Download - Infectious Diseases Clinical Controversiesprevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database of Systematic Reviews 2013, Issue 5. Art.

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Infectious Diseases Clinical Controversies Series

Jonathan Cho, PharmD, MBA, BCIDP, BCPS; Crystal Howell, PharmD, BCIDP, BCPS

Associate Professor; Assistant ProfessorUT Tyler College of Pharmacy; UNT System College of Pharmacy

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To enter the Q&A and polling questions for this activity, go to ascp.com/qa and click on the title of this activity, as seen below.

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Speaker Information – Jonathan Cho• PharmD from UOP• PGY1/PGY2 in ID at Lee Health• Associate Professor at UT Tyler

COP• Infectious Diseases Clinical

Pharmacist at Longview Regional Medical Center

• Board Certified Infectious Diseases Pharmacist

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Speaker Information – Crystal Howell • PharmD from UT Austin• PGY1 and PGY2 in ID at Emory • Assistant Professor at UNT SCP• Infectious Diseases Clinical

Pharmacist at Medical City Dallas Hospital

• Board Certified Infectious Diseases Pharmacist

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Disclosure – Jonathan Cho and Crystal Howell

• The speakers have no conflicts of interest to disclose.

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Learning Objectives

• Analyze the advantages and disadvantages of antimicrobial therapy for use in Clostridioides difficile infection.

• Given a patient case, analyze the advantages and disadvantages of antimicrobial therapy use for gram-positive infections.

• Given a patient case, analyze the advantages and disadvantages of antimicrobial therapy use for gram-negative infections.

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Clostridioides difficile infection (CDI)

Prophylaxis and Probiotics

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To access the polling questions, go to this link: ascp.com/qa and select the “Infectious Diseases Clinical Controversies Series” activity, as seen below.

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Poll: Which CDI prevention strategies do you currently use at your institution?

A. ProbioticsB. Metronidazole prophylaxisC. Vancomycin prophylaxisD. Fidaxomicin prophylaxis

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CDI

• Clostridium difficile was renamed to Clostridioides difficile• “>20% of all CDIs identified in

2011 had onset in LTCFs”

Mullane KM, Winston DJ, Nooka A, et al. A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile – associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2019;68(2):196-203 / https://www.niaid.nih.gov/sites/default/files/Cdifficile.jpg

10 – 30% incidence of recurrence

83,000 estimated 1st

recurrences in 2011

Patients with recurrence had a 33% increased risk of mortality

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https://www.niaid.nih.gov/sites/default/files/Cdifficile.jpg

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Clinical Controversy – CDIGuideline Options to Prevent

Recurrence: • Tapered and pulsed regimen • Fecal microbiota transplantation

(FMT)

Other Proposed Methods to Prevent Recurrence:

• Bezlotoxumab• Not discussed today

• Probiotics • Guidelines do not make a

recommendation

• Prophylaxis • Not mentioned in guidelines

Mullane KM, Winston DJ, Nooka A, et al. A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile – associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2019;68(2):196-203

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Probiotics – Pro

• Primary obj: “assess efficacy and safety of probiotics for the prevention of C. difficile-associated diarrhea (CDAD) in adults and children.”• Details:

• 31 RCTs, 4492 patients • 23 studies indicate effectiveness of probiotics

• Pertinent Results:• CDAD reduced by 64% when given with antibiotics• NNT = 29 patients• Would prevent 35 CDAD per 1000 patients treated• LOS was 0.32 days lower • RR for adverse effects was 0.8 (95% CI 0.68-0.95)

Goldenberg JZ, Ma SSY, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD006095.

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Probiotics – ProCitation Study Type Results / Conclusion

Pattani R, Palda VA, Hwang SW, Shah PS. Probiotics for the prevention of antibiotic-associated diarrhea and Clostridium difficile infection among hospitalized patients: systematic review and meta-analysis. Open Med 2013; 7:e56–67.

SR and MA of 16 trials

• RR of antibiotic associated diarrhea 0.61 (95% CI 0.47 –0.79)

• RR of CDI 0.37 (95% CI 0.22 –0.61)

• NNT = 11

Johnson S, Maziade PJ, McFarland LV, et al. Is primary prevention of Clostridium difficile infection possible with specific probiotics? Int J Infect Dis 2012; 16:e786–92.

