1. BSAC regional educational workshop
Case presentation prepared by
Dr Sylviane Defres
Consultant Infectious diseases, Royal Liverpool University Hospital

2. background
Worldwide increasing incidence of antibiotic resistant gram negative organisms The major representative of extensively resistant and pan drug resistant gram negative organisms with very limited treatment options include; Klebsiella pneumoniae, Acinetobacter baumanii and Pseudomonas aeruginosa
The background to this case as you well know is based on the worldwide increasing incidence of antibiotic resistant gram negative organisms which we all face day to day.
To illustrate one such organism we present the following case

3. 63 yr man Presents 30th April 2017 with acute Type A aortic dissection
Background
Hypertension
Smoker
Otherwise fit and well
Type A aortic dissection ie dissection of the aorta in the ascending aorta. Unknown type of graft was inserted. We don’t have that information as operation was in a different hospital
Could discuss here what treatment pending sensitivities (or on next slide, told fully sensitive and then discuss which choice of antibiotics?)
Emergency repair, vascular graft
Bleeding anastomosis 1/5/17 > return to theatre >> intraoperative cardiac arrest
Prolonged ITU admission:
VAP, 2x strokes, patent foramen ovale closure, pseudomonal bacteraemia

4. 63 yr man pseudomonas bacteraemia
Fully sensitive Pseudomonas aeruginosa
What treatment would you give?
Areas to discuss: Which drug? Which route? Which dose? Monotherapy or dual therapy?

5. Anti-pseudomonal agents
Class
Agent
Dose
Penicillin β lactamase combinations
Piperacillin-tazobactam
4.5g QDS
Cephalosporins
Ceftazidime
2g TDS
Cefepime
2g every 8-12 hours
Advanced β lactamase combinations
Ceftazidime-avibactam
2.5g TDS
Less experience and cost for both
Ceftolozane-tazobactam
1.5-3g TDS
Monobactams
Aztreonam
Fluoroquinolones
Ciprofloxacin
400mgTDS IV
Levofloxacin
750mg OD
Carbapenems
Imipenem
500mg every 6-8 hours
More acquired resistance
Meropenem
1g TDS
Aminoglycosides
Tobramycin, gentamicin
Dosing schedules
Toxicity
Gen. not alone due to lack of clinical efficacy
Polymixins
Colistin/ polymixin
Which drug? Which route? Which dose? Monotherapy or dual therapy?
The selection og individual agents from this group depends on factrs such as the site of the infection, local resistance patterns, prior culture data the patients history of allergies and the local hospital formulary. Certain agents require higher doses than normally used for non pseudomonal infections. Doses here are for normal renal function. Some may need renal dose adjustment
Levofloxacin has no advantage over cipro since its additional spectrum of coverage is usually unnecessary . Primarily indicated for treatment of respiratory tract infections when additional empiric P aeruginosa cover is required
Imipinem has the highest MIC of the carbapenems and the highest propensity to induce resistance during treatment. Though all carbapenems have been associated with emergent resistance
Aminoglocides should be adjunctive not monotherapy, due to lack of clinical efficacy (eg don’t use in pneumonia as perform poorly in acidic environments; associated with high mortality rates when used alone in bacteraemia. May be used as single agents in lower UTIs. Favour tobramycin over gentamicin as greater intrinsic antipseudomonal activity. FQs only class that have an oral forumation reliably active against pseudomonas should be dosed at 750mg bd

6. pseudomonal bacteraemia
Empirically in bacteraemia, and or sepsis may choose dual therapy pending sensitivities
Ensure receipt of an active agent
Especially in patients with high risk of resistant strains
1-2 day delay in administering appropriate antibiotics reduced the cure rate from 76-46%
Suggest 2 agents form different classes
When sensitivities known single agent sufficient
No convincing clinical data demonstrating a mortality benefit of combination therapy
Evidence is scant; 2nd agent is reasonable in endocarditis or bacteraemia in certain hosts, or infections that are slow or fail to respond to a single agent
Signs of sepsis or septic shock
Neutropaenic patients with bacteraemia
Burns patients with serious infections
ITU patients; prior use of broad spectrum antibiotics eg carbapenems, cephalosporins; invasive devices
Dual therapy empirically in hope to get one that is effective
Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med 1985; 145:1621.
1 study suggested beta lactam as 1st agent and ciprofloxacin as 2nd agent having better outcomes than beta lactam and aminoglycoside but more work needed in that area
Bodey GP et al Arch Intern Med 1985
Leibovici L et al Antimicrob agent chemother 1997
Siegman-Igra Y et al Int J Infect Dis 1998
Safdar N Lancet Infect dis 2004
Vardekas KZ et al In J Antimicrob Agents 2013

