Roland Solensky, MD, FAAAAI. The Corvallis Clinic Corvallis, OR

Transcription

1 Overview of Penicillin and β-lactam Allergy: Epidemiology, Cross-reactivity, Costs and Utility of Penicillin Skin Testing Roland Solensky, MD, FAAAAI The Corvallis Clinic Corvallis, OR

2 Conflict of Interest Financial: None Research: Merck, Allerquest Legal Consult/Expert Witness: Antibiotic Allergies Organizational: None Gifts: None

3 Alexander Fleming St. Mary s Hospital, London, 1943

4 Howard Florey, Ernst Chain and Alexander Fleming receiving Nobel Prize in Physiology or Medicine Stockholm 1945

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7 Penicillinn History Jan May 1943: 400 million units June Dec 1943: 20.5 billion units End of WWII (August 1945): 650 billion units per month 1946: Wilensky reported 1 st case of penicillin- induced fatal anaphylaxis in JAMA 1952: Biochemie (now Sandoz) developed the first acid-stable penicillin for oral administration (Penicillin VK)

8 Penicillin Allergy: Epidemiology Most frequently reported medication allergy 5-10% patient-reported prevalence ~ 90% of patients labeled penicillin allergic are not aller rgic and able to tolerate penicillins Penicillin skin test-positive rate declining over last years 1,2 1. Jost B, et al. Ann Allergy Asthma Immunol 2006; 97: Macy E, et al. Perm J 2009; 13:12-8.

9 Penicillin Allergy: Epidemiology (cont) Discrepancy between reported and confirmed penicillin allergy Reaction mislabeled as allergic Reaction due to underlying illness Reaction due to illness/antibiotic interaction Penicillin-specific IgE wanes over time Penicillin allergy label associated with: use of vancomycin & quinolones antibiotic resistance (VRE, MRSA) and C. diff medical costs

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11 Antibiotic Choices for Inpatients with History of β-lactam Allergy 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Vancomycin (p<0.001) Levofloxacin (p<0.001) Pcn/Ceph Allergy No Allergy Lee CE, et al. Arch Intern Med 2000; 160:

12 Antibiotic Choices for Inpatients with History of β-lactam Allergy cont. Sade K, et al. Clin Exp Allergy 2003; 33:501-6.

13 Vancomycin Resistant Enterococcus (VRE) and Use of Broad-Spectrum Antibiotics Risk factors for VRE acquisition in MICU: Odds Ratio Pre-MICU Antibiotic (95% CI) P Value Vancomycin 5.1 ( ) 0.02 Cephalosporins 6.0 ( ) 0.03 Quinolones 8.6 ( ) Penicillins + -lactamase inhibitors 1.8 ( ) 0.24 Martinez JA, et al. Arch Intern Med 2003; 163:

14 Risk Factors for C. difficile in hospitalized patients Antibiotic use during 6 weeks prior to diagnosis of C. difficile Fluoroquinolones Cephalosporins Clindamycin Odds Ratio (95% CI) 3.9 ( ) 3.8 ( ) 1.6 ( ) P Value <0.001 <0.001 NS Penicillins + -lactamase inhibitors 1.2 ( ) NS Penicillins 0.7 ( ) NS Macrolides 1.3 ( ) NS Aminoglycosides 0.7 ( ) NS Carbapenems 1.4 ( ) NS Loo VG, et al. NEJM 2005; 353:

15 Pepin J, et al. Clin Infect Dis 2005; 41:

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17 Penicillin Allergy as Risk Factor for VRE, MRSA, C difficile

18 Penicillin Skin Testing: Effect on Antibiotic Use Study % Pcn ST Negative Effect on Broad Spectrum Antibiotic Use (% of Patients) Harris AD (1999) 86% Vancomycin 25% 0% Quinolones 27% 14% Arroliga ME (2003) 89% Vanco/Quinolones 100% 58% Nadarajah K (2005) 92% Vancomycin 77% 8% Quinolones 26% 3% Park M (2006) 96% Vancomycin 30% 16% del Real GA (2007) 88% Vancomycin 37% 16% Quinolones 36% 13% Frigas E (2008)? Vancomycin 28% 10%

19 Antibiotic Costs in Penicillin Allergic Patients Study Cost Penicillin Allergic Patients Cost No Penicillin Allergy P Value Kraemer MJ (1987) 1 $4.6 MacLaughlin EJ (2000) 2 $28.6 Sade K (2003) 3 $81.7 Sade K (2003) 4 $43.0 $1.75 < $ $ $31.0 < Average antibiotic costs per patient during 24 month period 2. Average antibiotic costs per patient (one course) 3. Average antibiotic costs per day during hospitalization 4. Average antibiotic costs per day post-hospitalization treatment

20 Elective Penicillin Skin Testing: Cost Savings 236 outpatients 83% penicillin skin test-negative Average antibiotic cost per penicillin skin test-negative patient $71.17 during year before penicillin skin test $49.63 during year after penicillin skin test P value = Macy E. JACI 1998; 102:281-5.