MA of 11 trials • RR of CDI = 0.39 (95% CI 0.19 –0.79)

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Probiotics – Pro Conclusion

There is sufficient data to suggest that probiotics are both safe and effective as prevention of CDAD with concomitant antibiotic use.

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Probiotics – Con

• Guidelines: insufficient data to support probiotic use!• Greater benefit shown when studies with CDI incidence 7-20x higher

in placebo arms than normally expected were included• Baseline risk ranged from 0-40%; differences in CDI definition

• Post-hoc subgroup analysis based on baseline CDAD risk• Low (0-2%) à RR 0.77 (95% CI 0.45 to 1.32, n = 5845) [P=0.34]• Mod (3-5%) àRR 0.53 (95% CI 0.16 to 1.77, n = 373) [P=0.70]• High (>5%) à RR 0.30 (95% CI 0.21 to 0.42, n = 2454) [P<0.01]

• Which probiotic do you use? What dose? How long?

Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database of Systematic Reviews 2017 Dec 19;12:CD006095.

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Probiotics – ConCitation Study Type Results / Conclusion

Saltzman T, Fazzari M, Chung S, et al. The effect of probiotics on the incidence of Clostridium difficile. Poster presentation at: IDWeek 2018; October 3-7, 2018; San Francisco, CA. Poster 514.

Retrospective cohort study

• Higher correlation of probiotic use and number of antibiotics taken

• RR of CDI 1.88 (95% CI 1.1 –3.16) [P=0.02]

• After adjustment, positive correlation still, but not signif.

Box MJ, Ortwine KN, Goicoechea M. No impact of probiotics to reduce Clostridium difficile infection in hospitalized patients: a real-world experience. Open Forum Infect Dis. 2018 Dec 13;5(12):ofy192.


• Healthcare facility-onset CDI 1.8% vs 0.9%; P=0.16

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Probiotics – ConCitation Study Type Results / Conclusion

Costa RL, Moreira J, Lorenzo A, et al. Infectious complications following probiotic ingestion: a potentially underestimated problem? A systematic review of reports and case series. BMC Complement Altern Med. 2018 Dec 12;18(1):329.

Systematic review

• Fungemia most common complication (37.6%)

• Elderly, colitis and immunocompromised were at increased risk

• Saccharomyces most frequent

Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trails. Am J Clin Nutr. 2010Mar;91(3):687-703.

Systematic review

• Patients w/pancreatitis had increased mortality and bowel ischemia

• Patients w/enteral nutrition had increased noninfectious complications

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Probiotics – What Do We Think?

Our Thoughts

Evidence Quality

Alternatives

Cost vs. Benefit

ADE

Which one?

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Prophylaxis – Pro

• Purpose: “examine the efficacy and safety of fidaxomicin as prophylaxis against CDAD” in Hematopoietic Stem Cell Transplant (HSCT) patients receiving fluoroquinolone prophylaxis during neutropenia• Details:

• RCT, double-blind, placebo controlled, multi-center • Intervention: fidaxomicin 200mg or placebo daily

• Pertinent Results:• Confirmed CDAD incidence was 4.7% vs 10.7% (p = 0.0026)• NNT = 17

Mullane KM, Winston DJ, Nooka A, et al. A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile – associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2019;68(2):196-203

https://www.idstewardship.com/wp-content/uploads/2017/08/Screen-Shot-2017-08-26-at-12.09.16-PM.png

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Prophylaxis – Pro

• Purpose: Compare CDI prophylaxis with oral vancomycin to no prophylaxis in allogeneic HSCT• Details

• Primary outcome: association between CDI prophylaxis and diagnosis of CDI

• Retrospective cohort review of a change in practice• Vancomycin 125mg PO bid from admission through

discharge • Pertinent Results:

• CDI incidence: 0/90 (0%) with vancomycin, 11/55 (20%) without (P<0.001)

• NNT = 5

Ganetsky A, Jan JH, Hughes ME, et al. Oral Vancomycin Prophylaxis Is Highly Effective in Prevention Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients. Clin Infect Dis 2018;xx(xx):1-7

https://cutispharma.com/wp-content/uploads/2016/11/vancomycin-

img.jpg

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Prophylaxis – Pro Conclusion

The use of vancomycin 125mg PO bid or Fidaxomicin 200mg PO daily can be used to prevent CDI

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Prophylaxis – Con

• Show me the data?!• The doses and durations use vary drastically• Long-term benefit of secondary prophylaxis is unknown

• Physician practice varies:• 54.2% use in patients with history of CDI recurrence• 29.9% use in patients with history of CDI receiving antibiotics

• No prospective, randomized studies evaluating secondary prophylaxis to provide guidance• Is there outcomes data?!• Cost vs. benefit

Sampson M, Zeitley K, Marcelin JR, et al. Secondary prophylaxis for Clostridium difficile infection – a physician practice assessment. Poster presentation at: IDWeek 2018; October 2-7, 2018; San Francisco, CA. Poster 496.

