1. Managing CF patients with antibiotic hypersensitivity
Oded Breuer, MD
Pediatric Pulmonology and CF center Hadassah Hebrew University Medical Center

2. Drug Hypersensitivity
ADRs are known (or presumed) to be mediated by an immunologic mechanism
Solenski R. Med Clin N Am 90 (2006) 233–260

3. Drug Hypersensitivity
Immediate
<1hr
Non immediate
>1hr Vs
IgE
Non IgE Vs
Serious adverse drug reactions occur in 6.7% of hospitalized patients.
and are one of the leading cause of death in these patients
Castells et al, JACI 2008; 122:

4. Immediate Vs non immediate
Immediate reactions occur within 1 hour
nonimmediate reactions occur after more than 1 hour.
Clinical and immunologic studies suggest that type-I (IgE-mediated) and type-IV (T cell– mediated) pathogenic mechanisms are involved in most immediate and nonimmediate reactions, respectively
Romano A. ALLERGY CLIN IMMUNOL 127, 3;S67-S73

5. IgE mediated vs. Non IgE mediated
Immediate allergic reactions are thought to be IgE-mediated
mechanisms involved in nonimmediate reactions seem to be heterogeneous

6. Burrows JA, et al. Journal of Cystic Fibrosis 6 (2007) 297–303
Up to 30% of cystic fibrosis patients develop hypersensitivity reactions after multiple exposures to b-lactams
Burrows JA, et al. Journal of Cystic Fibrosis 6 (2007) 297–303

7. prevalence of allergic reactions to antibiotics is high in adults with CF (up to 36%)
Risk factors:
Increasing age
cumulative courses
decreasing FEV1
So the prevalence of ADR in Cf patients is relativlely high – 36%
And the tendancy is associated with the degree of exposure to Ab – which natrually increases with age, Resp Exacerbations and disease severity.
Burrows JA, et al. Journal of Cystic Fibrosis 6 (2007) 297–303

8. What is desensitization?

9. First series of penicillin desensitizations
Escalating oral doses
15 pregnant syphilis- infected women
להגיד
This success has led to the understanding that it is possible to induce temporary clinical tolerance in the allergic patient which permits treatment with the desired drug.
Wendel G et al . N Engl J Med 1985; 312:1229– 1232.

10. Principles of desensitization
Providing essential medications
Successful cases of rapid progressive penicillin readministration led to the concept of temporary clinical tolerization
The administration of suboptimal doses of drug antigens followed by the full therapeutic dose was safely achieved in highly allergic patients, permitting the treatment of severe infections
Following the early success with antibiotics, other empiric protocols were developed to treat hypersensitivity reactions to essential drugs that could not be substituted in allergic patients
Temporary tolerization can be achieved in a relatively short period of time (typically 4-8 hours) with the use of rapid desensitization
Successful cases of rapid progressive penicillin readministration led to the concept of temporary clinical tolerization [3]. The administration of suboptimal doses of drug antigens followed by the full therapeutic dose was safely achieved in highly allergic patients, permitting the treatment of severe infections
Recent studies of in-vitro rapid antigen desensitizations implicate mast cells and basophils as cellular targets, as well as syk [9], a signal-transducing
molecule, and STAT6 [10], a signal transducer and transcription activator responsible for the transcriptio of IL-4 and IL-13.

11. Cernadas JR, et al. Allergy 2010; 65: 1357–1366.
להגיד
Following the early success with antibiotics, other empiric protocols were developed to treat hypersensitivity reactions to essential drugs that could not be substituted in allergic patients
Cernadas JR, et al. Allergy 2010; 65: 1357–1366.

12. A typical protocol
להגיד
The idea is to administer suboptimal doses of drug followed by the full therapeutic dose this achieves Temporary tolerization in a relatively short period of time (typically 4-8 hours). This tolerozation is maintained as long as the drug is being administered. And thus it may allow a two week treatment course for a selected Ab.
Henry J. Legere et al, Journal of Cystic Fibrosis 8 (2009) 418–424

13. Cernadas JR, et al. Allergy 2010; 65: 1357–1366.
Mechanism
“Despite its clinical success, little is known about the mechanisms and molecular targets of drug desensitization”
Cernadas JR, et al. Allergy 2010; 65: 1357–1366.
The consecutive administration of suboptimal doses prior to the optimal dose cause tissue mast cells to become nonreactive to the implicated drug after desensitization has been achieved
seems to render these cells unresponsive to the drug compound but not to other stimuli
Cernadas JR, et al. Allergy 2010; 65: 1357–1366