7. 63 yr man pseudomonal bacteraemia
June 2017 bacteraemia
Pseudomonas aeruginosa
6 weeks ceftazidime 2g TDS IV
July 2017 bacteraemia
Pseudomonas aeruginosa again
Unacceptable operative risk for revision surgery
Plan for lifelong ciprofloxacin 750mg BD PO
Transfers to rehab unit

8. 63 yr man pseudomonal bacteraemia
20/11/2017 admitted from rehab unit with symptomatic hypotension
recurrent pseudomonal bacteraemia
Ciprofloxacin resistant
Treated Piperacillin/tazobactam 4.5 g qds IV
December 2017
Breakthrough pseudomonal bacteraemia
Ceftazidime and Pip/Taz resistant
Prescribed Meropenem 1g TDS IV
Developed Meropenem intermediate resistance; had 4 days amakicin
Plan for palliative ceftolozane/ tazobactam 1.5 g TDS IV : started January 2018
Daughter trained for OPAT
Transferred region to be closer to daughter – April 2018
Daughter was trained for delivery of antibiotic as TDS hourly infusion and community nurses did not have capacity. Also ‘lifelong’ was difficult to convince community team to get involved as not a predefined time. Ultimately they agreed to visit once a week to check the line and take bloods, but did not administer the antibiotics

9. 63 yr m – summary MICs
Criteria for Pseudomonas resistance based on Magiorakos et al international definition
Carbapenem resistance defined when an isolate had a imipenem or meropenem MIC of > or = 8mg/L
Decision for ceftolozane tazobatam over ceftazidime-avibactam was made originating hospital. 1 assumption is because of an isolate that was resistant to ceftazidime this may have been one reluctance. There is also some evdience that success rates are lower with ceftazidime-avibactam versus ceftolozane and that may have been the other reason. Also due to side effect profile colisint was not considered at this point

10. 63 yr m – pseudomonal bacteraemias
Arrival in new region – clinical review
Symptoms & examination
Frail and cachectic
Wheelchair – poor muscle strength post prolonged ITU admissions: with transferring regions had had no physio for weeks
Investigations
Routine bloods 8/5/18
CRP 9 mg/L WCC 9.1 x 109/L eGFR 79 ml/min/1.73m2. Blood cultures – no growth
normal renal & liver function other than albumin 33 g/L
Plan to get all previous images and discuss with surgeons locally as patient keen to have operation reconsidered, as feeling much stronger than before

11. 63 yr m – pseudomonal bacteraemias
Meantime
April to July 2018 continued ceftolozane/ tazobactam TDS as OPAT, no adverse effects, no symptoms
Surgeons locally unkeen for further surgical intervention
Line change June
BCs negative x2 & line tip No growth
Attempt for curative treatment : start tobramycin with planned 6-8 weeks course
Started 5mg/kg on 23/7/19
Tobramycin had lowest MIC level
Followed gentamcin normogram
Audiometry
August 2018 CRP normalised
Attempt for curative treatment July 2018 started tobramycin (for a planned 8 week course)
August 2018 CRP normalised.
However, eGFR deteriorated after 4 weeks despite tobramycin dose reduction. All abx stopped in August 2018
Started July 23rd Ended August 22nd (planned stop date 4th september) Last positive blood culture was at the end of December 28th

12. 63 yr m – pseudomonal bacteraemias
But eGFR deteriorated after 4 weeks Rx despite dose reductions of tobramycin
Managed 5 weeks IV tobramycin
Tobramycin maintained in therapeutic
window levels ranging from
All antibiotics stopped August 2018
To date (August 2019) no relapse of pseudomonal bacteraemia
Started July 24th Ended August 22nd
Discharged from OPAT September 2018
Follow-up BCs – no growth 28/8/18, 29/1/19 x3
Incidentally presented jan 2019 due to low BP systolic 65, during workup, multiple BCs done all negative. CT scan should a type B aneurysm ie now in the descending aorta. PET scan performed and tiny increase uptake around 1 end of graft which was thought to be the graft material itself and NOT infection

13. 63 yr m – pseudomonal bacteraemias
Unfortunately eGFR did not return to previous baseline

14. Summary of case
63 yr M
Prolonged hospital and rehabilitation stays post emergency AAA repair with recurrent Pseudomonas aeruginosa bacteraemias ( x5)
Development of multi drug resistance
Unacceptable operative risk for revision
Plans for palliative therapy, transfer to OPAT in region near daughter, on IV ceftolozane/tazobactam
at 4 months of therapy attempt at cure by adding tobramycin for planned 4-6 weeks (tolerated 5 weeks)
No recurrence of pseudomonal bacteraemia, either during or after therapy
Now off antibiotics for 12 months