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Prophylaxis – Con

• More patients not receiving prophylaxis were on metronidazole before and after HSCT• 30-days before: 0% vs. 7%, P=0.02• 30-days after: 7% vs. 16%, P=0.09

• No differences in outcomes:• Median length of stay 29 vs. 28 days; P=0.22• 1-year estimated rate of overall survival (HR 0.60; 95% CI 0.32–1.12; P=0.11)• Non-relapse mortality (HR 0.72; 95% CI 0.29–1.83; P=0.49). • Graft vs Host Disease (GVHD)-free, relapse-free survival rates (38.2% vs.

45.6%, respectively; P=0.39)

Ganetsky A, Jan JH, Hughes ME, et al. Oral Vancomycin Prophylaxis Is Highly Effective in Prevention Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients. Clin Infect Dis 2018;xx(xx):1-7

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Prophylaxis – ConCitation Study Type Results / Conclusion

Carignan A, Poulin S, Martin P, et al. Efficacy of secondary prophylaxis with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol. 2016 Dec;111(12):1834-1840.


• Decreased risk for recurrent CDI (AHR, 0.47; 95% CI, 0.32-0.69; P<0.0001) but not for initial episodes (AHR, 0.91; 95% CI, 0.57-1.45; P=0.68)

Splinter LE, Kerstenetzky L, Jorgenson MR, et al. Vancomycin prophylaxis for prevention of Clostridium difficile infection recurrence in renal transplant patients. Ann Pharmacother. 2018 Feb;52(2):113-119.


• No significant difference in CDI recurrence (0% [0/12] vs 8% [2/24], P = 0.54)

Zhang K, Beckett P, Abouanaser S, et al. Prolonged oral vancomycin for secondary prophylaxis of relapsing Clostridium difficile infection. BMC Infect Dis. 2019 Jan 14;19(1):51.


• 31% relapse rate• Increased doses throughout

therapy if diarrheal episodes

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Prophylaxis – What Do We Think?

Our Thoughts

Specific Patients (HSCT)

Cost vs. Benefit

Dose? Duration?

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Gram Positive InfectionsLinezolid for bacteremia and double coverage for MRSA

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Poll: Which of the following would you use to treat MRSA bacteremia?

A. LinezolidB. VancomycinC. Daptomycin + ceftarolineD. Vancomycin + cefazolin

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Clinical Controversy - Linezolid for Bacteremia

• There are no bacteremia guidelines • MRSA bacteremia mortality 20-30% • MRSA guidelines recommend vancomycin or daptomycin

VS

Geriak M, Haddad F, Rizvi K, et al. Clinical Data on Daptomycin Plus Ceftaroline Versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother2019;63(5):e02483-18.

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Linezolid for Bacteremia – Pro

• SR and MA to compare daptomycin and linezolid for vancomycin resistant Enterococcus (VRE) • Details:

• 13 studies; 1188 patients (532 daptomycin, 656 linezolid)

• Pertinent Results:• Mortality OR 1.46 with daptomycin compared to linezolid (95% CI 1.02-2.09)• Microbiologic relapse OR 2.65 with daptomycin (95% CI 1.03-6.78)

Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infectious Diseases 2014;14:687

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• Open-label, multicenter, non-inferiority study of patients with catheter-related bloodstream infection (CRBSI) randomized to linezolid or vancomycin • Details:

• 294 patients needed for a power of 80%-> 393 completed treatment

• Pertinent Results:• Microbiologic success in 66.7% of linezolid patients and 66.7% of vancomycin

patients (95% CI -19 to 19)• MRSA: linezolid 79.2% vs 76.2% (95% CI -21.4 to 27.4)

Wilcox MH, Tack KJ, Bouza E, et al. Complicated Skin and Skin-Structure Infections and Catheter-Related Bloodstream Infections: Noninferiority of Linezolid in a Phase 3 Study. Clin Infect Dis 2009;48:203-12