14. Adverse Events
Castells et al, JACI 2008; 122:

15. Adverse Events
הבעיות הן שתופעות הלוואי לא מתרחשות רק ביום הראשון בזמן מתן הדהסנסיטיזציה, אלא חלקן מתרחשות בזמן מתן הטיפול השוטף, וגורמות לכך שלא נשלים את הקורס הטיפולי במלואו.
And that is a big problem – if we can only complete the Desensi. Protocol and not the full Ab course.
So its not perfect and it may fail
Burrows et al. Antibiotic desensitization in adults with cystic fibrosis Respirology (2003) 8, 359–364

16. Our experience

17. Our patients Patient Age Sex FEV1 Sputum Culture
Prior allergic reactions 1 38 F
38-42
B. cepacia
Ceftazidime – severe
Piperacillim – Severe
Meropenem – Mild 2 19 M
20-25 PA
Ceftazidime, Cefepime, Piperacillin Tazobactam, Aztreonam - Mild 3 26
<30
Ceftazidime, piperacillin –mild 4 37
44-57
Ceftazidime – Severe
Piperacillin - Severe 5 21 39
Ceftazidime – Mild
Piperacillin - Mild 6 25
30-45 7 14
>80
PA, MSSA 8 42
64-77
Achromo. xyl.
Piperacillin and Ceftazidime – severe
Mild – Urticaria mild angioedema
Moderate – Systemic Symptoms non life threatening (fever, shivering)
Sever – life threatening (hypotension, Respiratory distress)
Or:
A mild reaction was defined as absence of chest pain, changes in blood pressure, dyspnea, oxygen, desaturation, or throat tightness. A severe reaction included 1 of these

18. Our protocol Ceftazidime 2gr Step
Ceftazidime 2gr
Step
Concentration of Stock solution (mg/ml)
Concentration of infused solution – in 50 ml NS (mg/ml)
Total cumulative dose (mg)
syringe n 1
0.0002
syringe n 2
0.002
syringe n 3
0.02
syringe n 4
0.0036
0.2
syringe n 5
0.036 2
syringe n 6
0.36 20
syringe n 7
3.6
200
syringe n 8 36
2000
Infused over 30 min
Borish L,et al. The Journal of allergy and clinical immunology. Sep 1987;80(3 Pt 1):

19. Completed successfully
Patient
antibiotic
Reaction/step
Treatment
Completed successfully 1
Ceftazidime No -
Yes
Anaphylaxis/D2
In ICU
Meropenem
Pruritus 2
Aztreonam
Urticaria/D1 AH
Piperacillin/tazobactam
Cefepime 3
Rash/D6 4
Fever and dyspnea/D2
No data
Hypotension/D1
Fluids 5
Urticaria/D2 6
Piperacillin
Pruritus/D1 7
So its not perfect and it may fail

22. For β Lactam Ab Time which drug concentration remains above the MIC
Bacterial Killing Characteristics

23. If we give continous infusion instead of bolus dosing we increase the time which drug concentration is above the MIC,

25. 200 mg/kg per day ceftazidime in three doses as a 30-min intravenous infusion
“equally effective
regimens for antipseudomonal therapy in clinically
stable patients with CF.”
“Continuous infusion of ceftazidime was no different from that achieved with the conventional bolus infusion regimen” Vs
continuous 23.5-h infusion of 100 mg/kg per day ceftazidime

26. Bolus Vs. Continuous X 16 reduction in administered dose per time
Bolus - 6 gr per day q8h 2 gr over 30 min
Continuous - 6 gr per day 2 gr over 8 hr
X 16 reduction in administered dose per time

27. In high risk patients for severe allergic reaction
Our new protocol
In high risk patients for severe allergic reaction
Standard 8 step RDD
Continuous infusion of a β lactam Ab

28. Novel protocol for patient 1,4 and 8

29. The new protocol - Results
Patient
antibiotic
Reaction/step
Continuous IV
reaction Tx
Completed successfully 1
Ceftazidime No
Yes - 4
Piperacillin/tazobactam 8

30. Conclusions
1. RDD protocols have allowed providing allergic CF patients with first-line therapy
2. Still, some CF patients cannot complete a full treatment course due to severe allergic reactions
3. Our novel protocol allows these patients to complete the desired treatment course and receive effective first line therapy

31. Thank you

32. Acknowledgments Hadassah Hebrew University Medical Center
The Pediatric Pulmonology and CF Center:
Eitan Kerem, MD
David Shoseyov, MD
Malena Cohen-Cymberknoh, MD
Shoshana Armoni, RN