Is it safe to use cephalosporin in a patient with ampicillinsulbactam allergy

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Is it safe to use cephalosporin in a patient with ampicillinsulbactam allergy

  1. 1. Is it safe to use in a patient with ? 臨床藥學與藥物科技研究所 陳秋縈 指導老師 李佳雯醫師 林妏娟藥師 2013. 10. 30
  2. 2. Age 83 Gender Female HT/BW 150 cm/47.5 kg BMI 21.1 2 Social History Negative Family History Not contributory Drug Allergy NKDA Past medical history • Type 2 DM (diagnosed for 1 year) • Hypertension • Osteoporosis, compression fracture of spine • Carpal tunnel syndrome • Knee osteoarthritis • Cataract s/p Phaco+PCIOL at 2008 Admission date 2013/02/18 Regular medication • Raloxifene 60mg QD • Flurbiprofen 40mg/patch • Metformin 500mg BID • Nifedipine 20mg QD • Imipramine
  3. 3. 3 Chief complaint • Right lower leg erythematous, painful and swelling for 2 days • Pain got worse today so she could not walk • She went to 官田衛生所 for help and then was referred to NCKUH • First episode • Denied salt water exposure, animal bite, wound, crepitus 2/18 11:55 ED Physical examination • Consciousness: E4V5M6 • Vital sign: TPR 36.8/82/18, BP 163/73mmHg, SpO2: 98% • Extremities: right lower leg painful, swelling with a wound with clear discharge, local heat(+), erythema(+), bullae(-+), inguinal lymph note(+) • Tinea pedis was noted
  4. 4. 4 檢驗項目 參考值 2/18 2/25 WBC(10^3/μL) 3.4-9.1 10.7 5.9 RBC(10^6/μL) 4.26-5.56 3.37 Hb(g/dL) 13.5-17 11.5 Hct(%) 39.1-48.9 34.1 MCV(fl) 82.6-97.4 101.2 MCH(pg) 28.5-34 34.1 MCHC(g/dL) 33.8-35.6 33.7 RDW(%) 11.9-14.3 13.9 Plt(10^3/μL) 138-353 162 Blast(%) 0 Pro(%) 0 Myelo(%) 0 Meta(%) 0 Band(%) 22 Seg(%) 43-64 73 60.9 Eos(%) 0-1 0 0.2 Baso(%) 0-6 0 0.3 Mono(%) 3-9 1 7.1 Lymph(%) 27-47 4 31.5 檢驗項目 參考值 2/18 2/25 BUN(mg/dL) 7-21 45 13 CREA(mg/dL) 0.7-1.5 0.77 0.49 eGFR 72 ≧90 AST(U/L) 0-39 51 ALT(U/L) 0-54 55 NA(mmol/L) 135-148 132 136 K(mmol/L) 3.5-5 3.5 3.6 Glucose(mg/dL) <140 269 Impression • Right leg cellulitis • DM • Hypertension • Hyponatremia
  5. 5. 5 11:55 ED Diagnosis: right leg cellulitis TPR 36.8/82/18, BP 163/73mmHg 12:20 Penicillin skin test: negative 12:50 Ampicillin/sulbactam 3g stat & q6h IVD 14:00 呼吸平順,無不適 18:00 Ampicillin/sulbactam 3g IVD 18:20 Chin rash and maculopapular leision Periorbital erythematous swelling TPR 38.1/100/20, BP 166/59mmHg DC ampicillin/sulbactam 18:45 Diphenhydramine 30mg IVD Acetaminophen 500mg stat 21:00 發燒改善(36.9),臉部紅疹情形仍存,無發癢不適 Moxifloxacin 400mg qd IVD & stat Withhold imipramine due to drug drug interaction Keep monitoring hemodynamic status for severe anaphylaxis 2/18 Interaction Severity Warning Moxifloxacin Imipramine Major increased risk of cardiotoxicity (QT prolongation, tdp, cardiac arrest) day1
  6. 6. 6 Event Management • Periorbital swelling improved • Mild fever, BT: 37.9 • Hypertension, BP: 169/70 mmHg • Diphenhydramine 30mg IVD • Acetaminophen 500mg stat • Amlodipine 5mg qd • Metformin 500mg bid • Periorbital swelling subsided Chin and forehead wheal lesion resolved • Fever subsided • Leg swelling and bulla progressed, Edema: 4+ • Neomycin/bacitracin/polymyxin B skin oint • Furosemide 20mg IVD stat • Leg: aseptic pierced bulla  discharge culture • BP: 165/68 mmHg • No stool passage for 4 days • Shift amlodipine to nifedipine 20mg qd • Bisacodyl 10mg supp 2/19 2/20 2/21 day2 day3 day4