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• Prospective cohort study of propensity score matching patients (2:1) with Staphylococcus aureus bacteremia (SAB)• Purpose: efficacy and safety of completing SAB treatment with oral

linezolid in low risk patients • Low risk: clinically stable, appropriate source control, negative follow up

blood culturesOutcome Oral Linezolid

(n =45)Standard Treatment

(n = 107)P value

90 day relapse 1 (2.2) 4 (3.7) 1.00

30 day mortality 1 (2.2) 17 (15.9) 0.04

LOS after 1st culture 8 (7-10) 19 (15-32) < 0.01

Willekens R, Puig-Asensio M, Ruiz-Camps I, et al. Early Oral Switch to Linezolid for Low-risk Patients with Staphylococcus aureus Bloodstream Infections: A Propensity-matched Cohort Study. Clin Infect Dis 2018;xx(xx):1-7

Transitions of Care!

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Linezolid for Bacteremia – Pro Conclusion

Linezolid can be used for MRSA bacteremia

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Linezolid for Bacteremia – Con

• Bacteriostatic• Data for treatment of serious infections are extremely limited • Would not use for extended period of time

• Increase risk for thrombocytopenia

• Some data show benefit of linezolid vs. daptomycin for VRE• Limitations: variable case definitions, small sample size, variations in

outcome measures, insufficient daptomycin dosing

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• Multicentered, retrospective cohort study evaluating linezolid vs daptomycin for treatment of VRE-BSI• Results are even more impressive as daptomycin dose was 6 mg/kg

• Linezolid had ↑ risk of treatment failure (RR 1.37; 95% CI 1.13-1.67; P = 0.001) • After adjusting for confounding factors treatment failure persisted (adjusted

RR 1.15; 95% CI 1.02-1.30; P = 0.026)• Higher 30-day mortality (42.9% vs 33.5%; RR, 1.17; 95% CI, 1.04-1.32; P =

0.014) • Higher microbiologic failure rates (RR, 1.10; 95% CI, 1.02-1.18; P = 0.011)

Britt NS, Potter EM, Patel N, et al. Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients. Clin Infect Dis 2015 Sep 15;61(6):871-8.

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• Prospective, single-centered, observational study evaluating linezolid vs. lipopeptide for treatment of persistent MRSA bacteremia• Duration of persistent bacteremia (median 16 days vs. 10 days;

P = 0.008) was longer in linezolid-based salvage group • 30-day mortality (11% vs. 25%; P = 0.08)• Adverse reactions were not followed• No significant difference in outcomes between the two groups

Park HJ, Kim SH, Kim MJ, et al. Efficacy of linezolid-based salvage therapy compared with glycopeptide-based therapy in patients with persistentmethicillin-resistant Staphylococcus aureus bacteremia. J Infect. 2012 Dec;65(6):505-12.

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Linezolid for Bacteremia – What Do We Think?

Our Thoughts

Great for transitions of

care (TOC)

Evaluate risk factors for persistent

bacteremiaAdverse drug

reactions

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Clinical Controversy – Double Coverage of MRSA• CDC considers MRSA a serious threat• MRSA bacteremia mortality 20-30%

PSSA • Beta lactamase

MSSA • mecA

MRSA

VRSA •vanA

VISA •Thick cell wall

Geriak M, Haddad F, Rizvi K, et al. Clinical Data on Daptomycin Plus Ceftaroline Versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother 2019;63(5):e02483-18.

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Double Coverage for MRSA – Pro

• Details:• Open-label prospective RCT of adults with MRSA bacteremia• All patients had an ID consult• Randomized to either:

• Daptomycin 6 – 8 mg/kg/day + ceftaroline 600mg IV q8h• Monotherapy with either vancomycin dosed by pharmacy or daptomycin 6 - 8

mg/kg/day

• Pertinent Results: • Trial stopped early to significant mortality benefit in the combination arm• Combination arm 0% vs 26% in monotherapy arm (p = 0.029)

Geriak M, Haddad F, Rizvi K, et al. Clinical Data on Daptomycin Plus Ceftaroline Versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother 2019;63(5):e02483-18.

