Dosing of piperacillin- tazobactam in Pseudomonas aeruginosa - - PowerPoint PPT Presentation

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Dosing of piperacillin- tazobactam in Pseudomonas aeruginosa infections: is bigger better?

Adam Mah – LMPS resident Antimicrobial Stewardship rotation November 9th, 2017

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Learning Objectives

• Review literature to support dosing of

piperacillin-tazobactam (pip/tazo) depending on source

• Apply PK/PD data to support dosing

recommendations for pip/tazo

• Provide dosing recommendations for

HAP/VAP, UTI, IAI, OM, diabetic foot infections

Pseudomonas aeruginosa

• Gram-negative non-fermenting bacilli3
• Facultative anaerobe3
• Intrinsically resistant to multiple ABX - low

permeability of outer cell membrane3

• Found in soil, water, and infrequently part
• f skin flora2
• Associated with respiratory tract infections,

UTI, IAI, SSTI, osteomyelitis3

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Piperacillin-tazobactam

• Time-dependent kill – t1/2 = 0.7-1.2 hrs1
• Good penetration: lungs, intestinal

mucosa, interstitial fluid, gallbladder1

• Poor penetration: CNS1

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Overall PICO

P For patients with infection involving

• P. aeruginosa at varying sites…

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Is piperacillin-tazobactam 4.5 g IV q6h…

C Superior to 3.375 g IV q6h or

4.5 g IV q8h…

O For mortality, and microbiological and

clinical cure?

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IDSA guidelines

• HAP/VAP4: piperacillin-tazobactam 4.5 g

IV q6h recommended

• Complicated intraabdominal infections

(IAI)5: “For Pseudomonas aeruginosa…dosage may be increased to…4.5 g IV q6h”

• Non-cath and cath UTI6,7: no dosing

recommendations

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More IDSA guidelines…

• Diabetic foot ulcer8: no dosing

recommendations

• Vertebral osteomyelitis9: pip/tazo not

mentioned (cefepime or meropenem)

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VAP

Study Population Cultures Outcome

Rea-Neto et al (2008)14 >18 yo with nosocomial PNA +/- ventilation. 22% VAP Pseudomonas in 58% of isolates Pip/tazo 4.5 g q6h IV = doripenem 500 mg q8h IV for clinical and microbiological cure Brun- Buisson et al (1998)15 ICU pts, n = 204, all were VAP Pseudomonas isolated in 32% of pts Pip/tazo 4.5 g q6h IV = ceftazidime 1 g q6h when either combined w/AMG for clinical cure

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Lerma et al (2001) - HAP11

S/P OL RCT - 124 ICU patients with HAP requiring

mechanical ventilation

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Pip/tazo 4.5 g IV q6h + amikacin 7.5 mg/kg IV BID

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Ceftazidime 2 g IV q8h + amikacin 7.5 mg/kg IV BID

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10: Clinical cure: NSS. Clinical improvement: NSS

• P. aeruginosa subgroup (22% of isolates):

NSS for both clinical cure and clinical improvement.

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HAP

Study Population Cultures Outcomes

Schmitt et al (2006)12 n = 217, non- ICU, RCT, PNA >48 h post-admit, no septic shock Pseudo not reported Pip/tazo 4.5 g IV q8h = imipenem/cilastatin for clinical cure (~75% in each arm) Yamamoto et al (2013)13 n = 67, non-ICU, RCT, hospitalized >2 days in past 90 days Pseudo in 12% of pts, equal in each arm Pip/tazo 4.5 g IV q8h = meropenem for clinical cure (88% in pip/tazo arm, trend favouring pip/tazo)

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Overall limitations

• Lacking Pseudomonas isolate frequency

reporting

• No subgroup analyses
• Microbiologically heterogeneous

populations

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HAP/VAP: bottom line

• For HAP (ICU or non-ICU) and VAP:

4.5 g q6h

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Intraabdominal infections

Study Population Cultures Outcomes

Solomkin et al (2003)16 n = 396, RCT, IAI post-op (laparotomy or percutaneous drain) Pseudo in 12% of pts Pip/tazo 3.375 g IV q6h: 88.5% Pseudomonas clinical cure rate Niinikoski et al (1993)17 n = 86, RCT, heterogeneous IAI population Pseudo reported as a pathogen but rates not reported Pip/tazo 4.5 g IV q8h: 100% micro cure, 87% clin cure Murao et al (2017)18 n = 10, single- dose pre-op, PK model analysis No cultures, PK study Pip/tazo 4.5 q8h

• r 3.375 g q6h

achieved >50% time >MIC of 16

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Limitations

• RCTs looked at pip/tazo vs carbapenem
• Not a lot of RCT data
• Requires invoking PK principles
• Heterogeneous populations: IAIs all

grouped into one cohort

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Bottom line: intraabdominal infections