  7. 7. 7 Event Management • Leg erythema, swelling and pain improving • • BP: 165/73 mmHg • Decreased urine amount • Urinary incontinence • Nifedipine 20mg bid • Furosemide 20mg IVD stat • Bethanechol 25mg bid AC • Lorazepam 0.5mg stat • Leg: local heat(-), erythema(-), bulla(-) 水泡傷口結痂,無分泌物 • Shift ABX to oral form Moxifloxacin 400mg qd AC Discharge medication x 7 days • Moxifloxacin 400mg qd AC • Metformin 500mg bid • Nifedipine 20mg qd 2/24 2/25 2/28 2/18 blood culture (-) 2/21 discharge culture (-) 3/01 day7 day8 day11 day12
  8. 8. 8 3/03 Emergency Department • CC: Right lower leg swelling, erythema and pain developed on 03/02 night • No fever, chills, cough • Tinea pedis was also noted • Diagnosis: Right lower leg cellulitis Admission • Cefuroxime 1500 mg q8h IVD • Miconazole cream 3/01 Discharge 3/02 N/V after moxifloxacin oral intake Suspect moxifloxacin related
  9. 9. Suspect moxifloxacin induced NV 9 Admission Rt leg cellulitis Discharge 2/18 19 20 21 22 23 24 25 26 27 28 3/1 3/3 Ampicillin/sulbactam 3g q6h Moxifloxacin 400mg 1bot IVD 1# PO QD AC Diphenhydramine 30mg stat stat Acetaminophen 500mg 1# q6h prn Metformin 500mg 1# bid Amlodipine 5mg 1# qd Nifedipine 20mg 1# qd 1# bid Furosemide 20mg stat stat stat Bisacodyl 10mg stat Bethanechol 25mg 1# bid AC Lorazepam 0.5mg stat stat Resolved Admission Rt leg cellulitis Chin rash and maculopapular leision Periorbital erythematous swelling Fever
  10. 10.  Overview of Penicillin allergy  Classification  Pathogenesis  Case Discussion  What is the role of penicillin skin testing ?  Is it safe to use cephalosporin in a patient with penicillin allergy ?  Choice of antibiotic for our patient ?  Take home massage 10
  11. 11.  A specific immunologic reaction to a drug, no correlation with known pharmacological properties  Consists of two phases  Induction of an immune response on initial exposure  Election of symptoms on subsequent allergen exposure  In the absence of prior exposure  Allergic symptoms rarely appear before one weeks  But after sensitization  The reaction may be rapid triggered by a drug amount that is far below the therapeutic range 11 J Am Pharm Assoc (2003). 2008 Jul-Aug;48(4):530-40.
  12. 12. 12 Type Onset Mediators Manifestations Comments I < 1 h IgE Anaphylaxis Urticaria Angioedema Bronchospasm Accelerated reactions occurring 1-72 h after exposure may be IgE mediated II (cytotoxic) > 72 h IgG, IgM, complement Hemolytic anemia Cytopenia Intersitial nephritis non IgE-mediated III (immune complex) > 72 h IgG and IgM immunomplex Serum sickness Vasculitis Drug fever non IgE-mediated IV (Delayed, cell-mediated) > 72 h T-lymphocytes, cytokines Contact dermatitis exanthems non IgE-mediated Other (Idiopathic) Usually > 72 h Unknown mechanism Maculopapular or morbilliform rash SJS, TEN, DRESS non IgE-mediated Delayed Immediate
  13. 13. Penicillin-induced anaphylaxis: IgE-mediated  Incidence: 0.004–0.015%  Fatality rate: 0.0015-0.02%  The most concern: life-threatening  Responsible for 75% of anaphylactic deaths in the United States Classification problem  Most penicillin class antibiotic reactions involve cutaneous eruptions  Frequency of skin reactions Amoxicillin: 5.1%, ampicillin: 4.5%, penicillin:1.6%  Most of these reactions were macular, morbilliform, or urticarial  Mechanism responsible for the reaction is not clear 13 1. Bull WHO. 1968;38:159–188. III. 2. Pharmacotherapy 2007;27:542-5 3. JAMA. 1986 Dec 26;256(24):3358-63.