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Double Coverage for MRSA – Pro

• Details:• Case series of 7 patients with persistent MRSA bacteremia• Sources: endocarditis, abscess, and unknown• 1st line therapy: vancomycin • 2nd line therapy: daptomycin

• Daptomycin doses ranged from 6-10 mg/kg

• Pertinent Results: • When an anti-staphylococcal β lactam was added, blood cultures cleared within

24 hrs• Theory:

• Anti-staphylococcal β lactams reduce the surface charge of the bacteria which enhances daptomycin binding

Dhand A, Bayer AS, Pogliano J, et al. Use of Antistaphylococcal β-Lactams to Increase Daptomycin Activity in Eradicating Persistent Bacteremia Due to Methicillin-Resistant Staphylococcus aureus: Role of Enhanced Daptomycin Binding. Clin Infect Dis 2011;53(2):158-163

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Double Coverage for MRSA – Pro Conclusion

Dual coverage should be used to treat MRSA infections, especially bacteremia

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Double Coverage for MRSA – Con

• Is double coverage considered standard of practice for most infections? • Most guidelines recommend monotherapy

• Skin and skin structure infections• Respiratory infections• Urinary tract infections

Citation Study Type Results / Conclusion

Wargo KA, McCreary EK, English TM. Vancomycin combined with clindamycin for the treatment of acute bacterial skin and skin-structure infections. Clin Infect Dis. 2015 Oct 1;61(7):1148-54.


• 3.7 ± 1.5 days vs 4.0 ± 2.0 days, P = 0.192, combination and monotherapy, respectively

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Double Coverage for MRSA – ConCitation Study Type Results / Conclusion

Martin TC, Chow S, Johns ST, et al. Ceftaroline-associated encephalopathy in patients with several renal impairment. Clin Infect Dis. 2019 Aug. ciz857.

Case report • Among 28 patients with eGFR<30 + ≥5 days of ceftaroline, 3 cases of encephalopathy.

LaVie KW, Anderson SW, O’Neal HR Jr, et al. Neutropenia associated with long-term ceftarolineuse. Antimicrob Agents Chemother. 2015 Oct 26;60(1):264-9.


• Mean duration of 27 days for ceftaroline

• 7/39 (18%) developed neutropenia with majority have an ANC<500 cells/mm3

Blumenthal KG, Kuhlen JL, Weil AA, et al. Adverse drug reactions associated with ceftaroline use. J Allergy Clin Immunol Pract. 2016 Jul-Aug; 4(4): 740–746.

Two-center retrospective cohort study

• Median duration of 13 days for ceftaroline

• 20/96 (21%) developed adverse reactions

• Hematologic abnormalities, rash, fever were most common

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Double Coverage of MRSA – What Do We Think?

Our Thoughts

Endovascular source?

Endocarditis?

Persistent bacteremia?

Different dosing and education

Adverse drug reactions

$$$$$

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Gram Negative InfectionsDouble coverage and the treatment of ESBLs and Amp-Cs

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Poll: Which of the following would you use to treat bacteremia due to an ESBL-producing organism?

A. MeropenemB. Piperacillin/tazobactamC. CefepimeD. Levofloxacin

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Clinical Controversy – Double Coverage of Gram Negative Organisms

Efficacy Feasibility

Cost

Safety

Clearance

Mortality

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Double Coverage of Gram Negative Organisms –Pro• Details:

• SR and MA of patients with multi-drug resistant Acinetobacter baumannii• 25 studies, 2379 patients

• Pertinent Results:• Combination therapy with colistin compared to monotherapy with colistin

increased microbiologic clinical cure (RR 1.21, 95% CI 1.1 – 1.34)• Combination therapy with colistin significantly decreased all-cause mortality

(RR 0.58, 95% CI 0.35 – 0.96)

Kengkla K, Kongppakwattana K, Saokaew S, Aprisarnthanarak A, Chaiyakunapruk N. Comparative efficacy and safety of treatment options for MDR and XDR Acinetobacter baumannii infections: a systematic review and network meta-analysis. J Antimicrob Chemother 2018;73:22-32

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Double Coverage of Gram Negative Organisms –Pro• Details:

• Retrospective cohort of 41 patients with Klebsiella pneumoniaecarbapenemase (KPC)

• Treatments: • Combination: carbapenem + (colistin/polymixin B or tigecycline)• Monotherapy: colistin/polymixin B or tigecycline

• Pertinent Results:• 28 day crude mortality OR was 0.07 when combination therapy was used

compared to monotherapy (95% CI 0.009 – 0.71)

Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment Outcome of Bacteremia Due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial regimens. Antimicrob Agents Chemother 2012;56(4):2108-13