15. ceftolozane/tazobactam (1g/0.5g)
Novel beta lactam/beta-lactam inhibitor combination
Tazobactam
Inhibits some beta-lactamases (eg certain penicillinases and cephalosporinases) and can bind covalently to some chromosomal & plasmid mediated bacterial betalactmaases
Ceftolozane: new oxyimino-cephalosporin, structurally similar to ceftazidime
inhibition of cell wall biosynthesis; Bactericidal
High affinity for the penicillin binding proteins essentially for P aeruginosa and E coli
Common mechanisms of resistance for P aeruginosa (over-expression efflux pumps, loss outer membrane porin OprD and AmpC overproduction )
do not affect ceftolozane

16. ceftolozane-tazobactam PK/PD
Absorption
Peak plasma concentrations increase in proportion to dose
Doesn’t increase appreciably following multiple IV infusions up to 3g given every 8 hours , up to 10 days
Distribution
Steady state volume in healthy adult males following a single IV dose was 13.5L and 18.2 L for ceftolozane and tazobactam respectively
Metabolism
Ceftolozane is eliminated in the urine as unchanged parent drug.
The beta lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive tazobactam metabolite M1
Elimination
Ceftolozane and the metabolite M1 are eliminated by the kidneys
Doesn’t increase appreciably following multiple iv infusions for up to 10 days in adults with normal renal function

17. ceftolozane-tazobactam adverse effects
Adverse reactions
Common (>= 5%) nausea diarrhoea headache and pyrexia
Other reactions in 1% or more in clinical trials
Constipation
Insomnia
Vomiting
Hypokalaemia
ALT and AST increased
Anaemia
Thrombocytosis
Abdominal pain
Anxiety
Dizziness
Hypotension
Atrial fibrillation
rash
C/I in cephalosporin hypersensitivity reactions
% of penicillin sensitive patients will also be allergic to cephalosporins
If immediate hypersensitivity to penicillin then do not administer
Can give false positive urinary glucose and false positive Coombs’ test
NHS indicative price
£ per vial
Decreased efficacy in patients with baseline CrCl of 30-50ml/min. monitor CrCl at least daily in patients with changing renal function and adjust dose
Serious hypersensitivity (anaphylactic reactions have been reported with beta lactam antibacterial drugs exercise with caution in patients with hypersensitivity
C difficile diarrhoea has been reported
Cost for our patient’s course was approx. £40K

18. ceftolozane/tazobactam (1g/0.5g)
1.5 g every 8 hours IV in patients with normal renal function
Off label pneumonia, double doses above
Intravenous infusion (Zerbaxa®), in Glucose 5% or Sodium chloride 0.9%; give over 1 hour
eGFR
Dose
Ceftolozane/ tazobactam
> 50ml/min
1.5 g 8 hourly
1g/0.5g
30-50ml/min
750mg 8hourly
500/250mg
15-29 ml/min
375mg 8hourly
250/125mg
<15ml/min
750mg loading then 150mg 8 hourly

19. Following on from the early studies of Ceftolozane tazobactam in complicated UTI and complicated intra-abdominal infections, further studies are now being done in HAP

20. Ceftolozane- Tazobactam
Only approved for cUTIs & cIAIs,
Attractive option for a range of infections caused by
MDR Pseudomonas aeruginosa
In vitro activity also against
Burholderia spp
Stenotrophomonas maltophila *
No activity against
Acinetobacter baumanii
Streptococcus pneumoniae
Staphylococci
Enterococci
With further studies suggesting effectiveness of Ceftolozane in a range of other organisms
There is mixed evidence of sensitivity of stenotrophomonas to ceftolozane. Some studies have found it effective and others not

21. Ceftolozane- Tazobactam - ASPECT cIAI trial
Here in the ASPECT trial (The Assessment of the Safety Profile and Efficacy of Ceftolozane / Tazobactam) in complicated intra-abdominal infections. This was a prospective randomized double blind trial, either receiving ceftolozane tazobactam plus metronidazole or meropenem. With the defined objectives to demonstrate statistical non inferiority in clinical cure rates at the test of cure visit days from start of therapy. The study showed indeed non-inferiority with meropenem. Pseudomonas made up 9% of all the organisms in the trial and 11% of these had resistance to >= 3 antipseudomonal drug classes.
Non inferior to Meropenem in complicated intra-abdominal infections
Solomkin J et al CID 2015