  14. 14. 14 Trends Immunol. 2008 Dec;29(12):633-42. 2nd allergen exposure 1st allergen exposure
  15. 15.  Most anaphylaxis caused by minor determinant 15 N Engl J Med. Feb 9;346(6):601-609 Penicillin Penicilloyl Penicilloate Penilloate Side chain β lactam ring Thiazolidine ring Degrades Hapten-protein complex Physiologic condition Minor Determinant Minor Determinant Major Determinant 95% 5% Minor Determinant Type Onset Most common cause Immediate reaction < 1 h Minor determinant Accelerated reaction 1-72 h Major determinant Late reaction Usually >72 h Physiopathological mechanism is not known
  16. 16. 16
  17. 17. Utility of patient history  5-10% of patients self-report a history of penicillin class antibiotic allergy 17 1. Chest. 2000;118:1106-8. 2. J Allergy Clin Immunol. 1981;68(3):171. 3. J Allergy Clin Immunol. 1999;103(5 Pt 1):918. 4. Ann Allergy Asthma Immunol. 2006;97(2):169. May be unreliable True allergy Q: Only about 10% of patient with history of “penicillin allergy” present positive skin tests Drug-related side effects rather than a true allergic reaction A:
  18. 18.  Patients labeled penicillin-allergic  more likely to be treated with broader-spectrum antibiotics  development and spread of multiple drug-resistant bacteria 18 1. Arch Intern Med. 2000 Oct 9;160(18):2819-22. 2. Ann Allergy Asthma Immunol. 2000 Mar;84(3):329-33. Patients with PCN allergy Patients without any ABX allergy Vancomycin 39.7 % 17.4 % P< .001 Levofloxacin 21.5 % 8 % P< .001 Erythromycin Quinolone Vancomycin Antibiotic choices in PCN allergy
  19. 19. 19 Clin Exp Allergy. 2003 Apr;33(4):501-6. Objective Estimated the costs and usage of antibiotic treatment of 'penicillin-allergic' patients in comparison to non-allergic patients in a tertiary care hospital Method  Retrospective review of medical records in a hospital  118 randomly chosen 'penicillin-allergic' patients who were hospitalized due to infection  Match with 118 non-allergic patients who were hospitalized due to similar cause  Antibiotic selection and cost of the patients were compared
  20. 20. 20 Clin Exp Allergy. 2003 Apr;33(4):501-6. The mean antibiotic cost for patients allergic to penicillin is 63% higher than for those not allergic to penicillin
  21. 21. Why penicillin allergy testing?  Improved antibiotic selection  Combating drug resistance  Reduced antibiotic costs Detects the presence or absence of penicillin specific IgE antibodies (type I reaction)  Will not detect non-IgE-mediated reactions  ex: SJS, TEN  IgE antibodies decrease over time  50% of patients with IgE-mediated penicillin allergy lose their sensitivity 5 years after reacting, 80% in 10 years  6-12 month most sensitive 21 1. Cleve Clin J Med. 2003 Apr;70(4):313-4, 317-8, 320-1. 2. J Allergy Clin Immunol. 1999;103(5 Pt 1):918. 3. Ann Allergy Asthma Immunol. 2006;97(2):169.