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Double Coverage of Gram Negative Organisms – Pro Conclusion

Combination therapy improves mortality in multi-drug resistant gram negative infections

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Double Coverage of Gram Negative Organisms –Con• Retrospective, single-center study comparing β-lactam monotherapy

with β-lactam/fluoroquinolone combination• Primary outcome: 28 day mortality

• Critically ill (25.6% [23 of 90] versus 27.8% [22 of 79]; adjusted HR, 0.87; 95% CI, 0.47 to 1.62; P = 0.660)

• Less-critically ill (4.2% [9 of 214] versus 8.8% [28 of 319]; adjusted HR, 0.44; 95% confidence interval [CI], 0.20 to 0.98; P = 0.044)• However, way more patients with bacteremia from a urinary source (P<0.01)

• No safety data collected (e.g. adverse reactions, QTc prolongation)

Al-Hasan MN, Wilson JW, Lahr BD, et al. Beta-lactam and fluoroquinolone combination antibiotic therapy for bacteremia caused by gram-negative bacilli. Antimicrob Agents Chemother. 2009 Apr;53(4):1386-94.

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Double Coverage of Gram Negative Organisms – ConCitation Study Type Results / Conclusion

Pena C, Suarez C, Ocampo-Sosa A, et al. Effect of adequate single-drug vs combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections. Clin Infect Dis. 2013Jul;57(2):208-16.

Post hoc analysis of a prospective cohort

• No significant advantage to combination therapy for both empiric and definitive therapy

• 69.4% (95% CI, 59.1-81.6) vs. 73.5% (95% CI, 68.4%-79.0%)

Vardakas, KZ, Tansarli GS, Bliziotis IA, et al. β-Lactam plus aminoglycoside or fluoroquinolone combination versus β-Lactam monotherapy for Pseudomonas aeruginosa infections. Int J Antimicrob Agents. 2013Apr;41(4):301-10.

Meta-analysis • No mortality difference for β-lactam monotherapy either as definitive (RR 0.97, 95% CI 0.77-1.22) or empiric (RR 1.02, 95% CI 0.78-1.34)

Chamot E, Boffi El Amari E, Rohner P, et al. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia. AntimicrobAgents Chemother. 2003 Sep;47(9):2756-64.


• ↑ mortality with monotherapy empiric (adjusted HR, 3.7 [95% CI, 1.0–14.1]), but no significant difference for definitive (adjusted HR, 0.70 [95% CI, .30–1.7])

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Double Coverage of Gram Negative Organisms –Con• Multi-national, open-label, randomized controlled trial from 2014-17

evaluating meropenem/vaborbactam vs. best available therapy (BAT)• mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15)

[P = 0.03] at End of Treatment and 59.4% and 26.7% [P = 0.02] at Test of Cure• Day-28 all-cause mortality was 15.6% and 33.3% • Treatment-related AEs and renal-related AEs were 24.0% and 4.0% for

meropenem-vaborbactam vs 44.0% and 24.0% for BAT• Monotherapy for CRE infection was associated with increased clinical cure,

decreased mortality, and reduced nephrotoxicity

Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther. 2018 Dec;7(4):439-455.

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Double Coverage of Gram Negative Organisms – What Do We Think?

Our ThoughtsOrganism?

Local Resistance

Empiric vs Definitive

Adverse drug

reactions

$$$$$

Johnson SJ, Ernst EJ, Moores KG. Is double coverage of gram-negative organisms necessary? Am J Health Syst Pharm. 2011 Jan 15;68(2):119-24.

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Clinical Controversy – Carbapenem Sparing ESBL and AmpC Treatments• Enzymatic resistance mechanism most common in gram negative

organisms• Extended Spectrum β-lactamase (ESBL) and AmpC are increasingly common

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Carbapenem Sparing Treatment – Pro

• Purpose: compare 30 day mortality of patients with ESBL bacteremia empirically treated with piperacillin-tazobactam vs a carbapenem• Details:

• Retrospective cohort study at 2 university hospitals of patients with ESBL E. coli and K. pneumoniae bacteremia.

