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

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

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: 574- 580

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

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

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

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

What is desensitization?

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.

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.

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.

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

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

Adverse Events Castells et al, JACI 2008; 122: 574- 580

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

Our experience

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

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 0.00002 0.000004 0.0002 syringe n 2 0.000036 0.002 syringe n 3 0.00036 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):314-319.

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

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

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

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

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

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

Novel protocol for patient 1,4 and 8

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

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

Thank you

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