  22. 22. 22 Am J Med. 2008 Jul;121(7):572-6. doi: 10.1016/j.amjmed.2007.12.005. History of PCN allergy No need PSTImmunologic reaction Yes No Nonpruritic late mobilliform rash No IgE-mediated Non IgE-mediated Avoid the drug Yes PST available PST not available Use alternative drug or desensitize PST + PST - Give drug causiously Use alternative drug or desensitize History of PCN allergy Yes No PST positive rate 65-93% 2%
  23. 23. 23 Reagent Concentration Major determinant Penicilloyl-polylysine (PPL, Pre-Pen®) 6 x 10-5 M Commercial available The only FDA approved skin test 1974-2004, 2009- Minor determinants Penicillin G 10,000 units/mL Penicilloate 0.01 M Not commercially available Penilloate 0.01 M Not commercially available Positive control Histamine 1 mg/ml Antihistamines, TCA can inhibit skin tests results Negative control Saline Minimal reagents required: PPL, penicillin G, positive & negative control Ann Allergy Asthma Immunol. 2008 Mar;100(3 Suppl 3):S1-148.
  24. 24.  Skin prick test (SPT)  Should be performed first  Both major and minor determinant are used  Read after 15-20 minutes  Positive: wheal size ≥ 3 mm than negative control  Intradermal skin test (IDT)  Performed only if skin prick test is negative  May induce systemic reactions  More sensitive than skin prick test  Positive: wheal size ≥ 4 mm than control 24 1. Mayo Clin Proc 2005 Mar;80(3):405 2. Clin Infect Dis 2001 Jun 15;32(12):1685 Positive SPT
  25. 25.  Suspected IgE-mediated accelerated reactions (1-72 h)  Non IgE-mediated reaction? Allergy to sulbactam?  Imipramine can inhibit skin tests results  Should be hold several days before the test half life: 6-18 h (elderly 25-30h)  Inappropriate testing reagent  IgE-mediated reaction 75-90 % caused by major determinant 15-16% caused by minor determinant (serious reaction)  Performed with both major and minor determinants are gold standard 25
  26. 26. 26 1. JAMA. 1993;270(20):2456. 2. J Allergy Clin Immunol. 2005;115(6):1314. Reagent Standard Practice in Taiwan Major determinant Penicilloyl-polylysine (PPL, Pre-Pen®) V X Minor determinants Penicillin G V V (1000 U/ml) Penicilloate X X Penilloate X X Predictive value NPV: 97-99 % PPV: 40-100 % 75% of PST(+) patients react only to PPL NPV is poor without PPL No positive and negative control Skin testing without PPL may fail to identify many penicillin-allergic individuals 會過敏 不會過敏 陽性 陰性 偽陰: 1-3% NPV: 97-99% 陰性預測值 Negative Predictive Value (NPV) 會過敏 不會過敏 陽性 PPV: 40-100% 偽陽: 0-60% 陰性 陽性預測值 Positive Predictive Value (PPV)
  27. 27. Who need PST ? PST (-) PST (+) or unavailable US History of IgE- mediated PCN allergy Give drug cautiously Use alternative drug or desensitize Taiwan ??? 27 Ann Allergy Asthma Immunol. 2008 Mar;100(3 Suppl 3):S1-148. NCKUH
  28. 28. 28 B B Cross reaction ?