21 Penicillin Allergy: Significance The most important and under-appreciated aspect of penicillin allergy is the morbidity, mortality, and economic costs associated with the unnecessary withholding of appropriate therapy in the large number of patients assumed to be penicillin allergic Solensky R. Clin Rev Allergy Immunol 2003; 24:

22 β-lactam Cross-reactivity

23 Cephalosporin Challenges in Patients with History of Penicillin Allergy Reference (Year) Cephalosporin Reaction Rate + History Pcn Allergy Dash CH (1975) 7.7% (25/324) 0..8% (140/17,216) No reaction details Petz LD (1978) 8.1% (57/701) 1..9% (285/15,007) No reaction details Goodman EJ (2001) 0.33% (1/300) 0.04% (1/2,431) Reaction questionable Dalat SB (2004) 0.17% (1/606) 0..06% (15/22,664) Reaction = eczema Fonacier L (2005) 8.4% (7/83) MacPherson RD (2006) 0% (0/84) - History Pcn Allergy N/A N/A Comments Reactions convincing

24 Cephalosporin Challenges in Penicillin ST + Patients Reference (Year) # of Patients # (%) of Reactions Reaction to Cephalosporin Skin Testing Girard JP (1968) 23 2 (8.7) Cephaloridine No Assem ESK (1974) 3 3 (100) Cephaloridine No Warrington RJ (1978) 3 0 Yes Solley GO (1982) 27 0 No Saxon A (1987) 62 1 (1.6) Not noted No Blanca M (1989) 16 2 (12.5) Cefamandole No Shepherd G (1993) 9 0 No Audicana M (1994) 12 0 Yes Pichichero ME (1998) 39 2 (5.1) Cefaclor and? No Novalbos A (2001) 23 0 Yes Macy E (2002) 42 1 (2.4) Cefixime No Romano A (2004) 75 0 Yes Greenberger PA (2005) 6 0 No Park MA (2010) 85 2 (2.4%) Cefazolin, cephalexin No TOTAL (3.1%)

25 Drug Allergy: An Updated Practice Parameter Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105: e78

26 Penicillin/Cephalosporin Cross-reactivity Recommendations* No penicillin skin testing Administer cephalosporin via full dose or graded challenge Consider cephalosporin skin testing Penicillin skin test-positive Administer cephalosporin via graded challenge or desensitization Consider cephalosporin skin testing *

27 Cephalosporin Reactions in Patients with Selective IgE-mediated Allergy to Amoxicillin/Ampicillin Reference (Year) Audicana M (1994) Sastre J (1996) Miranda A (1996) TOTAL Selective Allergy To Ampicillin Amoxicillin Amoxicillin Cephalosporin with Id dentical Side Chain Cephalosporin Reaction Rate Cephalexin 1/10 (10%) Cefadroxil 2/16 (12%) Cefadroxil 8/21 (38%) 11/47 (23%)

28 Cephalosporin/cephalosporin Cross-reactivity No clinical studies of patients allergic to one cephalosporin challenged with other cephalosporins Skin testing and/or RAST of patients allergic to cephalosporins 1-4 : 51/95 patients positive only to culprit cephalosporin 44/95 patients positive to culprit cephalosporin and other cephalosporin(s) 1. Romano A, et al. Int J Immunopathol Pharmacol 1997; 10: Romano A, et al. JACI 2000; 106: Romano A, et al. Clin Exp Allergy 2005; 35: Antunez C, et al. JACI 2006; 117:

29 Drug Allergy: An Updated Practice Parameter Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105: e78

30 Groups of β-lactamm Antibiotics with Identical R 1 Group Side-Chains Ampicillin Cefaclor Cephalexin Cephradine Cephaloglycin Loracarbef Amoxicillin Cefadroxil Cefpro ozil Cefatrizine Ceftriaxone Cefotaxime Cefpodoxime Cefditoren Ceftizoxime Cefmenoxime

31 Groups of β-lactamm Antibiotics with Identical R 1 Group Side-Chains Cefoxitin Cephaloridine Cephalothin Cefamandole Cefonicid Ceftazidime Aztreonam

32 Groups of β-lactamm Antibiotics with Identical R 2 Group Side-Chains Cephalexin Cefadroxil Cephradine Cefotaxime Cephalothin Cephalo oglycin Cephapirin Cefuroxime Cefoxitin

33 Groups of β-lactamm Antibiotics with Identical R 2 Group Side-Chains Cefotetan Cefamandole Cefmetazole Cefpiramide Cefaclor Loracarbef Ceftibuten Ceftizoxime

34 Carbapenem Challenges in Patients with Reference (Year) History of Penicillin Allergy Carbapenem Reaction Rate + History Penicillin Allergy McConnell SA (2000) 6.3% (4/63) Prescott WA (2004) 11% (11/100) Sodhi M (2004) 9.2% (15/163) Cunha BS (2008) 0% (0/110) - History Penicillin Allergy N/A P Value N/A 2.7% (3/111) % (4/103) N/A N/A

35 Carbapenem Challenges in Penicillin ST+ Patients Reference (Year) # of Patients # of Reactions Romano A (2006) Romano A (2007) Atanaskovic (2008) Atanaskovic (2009) Carbapenem Given Imipenem Meropenem Meropenem Imipenem Comment One patient imipenem ST+ One patient meropenem ST+ One patient meropenem ST+ One patient imipenem ST+ All challenged patients also skin test-negative to carbapenems

36 Drug Allergy: An Updated Practice Parameter Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105: e78

37 Summary Penicillin remains the most commonly reported medication allergy > 95% of patients labeled penicillin-allergic are able to tolerate penicillins (and other β-lactams) Evaluation of penicillin allergy use of broad-spectrumm antibiotics costs Extent of allergic cross-reactivity between penicillins and cephalosporins/carbapenems is low