22. Ceftolozane- Tazobactam Antimicrobial activity
Organism
MIC range mg/L)
P aeruginosa with efflux pumps
0.5
P aeruginosa with decreased OprD expression
E coli CTX-M-15
0.25-2
E coli SHV-5
K pneumoniae CTX-M-15
K pneumoniae KPC
>16
Bacteroides fragilis
< >16
And here this group assessed the MICs of ceftolozane for a range of other resistant organisms
Skalweit M, Drug design, development and therapy 2015

23. 2nd to Colistin in effectiveness against Pseudomonas
Ceftolozane- Tazobactam VAP pseudomonas isolates Greece, spain & italy- - magicbullet study
This study specifically looks at Pseudomonas isolates (granted isolated from patients with VAP and not bacteraemias) and showed that ceftolozane tazobactam was 2nd to colistin in its effectiveness against Pseudomonas. And that when carbapenemases exist and isolates are all resistant to ceftazidime avibactam, but ceftolozane tazobactam still susceptible
2nd to Colistin in effectiveness against Pseudomonas
Active in 77.4%

24. Literature- post clinical trials
No literature on ceftolozane/ tazobactam specifically in vascular graft infections
Publications of use of zerbexa in the real worl in the context of bacteraemias is limited to case reports

25. Literature post clinical trials
A number of case series or multicentre retrospective cohort analyses
Most Series published on pneumonia, or SSTIs
Some mixed infections though predominant part of cohort remain respiratory and SSTI
Global success rates around 73-88% (depending on study)
Respiratory tract infections had higher mortality and evidence would support higher dose 3g tds
As did those presenting with sepsis or on CRRT
Although there are some bacteraemia cases in these case series of patients treated with ceftolozane tazobactam in serious and MDR Pseudomonal infections .
Though in these case series the majority of cases described are in respiratory tract infections and in skin and soft tissue infections

26. Literature - most recent 2019
Retrospective cohort; 22 hospitals in Italy
20 month period
Adults , 101 patients, culture confirmed
Received > 4days of ceftolozane/tazobactam
Diverse infections; nosocomial pneumonia (31.7%), acute SSTIs (20.8%), complicated UTIs (13.9%) complicated IAI (12.9%), bone infection (8.9%) and primary bacteraemia (5.9%)
More than half of P aeruginosa strains were XDR (50.5%)
78.2% isolates resistant to at least 1 carbapenem
Ceftolozane/ tazobactam was used First line in 38.6%
Concomitant antibiotics 35.6%
Standard dose (1.5g TDS) in 69.3% and 3g TDS in remainder
Median duration 14 days
Overall clinical success 83.2%, lower success rates in patients with sepsis or receiving continuous renal replacement therapy
This study describes the largest clinical experience using ceftolozane/ tazobactam for different Pseudomonas infections. It was a retrospective cohort study at 22 hospitals in Italy over a 20 month period.
All adult patients treated with 4 or more days of CT were enrolled.. Successful clinical outcomes was defined as complete resolution of clinical signs / symptoms related to Pseudomonas infection and lack of microbiological evidence. 32% had pneumonia 21% CCTI, 14% UTI, complicated IAI 13%, primary bacteraemia 6%

27. Literature – most recent series
1/3 rd patients had chronic renal disease and 93% had at least 1 serious underlying disease
Charlson index mean 4.4
38.6% were admitted with sepsis or septic shock with 23.8% requiring ITU
Conclusions
Propensity to develop C/T resistance is low (here 3%)
No difference in clinical response rates between combination therapy and monotherapy
? Need to explore the role of combination therapy specifically in sepsis and CRRT patients
Excellent safety profile; only mild ADEs in 3 patients
Limitations of study in that observational; retrospective; lab testing not standardized, TDM not done and inability to take into account the effect of prior antibiotics effect
The cohort studies are representative of the co morbidities in our population with a mean charlson index (which measures comorbidity) and a significant proportion went to ITU (though here likely wouldve been less.) ITUs in some other countries are a mixture of high dependency units and ITUs
Appears from the real clinical use data, albeit these have the limitations of being retrospective cohorts, that the success of ceftolozane tazobactam in serious Pseudomonal infections is effective and has a low propensity to developing resistance .

28. learning points from case
Already approved on formulary for Micro/ID use only in our trust (may not be approved everywhere)
OPAT and self administration; training and waivers
Responsibilities daughter> patient> community nurses
Cost
Agreement from CCG
Good safety profile
Possibility of ‘cure’ with intensification of treatment with tobramycin

29. Thank you & any questions?