  29. 29. Limitations of the studies  Cephalosporins were contaminated with trace amounts of penicillin (Before 1980s)  Loosely defined ‘‘allergy’’ (based on patient history)  Probably a selection bias: less likely to treat with cephalosporins if patients had more severe or recent penicillin reaction histories  Did not consider 3-fold increased risk of ADR to any unrelated drugs in PCN allergic patients 29 1. J Antimicrob Chemother 1975;1(3 Suppl):107–118. 2. J Infect Dis. 1978;137(Supp):S74-79. 3. Clin Anesth. 2001;13:561-564. 4. J Allergy Clin Immunol. 2004;113:1220-1222. 5. N Engl JMed 274:998–1002. Reference History of PCN allergy No history of PCN allergy Cephalosporins administered Dash CH (1975) 25/324 (7.7%) 140/17,216 (0.8%) Cephalexin, cephaloridine Petz LD (1978) 57/701 (8.1%) 285/15,007 (1.9%) Cephalexin, cephaloridine, cephalothin, cefazolin, cefamandole
  30. 30. 30 Am J Med. 2006; 119(4):354 e311-359 ALE = allergic-like event Source population 3,375,165 patient use PCN 534,810 patient use cephalosporin at least 60 days later Study group ALE within 30 days of PCN: 3920 Comparison group No ALE within 30 days of PCN: 530,890 Cephalosporin ALE within 30 days 43 (1%) ALE within 30 days 581 (0.1%) Penicillin Retrospective cohort study United kindom general practice research database Risk of anaphylaxis is low
  31. 31. 31 1. Pediatrics 115: 1048-1057 2. Diagn Microbiol Infect Dis. 2007 Mar;57(3 Suppl):13S-18S. 6-position 7-position 3-position Structural differences Penicillin Cephalosporin Sulfur ring 5-membered thiazolidine ring 6-membered dihydrothiazine ring Side chains differentiate the activity and metabolic parameters 6-position 7,3-position
  32. 32. 32 1. J Allergy Clin Immunol. 2006 Feb;117(2):404-10. 2. Diagn Microbiol Infect Dis. 2007 Mar;57(3 Suppl):13S-18S. Cephalosporins undergo rapid fragmentation of the β- lactam and dihydrothiazine rings  The resultant compounds are extremely unstable  Rapidly form simple degradation products that do not function as haptens Immunologic cross-reactivity between the b-lactam rings of these compounds should be minimal
  33. 33. 33 Otolaryngology–Head and Neck Surgery (2007) 136, 340-347
  34. 34.  A considerable body of evidence has established that cross- reactivity is dependent on the side chain structure of these agents rather than the core ring structure  Between cephalosporins and penicillins  Between different cephalosporins 34 J Am Pharm Assoc (2003). 2008 Jul-Aug;48(4):530-40 6-position 7-position 3-position R1 R1 & R2
  35. 35. 35
  36. 36. 36 Pediatrics 2005;115;1048
  37. 37. 37 Ampicillin Cefuroxime
  38. 38. 38 Admission Discharge 2/18 19 20 21 22 23 24 25 26 27 28 3/1 3/3 Ampicillin/sulbactam 3g q6h Moxifloxacin 400mg 1bot IVD 1# PO QD AC Resolved • Chin rash and maculopapular leision • Periorbital erythematous swelling • Fever Suspect moxifloxacin induced NV Admission Rt leg cellulitis 2/18 blood culture (-) 2/21 discharge culture (-)
  39. 39. 39 BMJ 2012;345:e4955 Denied salt water exposure, animal bite, wound, crepitus
  40. 40.  Gram (-), anaerobic (usually in the presence of an ulcer) 40 BMJ 2012;345:e4955 Clin Infect Dis. 2005 Nov 15;41(10):1373-406. Likely organisms Source Empiric IV therapy Alternative β-hemolytic streptococci (most common) S. aureus (abscess or penetrating trauma) (evaluate risk for MRSA) Macerated or fissured interdigital toe spaces IV: Cefazolin Oxacillin Oral: Cephalexin Dicloxacillin Amoxicillin-clavulonate Moxifloxacin Clindamycin Vancomycin Risk: Tinea pedis Lower extremity cellulitis without evidence of abscess  Other consideration: Diabetes 健保給付規範 10.8.2.1.Moxifloxacin (如Avelox):(91/2/1、92/11/1、94/3/1、97/9/1) 限用於成人(18歲以上)之慢性支氣管炎的急性惡化、社區性肺炎、複雜性腹腔內感染。
  41. 41. 41 3/03 Emergency Department • Cefuroxime 1500 mg q8h IVD • Miconazole cream No further fever or chills developed during admission 3/06 • Shift to oral cefuroxime 500 mg q12h 3/11 Discharge
  42. 42.  Predict value of PST without major determinant is poor in taiwan  Fail to identify many penicillin-allergic individuals  Whether to dispense cephalosporin to patient with penicillin allergies should be based on  The type of allergic manifestations  The specific drug prescribed: side chain similarity as a major source of cross-reactivity 42 PCN allergy Use other class first cephalosporin without similar side chain Desensitization or graded challenge
  43. 43. 43

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