Presentation on theme: "Managing CF patients with antibiotic hypersensitivity"— Presentation transcript:
1Managing CF patients with antibiotic hypersensitivity Oded Breuer, MDPediatric Pulmonology and CF center Hadassah Hebrew University Medical Center
2Drug Hypersensitivity ADRs are known (or presumed) to be mediated by an immunologic mechanismSolenski R. Med Clin N Am 90 (2006) 233–260
3Drug Hypersensitivity Immediate<1hrNon immediate>1hrVsIgENon IgEVsSerious adverse drug reactions occur in 6.7% of hospitalized patients.and are one of the leading cause of death in these patientsCastells et al, JACI 2008; 122:
4Immediate Vs non immediate Immediate reactions occur within 1 hournonimmediate 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, respectivelyRomano A. ALLERGY CLIN IMMUNOL 127, 3;S67-S73
5IgE mediated vs. Non IgE mediated Immediate allergic reactions are thought to be IgE-mediatedmechanisms involved in nonimmediate reactions seem to be heterogeneous
6Burrows 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-lactamsBurrows JA, et al. Journal of Cystic Fibrosis 6 (2007) 297–303
7prevalence of allergic reactions to antibiotics is high in adults with CF (up to 36%) Risk factors:Increasing agecumulative coursesdecreasing FEV1So 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
9First series of penicillin desensitizations Escalating oral doses15 pregnant syphilis- infected womenלהגידThis 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.
10Principles of desensitization Providing essential medicationsSuccessful cases of rapid progressive penicillin readministration led to the concept of temporary clinical tolerizationThe 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 infectionsFollowing the early success with antibiotics, other empiric protocols were developed to treat hypersensitivity reactions to essential drugs that could not be substituted in allergic patientsTemporary tolerization can be achieved in a relatively short period of time (typically 4-8 hours) with the use of rapid desensitizationSuccessful 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 infectionsRecent studies of in-vitro rapid antigen desensitizations implicate mast cells and basophils as cellular targets, as well as syk , a signal-transducingmolecule, and STAT6 , a signal transducer and transcription activator responsible for the transcriptio of IL-4 and IL-13.
11Cernadas JR, et al. Allergy 2010; 65: 1357–1366. להגידFollowing the early success with antibiotics, other empiric protocols were developed to treat hypersensitivity reactions to essential drugs that could not be substituted in allergic patientsCernadas JR, et al. Allergy 2010; 65: 1357–1366.
12A typical protocolלהגידThe 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
13Cernadas 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 achievedseems to render these cells unresponsive to the drug compound but not to other stimuliCernadas JR, et al. Allergy 2010; 65: 1357–1366
15Adverse Eventsהבעיות 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 failBurrows et al. Antibiotic desensitization in adults with cystic fibrosis Respirology (2003) 8, 359–364
17Our patients Patient Age Sex FEV1 Sputum Culture Prior allergic reactions138F38-42B. cepaciaCeftazidime – severePiperacillim – SevereMeropenem – Mild219M20-25PACeftazidime, Cefepime, Piperacillin Tazobactam, Aztreonam - Mild326<30Ceftazidime, piperacillin –mild43744-57Ceftazidime – SeverePiperacillin - Severe52139Ceftazidime – MildPiperacillin - Mild62530-45714>80PA, MSSA84264-77Achromo. xyl.Piperacillin and Ceftazidime – severeMild – Urticaria mild angioedemaModerate – 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
18Our protocol Ceftazidime 2gr Step Ceftazidime 2grStepConcentration of Stock solution (mg/ml)Concentration of infused solution – in 50 ml NS (mg/ml)Total cumulative dose (mg)syringe n 10.0002syringe n 20.002syringe n 30.02syringe n 40.00360.2syringe n 50.0362syringe n 60.3620syringe n 73.6200syringe n 8362000Infused over 30 minBorish L,et al. The Journal of allergy and clinical immunology. Sep 1987;80(3 Pt 1):
19Completed successfully PatientantibioticReaction/stepTreatmentCompleted successfully1CeftazidimeNo-YesAnaphylaxis/D2In ICUMeropenemPruritus2AztreonamUrticaria/D1AHPiperacillin/tazobactamCefepime3Rash/D64Fever and dyspnea/D2No dataHypotension/D1Fluids5Urticaria/D26PiperacillinPruritus/D17So its not perfect and it may fail
25200 mg/kg per day ceftazidime in three doses as a 30-min intravenous infusion “equally effectiveregimens for antipseudomonal therapy in clinicallystable patients with CF.”“Continuous infusion of ceftazidime was no different from that achieved with the conventional bolus infusion regimen”Vscontinuous 23.5-h infusion of 100 mg/kg per day ceftazidime
26Bolus Vs. Continuous X 16 reduction in administered dose per time Bolus - 6 gr per day q8h 2 gr over 30 minContinuous - 6 gr per day 2 gr over 8 hrX 16 reduction in administered dose per time
27In high risk patients for severe allergic reaction Our new protocolIn high risk patients for severe allergic reactionStandard 8 step RDDContinuous infusion of a β lactam Ab
29The new protocol - Results PatientantibioticReaction/stepContinuous IVreactionTxCompleted successfully1CeftazidimeNoYes-4Piperacillin/tazobactam8
30Conclusions1. RDD protocols have allowed providing allergic CF patients with first-line therapy2. Still, some CF patients cannot complete a full treatment course due to severe allergic reactions3. Our novel protocol allows these patients to complete the desired treatment course and receive effective first line therapy