To Treat or Not to Treat

1. TO TREAT OR NOT TO
TREAT?
MDR P. AERUGINOSA: A
PATIENT CASE
ERIK CHIEUW PHARMD CANDIDATE 2018
HCA-CENTRAL FLORIDA REGIONAL HOSPITAL
APPE-ANTIMICROBIAL STEWARDSHIP
PRECEPTOR: KATRINA BABILONIA, PHARMD
Image from: http://www.news.com.au/lifestyle/health/health-problems/how-geneticallyaltered-ecoli-strain-can-kill-dangerous-boneeating-superbug-pseudomonas-aeruginosa/news-

2. OBJECTIVES
• INTRODUCE PATIENT MG
• DESCRIBE MULTI-DRUG RESISTANT (MDR) PSEUDOMONAS AERUGINOSA (P.
AERUGINOSA)
• MICROBIOLOGY
• EPIDEMIOLOGY
• ANTIBIOTIC OPTIONS
• DISCUSS PSEUDOMONAS COLONIZATION
• ANALYZE THE CASE OF MG

3. PATIENT CASE MG
• 77 YO F PRESENTS TO ED FROM SNF WITH CC: AMS X 2 DAYS (SLEEPY AND CONFUSED) AND
DIFFICULTY BREATHING
• PMH: HTN, DYSLIPIDEMIA, CHF, C DIFF, STAGE 3 B CKD, DM, DEMENTIA, ANEMIA; HAS TRACH,
PEG, AND PICC
• ALLERGIES: PCN (HIVES), CEFEPIME (HALLUCINATIONS), BACITRACIN, POLYMYXIN B, NEOMYCIN
(HIVES), TAPE
• WEIGHT: 61 KG; BASELINE SCR: 1.4
• HOME MEDS: ATORVASTATIN 10 MG PEG QHS, METOPROLOL TARTRATE 25 MG PEG Q12H,
FAMOTIDINE 20 MG PEG QD
• RECENTLY ADMITTED FOR HCAP 3 MONTHS AGO WITH MDR P. AERUGINOSA TREATED WITH
ZERBAXA

4. PATIENT CASE MG CONT.
• ED LABS/VITALS:
• ED U/A:
• CXR DAY 1: PERSISTENT DIFFUSE INTERSTITIAL OPACITIES
(INFECTION/INFLAMMATORY/EDEMA)
• CXR 1 MONTH AGO: STABLE MODERATE BILATERAL INTERSTITIAL
O2
Sat
(%)
BP
(mm
HG)
Temp
(C)
Puls
e
RR SCr
(mg/dL
)
CrCl
(mL/min)
WBC
(k/m
m3)
Plt
(k/m
m3)
Lactat
e
99 163/7
0
38.1 114 32 2.3 19.7 16.2 260 1.25
Nitrite Leukocyte
Esterase
WBC Epithelial
Cells
Bacteria
Negative Large 15-25 Moderate Moderate

5. PATIENT CASE MG CONT.
• DIAGNOSIS: HCAP SEPSIS, AKI ON CKD
• CONSULTS: NEPHRO, ID, PULMONARY
• INITIAL ABX TX: AZTREONAM 2GM IV X 1, TOBRAMYCIN 425 MG IV X 1,
VANCOMYCIN 1.25 GM X 1, LEVOFLOXACIN X 1
• ID D/C’D AZTREONAM AND STARTED ZERBAXA DAY 1 WITH PROJECTED 7 DAY
DURATION

6. EPIDEMIOLOGY OF P. AERUGINOSA
• P. AERUGINOSA IS THE CAUSE OF 10% OF HOSPITAL ACQUIRED INFECTIONS IN
THE WORLD
• MDR P. AERUGINOSA IN US: 15.4% (7452 ISOLATES FROM 2012-2015)
• MDR: RESISTANCE TO AT LEAST 1 ANTIBIOTIC IN 3 OR MORE ANTIMICROBIAL
CATEGORIES
• 2013 CDC REPORT ON P. AERUGINOSA
• CAUSE OF 51,000 HEALTHCARE ASSOCIATED INFECTIONS
• ASSOCIATED WITH ABOUT 400 DEATHS PER YEAR
• 13% OF THOSE BEING MULTI DRUG RESISTANT
References:
1) Chatterjee, Maitrayee, et al. "Antibiotic resistance in Pseudomonas aeruginosa and alternative therapeutic options." International Journal of Medical Microbiology 306.1 (2016): 48-58.
2) Sader HS, Huband MD, Castanheira M, Flamm RK. Pseudomonas aeruginosa Antimicrobial Susceptibility Results from Four Years (2012 to 2015) of the International Network for Optimal Resistance Monitoring Program in the United States.
Antimicrobial Agents and Chemotherapy. 2017;61(3):e02252-16. doi:10.1128/AAC.02252-16.
3) Magiorakos, A-P., et al. "Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance." Clinical microbiology and infection 18.3