• Pip/tazo 3.375 g IV q6h or 4.5 g IV q8h

achieves adequate concentrations in peritoneal fluid and GI tract

• Limited but favourable RCT data
• Recommend: 3.375 g IV q6h

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Cystitis and Pyelonephritis

• Piperacillin: 68% excreted in urine as

unchanged drug1

• Tazobactam: 80% excreted in urine as

unchanged drug1

• Limitation: no RCT data

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Bottom line: Cystitis and pyelonephritis

• Likely good penetration of drug to renal

tissue and bladder assuming good renal function1

• Similar PK/PD to other penicillins
• Recommend: Pip/tazo 3.375 g q6h IV

and monitor clinical response

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Diabetic foot infections

• Consider P. aeruginosa if travel to warm

climate, foot maceration, or colonization8

• Likely good penetration to soft tissue1
• Harkless et al (2005) OL RCT (n = 314)19

– Pip/tazo 4.5 g IV q8h associated with 85.8% microbiologic cure for Pseudomonas subgroup (most common Gram-negative) – Unclear how many isolates in total in trial – No reporting on proportion of species

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Bottom line: Diabetic foot infections

• Pip/tazo 4.5 g IV q8h has RCT data for P.

aeruginosa treatment success

• Pip/tazo 3.375 g IV q6h likely effective as

well given time-dependent kill

• Recommend: pip/tazo 3.375 g IV q6h

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Osteomyelitis

• Incavo et al (1994): single-dose PK in hip

replacement pts (n = 10)20

– Single 3.375 g IV dose – Bone:plasma concentration ratio ~1/8

• Laghmouche et al (2017): Retrospective

chart review26

– Bone culture confirmed Pseudomonas – No dosing information reported – Single-agent pip/tazo 10 endpt: clinical cure

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Osteomyelitis

• Saltoglu et al (2010) RCT21

– Pip/tazo 4.5 g IV q8h 96% complete microbiological response against diabetic foot ulcers associated with osteomyelitis – Limitation: 57% isolates were Gram- negative; not clear how many Pseudomonas – Limitation: 60% of patients in trial had amputation

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Bottom line: Osteomyelitis

• Single-dose study suggests

subtherapeutic levels of pip/tazo in bone

• Lacking RCT data
• Recommend: pip/tazo 4.5 g IV q6h

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• P. aeruginosa bacteremias
• High mortality rates (30-day = ~40%)22
• Complications23

– Infective endocarditis (rare, assoc. w/IVDU) – Ecthyma gangrenosum

• Pip/tazo likely achieves therapeutic

concentrations in plasma to sterilize

• Bottom line: dose for source

– Except febrile neutropenia24

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Case #1

• Ms. S, 69 yo female admitted for bilateral

leg cellulitis superimposed on top of chronic vascular insufficiency

• Wound Cx: heavy growth of P. aeruginosa
• XR leg: periosteal reaction. OM

diagnosed.

• On pip/tazo 4.5 g IV q6h
• Do you agree with the dosing regimen?

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Case #2

• Mr. K, 65 yo male admitted for hip fracture
• Develops HAP 10 days post-admission
• Hx of colonization with P. aeruginosa in

sputum, and MRSA in previous wound

• culture. Sputum cultures pending.
• On pip/tazo 4.5 g IV q6h + vancomycin

1.5 g IV q12h

• Do you agree with the dosing regimen

for pip/tazo?

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Case #3

• Mr. R, 70 yo male admitted for abdo pain
• Ascending cholangitis, underwent surgery

for source control

• Fever/chills ~5 days later, RUQ

tenderness and guarding

• Dx: Late-onset health care associated IAI.

No cultures.

• On pip/tazo 4.5 g IV q8h
• Do you agree with the dosing regimen?

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Case #4

• Mr. B, 75 yo male admitted for confusion

from assisted living with painful ulcers on feet and legs

• BCx and wound Cx: P. aeruginosa (3 of 4

bottles) susceptible to pip/tazo

• Presumed source: diabetic foot ulcer
• XR foot: no suspicion for osteomyelitis
• On pip/tazo 4.5 g IV q6h
• Do you agree with the dosing regimen?

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Summary of evidence

Indication Aggressive dosing? HAP in the ICU YES HAP not in ICU YES VAP YES

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Summary of evidence

Indication Aggressive dosing? Intraabdominal infections NO Cystitis or pyelonephritis NO Diabetic foot infection NO Osteomyelitis YES

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References

1. Piperacillin and tazobactam. In: Lexi-Drugs [database on the Internet]. Hudson (OH): LexiComp, Inc; 2017 [cited 26 Oct 2017]. Available from: http://online.lexi.com/action/home. 2. Cogen AL, Nizet V et al. Skin microbiota: a source of disease or defence? Br J Dermatol 2008;158(3):442-55. 3. Streeter K, Katouli M. Pseudomonas aeruginosa: A review of their Pathogenesis and Prevalence in Clinical Settings and the Environment. Infect Epidemiol Med 2016;2(1):25-32. 4. Kalil AC, Metersky ML, Klompas M et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infec Diseases 2016;63(5):e61- 111. 5. Solomkin JS, Mazuski JE, Bradley 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 Infec Diseases 2010;50:133-64. 6. Gupta K, Hooton TM, Naber KG et al. International Clinical Practice Guidelines of the Treatment

• f Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious

Diseases Society of America and the European Society for Microbiology and Infectious

• Diseases. Clin Infec Diseases 2011;52(5):e103-e120.