• 151 patients (piperacillin-tazobactam 94, carbapenem 57)

• Pertinent Results:• 30 day mortality was not statistically different (30.9% vs 29.8%, p = 0.89)• Carbapenems had an OR of 3.32 (95%CI 1.12-9.87) as a risk factor for

acquiring a multi-drug resistant organism

Ng TM, Khong WX, Harris PNA, De PP, Chow A, Tambyah PA, et al. (2016) Empiric Piperacillin-Tazobactam versus Carbapenems in the Treatment of Bacteraemia Due to Extended- Spectrum Beta-Lactamase-Producing Enterobacteriaceae. PLoS ONE 11(4): e0153696. doi:10.1371/journal.pone.0153696

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Carbapenem Sparing Treatment – Pro

• Purpose: “compare clinical outcomes of patients with invasive infections caused by AmpC” treated with cefepime vs meropenem• Details:

• Propensity score matched prospective observational cohort• Bacteremia, pneumonia, intra-abdominal infections• Enterobacter spp, Serratia marcescens, or Citrobacter spp• 78 patients (46 cefepime, 32 meropenem)

• Pertinent Results: • Primary outcome: 30 day mortality (10 vs 11, p = 0.99)• Matched OR for mortality receiving cefepime was 0.6 (95% CI 0.23 – 2.31)

Tamma PD, Girdwood SC, Gopaul R, et al. The use of cefepime for treating AmpC β-lactamase-producing Enterobacteriaceae. Clin Infect Dis 2013;57(6):781-8

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Carbapenem Sparing Treatment – Pro Conclusion

Piperacillin-tazobactam and cefepime are non-inferior treatment options for ESBL and AmpC producing organisms respectively

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Carbapenem Sparing Treatment – Con

• Single-center study comparing 14-day mortality of piperacillin-tazobactam vs. carbapenems for ESBL bacteremia• 141 (48%) piperacillin-tazobactam vs. 110 (52%) carbapenems

• Less immunocompromised patients in piperacillin-tazobactam arm

• Common bacteremia sources:• Catheter-related (46%), urinary (21%), intra-abdominal (17%)

• The adjusted risk of death was 1.92 times higher for patients receiving piperacillin-tazobactam (95% CI, 1.07-3.45)

Tamma PD, Han JH, Rock C, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis. 2015 May 1;60(9):1319-25.

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• Non-inferiority, randomized clinical trial comparing piperacillin-tazobactam (188) vs. meropenem (191) for ESBL bacteremia• Common bacteremia sources:

• Urinary (54.8% vs 67%), intra-abdominal (18.1% vs 14.7%)• Piperacillin-tazobactam arm had shorter time to receipt of appropriate

antibiotics (5.5 hrs vs 9 hrs)• Primary outcome: 30 day mortality (12.3% vs. 3.7%, RD 8.6%)• Adjustment for a urinary tract source and Charlson Comorbidity Index score

resulted in little change • Unadjusted OR, 3.69 (97.5% CI, 0 to 8.82); adjusted OR, 3.41 (97.5% CI, 0 to 8.38)

Harris PN, Peleg AY, Iredell J, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018 Sep 11;320(10):984-994.

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• Retrospective chart review of patients treated with carbapenem vs. either cefepime or piperacillin/tazobactam for Enterobacter sp., S. marcescens, C. freundii, Providencia sp., and M. morganii (ESCPM)• Respiratory infection (53.3%), bacteremia (46.7%)• E. cloacae (53.3%), S. marcescens (30%), C. freundii (6.7%)• All patients: 13.3% vs. 26.8%, P = 0.164• ICU patients: 9.1% vs. 29.6%, P = 0.046

• Trend favored carbapenems for those on mechanical ventilation, vasopressor

Jeffres M, Foster C, Mccollister B, et al. Outcomes of patients with Amp-C inducible Enterobacteriaceae infections treated with carbapenems versus cefepime or piperacillin/tazobactam. Poster presentation at: IDWeek 2016; October 25-30, 2016; New Orleans, LA. Poster 1998.

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Carbapenem Sparing Treatment –What Do We Think?

Our Thoughts

Source and Source Control

ESBL vs AmpC

Severity of Infection

Bacterial Burden

Adverse drug reactions

New Drugs as Carbapenem-

Sparing?

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To access Q&A, go to this link: ascp.cnf.io and select the “Infectious Diseases Clinical Controversies Series” activity, as seen below.

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Jonathan Cho, PharmD, MBA, BCIDP, BCPS; Crystal Howell, PharmD, BCIDP, BCPS

Associate Professor; Assistant ProfessorUT Tyler College of Pharmacy; UNT System College of Pharmacy

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