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

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Presentation on theme: "Managing CF patients with antibiotic hypersensitivity Oded Breuer, MD Pediatric Pulmonology and CF center Hadassah Hebrew University Medical Center."— Presentation transcript:

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

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

3 Drug Hypersensitivity Immediate <1hr Non immediate >1hr Vs IgENon 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

7  prevalence of allergic reactions to antibiotics is high in adults with CF (up to 36%)  Risk factors:  Increasing age  cumulative courses  decreasing FEV1 Burrows JA, et al. Journal of Cystic Fibrosis 6 (2007) 297–303

8 What is desensitization?

9 First series of penicillin desensitizations Wendel G et al. N Engl J Med 1985; 312:1229– Escalating oral doses 15 pregnant syphilis- infected women

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

11 Cernadas JR, et al. Allergy 2010; 65: 1357–1366.

12 A typical protocol Henry J. Legere et al, Journal of Cystic Fibrosis 8 (2009) 418–424

13 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.

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

15 Burrows et al. Antibiotic desensitization in adults with cystic fibrosis Respirology (2003) 8, 359–364 Adverse Events

16 Our experience

17 Our patients PatientAgeSexFEV1Sputum Culture Prior allergic reactions 138F38-42B. cepaciaCeftazidime – severe Piperacillim – Severe Meropenem – Mild 219M20-25PACeftazidime, Cefepime, Piperacillin Tazobactam, Aztreonam - Mild 326M<30PACeftazidime, piperacillin –mild 437F44-57PACeftazidime – Severe Piperacillin - Severe 521M39PACeftazidime – Mild Piperacillin - Mild 625M30-45PAPiperacillin - Mild 714F>80PA, MSSAPiperacillin - Mild 842F64-77Achromo. xyl. PA Piperacillin and Ceftazidime – severe

18 Our protocol Ceftazidime 2gr StepConcentration of Stock solution (mg/ml) Concentration of infused solution – in 50 ml NS (mg/ml) Total cumulative dose (mg) syringe n syringe n syringe n syringe n syringe n syringe n syringe n syringe n Infused over 30 min Borish L,et al. The Journal of allergy and clinical immunology. Sep 1987;80(3 Pt 1):

19 PatientantibioticReaction/stepTreatmentCompleted successfully 1CeftazidimeNo-Yes Anaphylaxis/D2In ICU No MeropenemNo-Yes No-Yes Pruritus- No 2AztreonamUrticaria/D1AHYes Piperacillin/tazobactamUrticaria/D1AHYes CefepimeUrticaria/D1AHYes CeftazidimeUrticaria/D1AHYes 3CeftazidimeRash/D6-Yes 4CeftazidimeFever and dyspnea/D2No data No Hypotension/D1Fluids No 5CeftazidimeUrticaria/D2- No 6PiperacillinPruritus/D1AHYes Piperacillin/tazobactamPruritus/D1AHYes 7PiperacillinNo-Yes No-Yes

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

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25 200 mg/kg 30-min 200 mg/kg per day ceftazidime in three doses as a 30-min intravenous infusion 23.5-h 100 mg/kg continuous 23.5-h infusion of 100 mg/kg per day ceftazidime Vs “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”

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

28 Novel protocol for patient 1,4 and 8

29 The new protocol - Results Patient antibiotic Reaction /step Continuous IV reactionTx Completed successfully 1 CeftazidimeNoYesNo-Yes NoYesNo-Yes 4 CeftazidimeNoYesNo-Yes NoYesNo-Yes Piperacillin/tazobac tam NoYesNo-Yes NoYesNo-Yes NoYesNo-Yes NoYesNo-Yes 8 CeftazidimeNoYesNo-Yes NoYesNo-Yes

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


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