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References

7. Hooton TM, Bradley SF, Cardenas DD et al. Diagnosis, Prevention, and Treatment of Catheter- Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. 8. Lipsky BA, Berendt AR, Comia PB et al. 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections. Clin Infec Diseases 2012;54(12):132-73. 9. Berbari EF, Kanj SS, Kowalski TJ et al. 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clin Infec Diseases 2015;61(6):e26-46. 10. Osmon DR, Berbari EF, Berendt AR. Diagnosis and Management of Prosthetic Joint Infection: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infec Diseases 2013;56(1):e1-25. 11. Lerma EA, Ordenana JI, Marcos RJ et al. Efficacy and tolerability of piperacillin/tazobactam versus ceftaidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial. Intensive Care Med 2001;27:493-502. 12. Schmitt DV, Leitner E, Welte T et al. Piperacillin/Tazobactam vs Imipenem/Cilastatin in the Treatment of Nosocomial Pneumonia – a Double Blind Prospective Multicentre Study. Infection 2006;34(3):127-34. 31

References

13. Yamamoto Y, Izumikawa K, Nakamura S et al. Prospective randomized comparison study of piperacillin/tazobactam and meropenem for healthcare-associated pneumonia in Japan. J Infect and Chemotherapy 2013;19(2):291-98. 14. Rea-Neto A, Niederman M, Lobo SM et al. Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study. Curr Med Res Opin 2008;24(7):2113-26. 15. Brun-Buisson C, Sollet JP, Schweich H et al. Treatment of ventilator-associated pneumonia with piperacillin-tazobactam/amikacin versus ceftazidime/amikacin: a multicenter, randomized controlled trial. VAP Study Group. Clin Infect Dis 1998;26(2):346-54. 16. Solomkin JS, Yellin AE, Rotstein OD et al. Ertapenem Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections. Ann Surg 2003;237(2):235-45. 17. Niinikoski J, Havia T, Alhava E et al. Piperacillin/tazobactam versus imipenem/cilastatin in the treatment of intra-abdominal infections. Surg Gynecol Obstet 1993;176(3):255-61. 18. Murao N, Ohge H, Ikawa K et al. Pharmacokinetics of piperacillin-tazobactam in plasma, peritoneal fluid and peritoneum of surgery patients, and dosing considerations based on site- specific pharmacodynamic target attainment. Int J Antimicrob Agents 2017;50(3):393-98. 19. Harkless L, Boghossian J, Pollak R et al. An open-label,randomized study comparing efficacy and safety of intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surg Infect (Larchmt) 2005;6(1):27-40. 32

References

20. Incavo S, Ronchetti PJ, Choi JH et al. Penetration of Piperacillin-Tazobactam into Cancellous and Cortical Bone Tissues. Antimicrobial Agents and Chemotherapy 1994;38(4):905-7. 21. Saltoglu N, Dalkiran A, Tetiker T et al. Piperacillin/tazobactam versus imipenem/cilastatin for severe diabetic foot infections: a prospective, randomized clinical trial in a university hospital. Clin Microbiol Infect 2010;16(8):1252-7. 22. Osmon S, Ward S, Fraser VJ et al. Hospital mortality for patients with bacteremia due to Staphylococcus aureus or Pseudomonas aeruginosa. Chest 2004;125(2):607. 23. Komshian SV, Tablan OC, Palutke W et al. Characteristics of left-sided endocarditis due to Pseudomonas aeruginosa in the Detroit Medical Center. Rev Infect Dis 1990;12(4):693. 24. Viscoli C, Cometta A, Kern WV et al. Piperacillin-tazobactam monotherapy in high-risk febrile and neutropenic cancer patients. Clin Microbiol Infect 2006;12(3):212-6. 25. Jaccard C, Troillet N, Harbarth S et al. Prospective Randomized Comparison of Imipenem- Cilastatin and Piperacillin-Tazobactam in Nosocomial Pneumonia or Peritonitis. Antimicrob Agents Chemother 1998;42(11):2966-72. 26. Laghmouche N, Compain F, Jannot A-S et al. Successful treatment of Pseudomonas aeruginosa osteomyelitis with antibiotic monotherapy of limited duration. J Infect 2017;75(3):198-206. 33

Questions?

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