. Tigecycline for the treatment of severe and severe complicated clostridium difificile infections. Infectious Disease Therapy (2): Shah N, Shaaban H, Spira R. Intravenous immunoglobulin in the treatment of severe clostridium difficile colitis. Journal of Global Infectious Disease (2):82-85 Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal biotherapy) for recurrent clostridium difficile infection. Clinical Infectious Disease (10): Lowry I, Colrine D, Leav B, et al. Treatment with monoclonal antibodies against clostridium difficile toxins. New England Journal of Medicine : Citron DM, Tyrrell KL, Merriam CV, et al. In vitro activities of CB-183,315, vancomycin, and metronidazole against 556 strains of clostridium difficile, 445 other intestinal anaerobes, and 56 enterobacteriaceae species. Anitmicrobial Agents Chemotherapy (3): Ting LS, Praestgaard J, Grunenberg N, et al. A first in-human, randomized, double-blind, placebo-controlled, single and multiple ascending oral dose study to assess the safety and tolerability of LFF571 in health volunteers. Antimicrobial Agents Chemotherapy (11): Turner RB, Smith CB, Martello JL, et al. Role of doxycycline in clostridium difficile infection acquisition. Annals of Pharmacotherapy (6):772-6 Valerio M, Pedromingo M, Munoz P, et al. Potential protective role of linezolid against clostridium difficile infection. International Journal of Antimicrobial Agents : Im GY, Modayil RJ, Lin CT, et al. The appendix may protect against clostridium difficile recurrence. Clinical Gastroenterology and Hepatology (12):