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

Dosing of piperacillin- tazobactam in Pseudomonas aeruginosa infections: is bigger better? Adam Mah – LMPS resident Antimicrobial Stewardship rotation November 9 th , 2017 1

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 2

Pseudomonas aeruginosa • Gram-negative non-fermenting bacilli 3 • Facultative anaerobe 3 • Intrinsically resistant to multiple ABX - low permeability of outer cell membrane 3 • Found in soil, water, and infrequently part of skin flora 2 • Associated with respiratory tract infections, UTI, IAI, SSTI, osteomyelitis 3 3

Piperacillin-tazobactam • Time-dependent kill – t 1/2 = 0.7-1.2 hrs 1 • Good penetration: lungs, intestinal mucosa, interstitial fluid, gallbladder 1 • Poor penetration: CNS 1 4

Overall PICO P For patients with infection involving P. aeruginosa at varying sites… Is piperacillin-tazobactam 4.5 g IV q6h… I C Superior to 3.375 g IV q6h or 4.5 g IV q8h… O For mortality, and microbiological and clinical cure? 5

IDSA guidelines • HAP/VAP 4 : 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 UTI 6,7 : no dosing recommendations 6

More IDSA guidelines… • Diabetic foot ulcer 8 : no dosing recommendations • Vertebral osteomyelitis 9 : pip/tazo not mentioned (cefepime or meropenem) 7

VAP Study Population Cultures Outcome Rea-Neto >18 yo with Pseudomonas Pip/tazo 4.5 g q6h IV et al nosocomial in 58% of = doripenem 500 mg (2008) 14 PNA isolates q8h IV for clinical and +/- microbiological cure ventilation. 22% VAP Brun- ICU pts, Pseudomonas Pip/tazo 4.5 g Buisson n = 204, all isolated in q6h IV = ceftazidime et al were VAP 32% of pts 1 g q6h when either (1998) 15 combined w/AMG for clinical cure 8

Lerma et al (2001) - HAP 11 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 1 0 : Clinical cure: NSS. Clinical improvement: NSS O P. aeruginosa subgroup (22% of isolates): NSS for both clinical cure and clinical improvement. 9

HAP Study Population Cultures Outcomes Schmitt et n = 217, non- Pseudo Pip/tazo 4.5 g IV q8h al (2006) 12 ICU, RCT, PNA not = imipenem/cilastatin >48 h post-admit, reported for clinical cure no septic shock (~75% in each arm) Yamamoto n = 67, non-ICU, Pseudo in Pip/tazo 4.5 g IV q8h et al RCT, hospitalized 12% of = meropenem for (2013) 13 >2 days in past pts, equal clinical cure (88% in 90 days in each pip/tazo arm, trend arm favouring pip/tazo) 10

Overall limitations • Lacking Pseudomonas isolate frequency reporting • No subgroup analyses • Microbiologically heterogeneous populations 11

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 n = 396, RCT, Pseudo in Pip/tazo al (2003) 16 IAI post-op 12% of pts 3.375 g IV q6h: (laparotomy or 88.5% percutaneous Pseudomonas drain) clinical cure rate Niinikoski n = 86, RCT, Pseudo Pip/tazo 4.5 g et al heterogeneous reported as IV q8h: 100% (1993) 17 IAI population a pathogen micro cure, but rates not 87% clin cure reported Murao et al n = 10, single- No cultures, Pip/tazo 4.5 q8h (2017) 18 dose pre-op, PK PK study or 3.375 g q6h model analysis 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 15

Cystitis and Pyelonephritis • Piperacillin: 68% excreted in urine as unchanged drug 1 • Tazobactam: 80% excreted in urine as unchanged drug 1 • Limitation: no RCT data 16

Bottom line: Cystitis and pyelonephritis • Likely good penetration of drug to renal tissue and bladder assuming good renal function 1 • Similar PK/PD to other penicillins • Recommend: Pip/tazo 3.375 g q6h IV and monitor clinical response 17

Diabetic foot infections • Consider P. aeruginosa if travel to warm climate, foot maceration, or colonization 8 • Likely good penetration to soft tissue 1 • 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 18

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 19

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 review 26 – Bone culture confirmed Pseudomonas – No dosing information reported – Single-agent pip/tazo 1 0 endpt: clinical cure 20

Osteomyelitis • Saltoglu et al (2010) RCT 21 – 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 21

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 22

P. aeruginosa bacteremias • High mortality rates (30-day = ~40%) 22 • Complications 23 – 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 neutropenia 24 23

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? 24

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? 25

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? 26

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? 27

Summary of evidence Indication Aggressive dosing? HAP in the ICU YES HAP not in ICU YES VAP YES 28

Summary of evidence Indication Aggressive dosing? Intraabdominal NO infections Cystitis or NO pyelonephritis Diabetic foot NO infection Osteomyelitis YES 29

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 of 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. 30