7. MICROBIOLOGY OF MDR P. AERUGINOSA
• P. AERUGINOSA IS A GRAM NEGATIVE ROD
• PSEUDOMONAS CAN COLONIZE THE NORMAL FLORA AND FORM BIOFILMS
• VIRULENCE FACTORS:
• ADHERENCE FACTORS (PILI)
• PSEUDOCAPSULE (PROTECTION)
• EXOTOXINS AND PROTEASES WHICH DAMAGES THE HOST TISSUE->(INVASION, SPREADING AND
INFECTION)
• TOXIN EFFECTS:
• PROTEIN SYNTHESIS INHIBITION
• PROTEASE ACTIVITY
• INHIBITION OF COMPLEMENT ACTIVATION AND NEUTROPHIL PHAGOCYTOSIS
• DEGRADATION OF PLASMINOGEN AND FIBRINOGEN, ETC.
References: Chatterjee, Maitrayee, et al. "Antibiotic resistance in Pseudomonas aeruginosa and alternative therapeutic options." International Journal of Medical Microbiology 306.1 (2016): 48-58.

8. RESISTANCE MECHANISMS OF MDR P.
AERUGINOSA
• ANTIBIOTIC MODIFYING ENZYMES: AMINOGLYCOSIDES, BETA LACTAMASES (ESBL
+METALLO BETA LACTAMASES)
• METALLO BETA LACTAMSES HYDROLYZE CARBAPENEMS AND OTHER BETA LACTAMS
EXCEPT AZTREONAM
• TAZOBACTAM DOES NOT INHIBIT
• EFFLUX PUMPS
• REMOVE OF PORINS (REDUCED PERMEABILITY FOR ABX)
References:
1) Hong DJ, Bae IK, Jang I-H, Jeong SH, Kang H-K, Lee K. Epidemiology and Characteristics of Metallo-β-Lactamase-Producing Pseudomonas aeruginosa. Infection & Chemotherapy. 2015;47(2):81-97. doi:10.3947/ic.2015.47.2.81.
2) Chatterjee, Maitrayee, et al. "Antibiotic resistance in Pseudomonas aeruginosa and alternative therapeutic options." International Journal of Medical Microbiology 306.1 (2016): 48-58.

9. Reference: Chatterjee, Maitrayee, et al. "Antibiotic resistance in Pseudomonas aeruginosa and alternative therapeutic options." International Journal of Medical Microbiology 306.1 (2016): 48-58.

10. ANTIBIOTICS FOR MDR P. AERUGINOSA
• ZERBAXA (CEFTOLOZANE-TAZOBACTAM): DOSE 1.5 GM IV Q8H
• AVYCAZ (CEFTAZIDIME-AVIBACTAM): DOSE 2.5 GM IV Q8H
• COLISTIN: NEPHROTOXIC AND OTOTOXIC (SALVAGE)
• COMBINATION THERAPY FOR SYNERGY
• RIFAMPIN + COLISTIN
• FOSFOMYCIN + CARBAPENEM
• FQ + CEFEPIME
Reference: "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections". June 22, 2017. Retrieved from: https://www.uptodate.com/contents/principles-of-antimicrobial-therapy-of-pseudomonas-aeruginosa-
infections#H6675731

