1

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

of skin flora2

• Associated with respiratory tract infections,

UTI, IAI, SSTI, osteomyelitis3

3

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…

I 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

6

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

8

Lerma et al (2001) - HAP11

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

mechanical ventilation

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

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

O 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

12

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

or 3.375 g q6h

achieved >50%

time >MIC of 16

13

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

14

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

16

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

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References

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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

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2006;34(3):127-34.

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References

13. Yamamoto Y, Izumikawa K, Nakamura S et al. Prospective randomized comparison study of

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and Chemotherapy 2013;19(2):291-98.

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Treatment of Complicated Intraabdominal Infections. Ann Surg 2003;237(2):235-45.

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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.

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References

20. Incavo S, Ronchetti PJ, Choi JH et al. Penetration of Piperacillin-Tazobactam into Cancellous

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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

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2017;75(3):198-206.

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Questions?

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