11. ZERBAXA VS AVYCAZ
• 2016 IN VITRO MEROPENEM RESISTANT P. AERUGINOSA (38 ISOLATES)
• AVYCAZ: 47% ISOLATES MIC AT OR ABOVE BREAKPOINT
• ZERBAXA: 13% ISOLATES MIC AT OR ABOVE BREAKPOINT
• RATES OF RESISTANCE FOR BOTH AGENTS: 8%
• 2017 IN VITRO P. AERUGINOSA ACTIVITY (31 ISOLATES)
• ZERBAXA MIC50: 0.75 MCG/ML VS AVYCAZ 1.5 MCG/ML
• MDR P. AERUGINOSA ACTIVITY: ZERBAXA 89% VS AVYCAZ 78%
References:
1) Alatoom, Adnan, et al. "Comparison of antimicrobial activity between ceftolozane–tazobactam and ceftazidime–avibactam against multidrug-resistant isolates of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa."
International Journal of Infectious Diseases 62 (2017): 39-43.
2) Buehrle, Deanna J., et al. "Evaluation of the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against meropenem-resistant Pseudomonas aeruginosa isolates." Antimicrobial agents and chemotherapy 60.5 (2016):
3227-3231.

12. ZERBAXA VS AVYCAZ CONT.
• ZERBAXA
• NO ACTIVITY AGAINST KPC
• BETTER MDR PSEUDOMONAL COVERAGE THAN AVYCAZ
• AVYCAZ
• KPC ACTIVITY
• BETTER FOR CRE
• NEITHER ACTIVE AGAINST METALLO BETA LACTAMASE (RARE IN US)
Reference: Liscio, Jordan L., Monica V. Mahoney, and Elizabeth B. Hirsch. "Ceftolozane/tazobactam and ceftazidime/avibactam: two novel β-lactam/β-lactamase inhibitor combination agents for the treatment of resistant Gram-negative
bacterial infections." International journal of antimicrobial agents 46.3 (2015): 266-271.

13. ZERBAXA (CEFTOLOZANE-TAZOBACTAM)
• MOA: CEFTOLOZANE (INHIBIT CELL WALL SYNTHESIS), TAZOBACTAM (BETA LACTAMASE
INHIBITOR)
• USUAL DOSING (CUTI/AP/CIAI): 1.5 GRAMS (CEFTOLOZANE 1 GRAM + TAZOBACTAM 500 MG) IV
Q8H
• INFUSION TIME: 60 MINUTES
• LOW TOXICITY PROFILE
• WARNINGS: CURE RATES LOWER IN PATIENTS WITH CRCL < 50 ML/MIN
• NO TRIALS COMPLETED FOR ZERBAXA FOR PNEUMONIA YET, BUT ONE IN PROGRESS (NO
RESULTS)
• COMPARING ZERBAXA 3 GRAMS (CEFTOLOZANE 2 GM + TAZOBACTAM 1 GM) Q8H VS MEROPENEM 1
GM Q8H
• WHY ZERBAXA 3 GM?
• ZERBAXA LEVELS ARE 50% IN LUNG COMPARED TO PLASMA
Reference: Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic‐derived dose justification for phase 3 studies in patients with nosocomial pneumonia. Journal of Clinical Pharmacology.
2016;56(1):56-66. doi:10.1002/jcph.566.

14. P. AERUGINOSA COLONIZATION
• P. AERUGINOSA COLONIZATION ASSOCIATED WITH 3 FOLD INCREASE IN MORTALITY IN
ADULTS WITH BRONCHIECTASIS
• 5 YEARS: 30-50% MORTALITY (COLONIZED) VS 5 YEARS: 9-15% MORTALITY (NOT-COLONIZED)
• CYSTIC FIBROSIS PATIENTS: FASTER LUNG DETERIORATION AND EARLIER MORTALITY
• RECOMMEND TO TREAT COLONIZED PATIENTS FOR ERADICATION (EUROPEAN RESP SOCIETY)
• “CONDITIONAL, VERY LOW QUALITY OF EVIDENCE”
• CHRONIC INFECTION: 2 OR MORE ISOLATES OF THE SAME ORGANISM AT LEAST 3 MONTHS APART IN
1 YEAR
• ONE THERAPY REGIMEN: IV ABX X 2 WEEKS THEN INHALED COLISTIN/TOBRAMYCIN/GENTAMICIN FOR
2.5 MONTHS
References:
1) Finch, Simon, et al. "A comprehensive analysis of the impact of Pseudomonas aeruginosa colonization on prognosis in adult bronchiectasis." Annals of the American Thoracic Society 12.11 (2015): 1602-1611.
2) Polverino, Eva, et al. "European Respiratory Society guidelines for the management of adult bronchiectasis." European respiratory journal 50.3 (2017): 1700629.

15. BACK TO PATIENT MG
Day 2
•Aerating well,
arousable, non-
communicative
•BP 125/58
•RR 25
•HR 82
•Tmax: 36.5
Day 3
•AMS
•BP: 127/61
•RR 32
•HR 81
•Tmax: 36.7
•UTI: P. Mirabilis grew
•Started Ceftriaxone IV
and azithromycin x 1
empiric for sputum gm
+ cocci per ID
•Zerbaxa D/C’d by ID
Day 4
•No productive phlegm;
no change in mental
•BP: 161/78
•RR: 23
•HR: 88
•Tmax: 36.7
•CXR: Interstitial and
airspace infiltrates
improving in left and
worsening in right lung
Day 5
•No productive phlegm
•BP 159/72
•RR 32
•HR 88
•Tmax 36.7
•Pulmonary switched
rocephin for aztreonam
d/t p. aeruginosa
growth
•C. diff + start PO
vanco; Abdomen: non-
tender, soft; no reports
of loose stools
Day 6
•No productive phlegm
•BP 168/70
•RR 16
•HR 98
•Tmax 37
•Pt alert to questions
and responsive to
questions, denies SOB
and pain
•Discharged for hospice
care
•Not discharged on PO
Vanco
•CXR: Near complete
opacification of left
hemithorax

16. BACK TO PATIENT MG-C/S
SPUTUM:

17. BACK TO PATIENT MG-C/S
• URINE:

18. BACK TO PATIENT MG-LABS
Day 1 Day 2 Day 3 Day 5 Day 6
WBC 16.2 10.6 12.3 12.3 10.1
Tmax 38.1 36.5 36.7 36.7 37
SCr 2.3 2.1 1.9 1.9 1.7
Procalcito
nin
<0.05
Lactate 1.1
C Diff
Toxin
Negative
C Diff Ag Positive
C Diff PCR Positive

19. BACK TO PATIENT MG-ABX
• ZERBAXA 1.5 GM IV Q8H: DAY 1->DAY 4 (4 DOSES) THEN D/CED BY ID
• FOR MDR P. AERUGINOSA HX HCAP
• AZITHROMYCIN 500 MG IV X 1 BY ID
• EMPIRIC
• CEFTRIAXONE 1 GM IV Q24H: DAY 2 (2 DOSES) THEN SWITCHED TO AZTREONAM BY
PULMONARY
• FOR P. MIRABILIS IN URINE
• AZTREONAM 1 GM IV Q12H (2 DOSES) DAY 5
• FOR + P. AERUGINOSA IN SPUTUM
• VANCOMYCIN 125 MG PO (4 DOSES) BY ID
• FOR + C. DIFF

20. CASE ASSESSMENT
• PT HAD S/SX OF INFECTION: AMS, SIRS (HR, RR, WBC, FEBRILE) WITH P. MIRABILIS
IN URINE (NOSOCOMIAL?) AND PROVIDENCIA STUARTII (NOT ADDRESSED BY ID)
• RECOMMEND A FULL TREATMENT COURSE FOR UTI AND PNEUMONIA FOR 7 TOTAL
DAYS
• CHANGE AZTREONAM TO CEFTRIAXONE 1 GM IV Q12H (BOTH SUSCEPTIBLE) FOR 3
MORE DAYS EVEN THOUGH PT TRANSFER TO HOSPICE
• AGREE WITH NOT RECOMMENDING TO TREAT COLONIZED MDR P. AERUGINOSA DUE
TO HOSPICE TRANSFER

21. CASE ASSESSMENT CONT.
• AGREE NOT TO TREAT RECURRENT C DIFF INFECTION
• TOXIN (-), AG +->PCR +->TREATMENT NOT INDICATED SINCE ASYMPTOMATIC
(CARRIER)
• ABX RENALLY DOSED APPROPRIATELY EXCEPT ZERBAXA 1.5 GM Q8H
• PT CRCL RANGE: 19.27-26.7 ML/MIN
• ZERBAXA RENAL DOSING: CRCL 15-29 ML/MIN: 375 MG Q8H

22. TO TREAT OR NOT TO
TREAT?
MDR P. AERUGINOSA: A
PATIENT CASE
QUESTIONS?