Management of Drug Allergy and Improving Antibiotic Stewardship

Transcription

1 Management of Drug Allergy and Improving Antibiotic Stewardship Roland Solensky, MD The Corvallis Clinic Oregon State University College of Pharmacy Corvallis, OR Conflict of Interest Financial: None Research: Astra Zeneca, Stallergenes Legal Consult/Expert Witness: Antibiotic allergies Organizational: None Gifts: None 1

2 Outline Drug allergy definitions and classifications Penicillin allergy β-lactam allergic cross-reactivity Cephalosporin allergy Macrolide allergy Quinolone allergy Macy E, Poon K-Y T. Am J Med 2009; 122:778.e.1-7 2

3 Drug Allergy History Name of drug When during course did reaction occur Characteristics of reaction, systems involved Previous exposure to same or similar drug Reason for administration Concurrent medications at time of reaction Management required for reaction Time elapsed since the reaction Subsequent exposure to same or similar drug Similar symptoms in absence of drug treatment Khan DA, Solensky R. J Allergy Clin Immunol 2010; 115:S Definitions Adverse Drug Reaction (ADR) WHO Definition Any noxious, unintended, and undesired effect of a drug which occurs at standard doses used in humans for prevention, diagnosis, or treatment Allergic Reactions = Hypersensitivity Reactions ADR s known (or presumed) to be mediated by an immunologic mechanism Account for about 10% of all ADR s Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105: e78 Classification of ADR s: Predictable vs Unpredictable Predictable Reaction Overdosage Side Effect Secondary Effect Drug-drug Interaction Example Acetaminophen hepatic necrosis Albuterol tremor Clindamycin C. difficile pseumembranous colitis Terfenadine/erythromycin torsades de pointes Unpredictable Reaction Example Intolerance Aspirin tinnitus (at usual doses) Idiosyncratic Dapsone hemolytic anemia in G6PD deficiency Allergic Penicillin Anaphylaxis Pseudoallergic Radiocontrast material anaphylactoid reaction 3

4 Classification of Allergic Reactions: Gell and Coombs Gell and Coombs Reaction Type Type I Type II Type III Type IV Mechanism Drug-specific IgE mast cell/basophil activation IgG/IgM-mediated cytotoxic reaction against cell surface Immune complex deposition reaction Delayed T-cell mediated reaction Example Anaphylaxis Hemolytic anemia Serum sickness Contact dermatitis Pichler WJ, et al. Med Clin N Am 2010; 94: Pichler WJ, et al. Med Clin N Am 2010; 94:

5 Penicillin History Jan May million units 20.5 billion units June Dec 1943 Aug 1945 End of WWII: 650 billion units per month 1st case of penicillininduced fatal anaphylaxis (Wilensky, JAMA) Biochemie (now Sandoz) 1st acidstable PO penicillin (Penicillin VK) Bud, Robert. Penicillin: Triumph and Tragedy. Oxford: Oxford University Press,

6 Penicillin Allergy: Epidemiology Most frequently reported medication allergy ~10% patient-reported prevalence >90% of patients labeled penicillin allergic are not allergic 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. 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 Group A Allergic to all penicillins Group B Allergic to only amox/amp Blanca M, et al. J Allergy Clin Immunol 1999; 103: Penicillin Allergy is Bad for Your Health use of vancomycin, quinolones, clindamycin, 3 rd gen cephalosporins incidence vancomycin resistant Enterococcus (VRE) Clostridium difficile methicillin-resistant Staph aureus (MRSA) efficacy medical costs length of hospitalization 6

7 Antibiotic Choices for Patients with History of Penicillin Allergy Solensky R, et al. Ann Allergy Asthma Immunol 2000; 84: Percent of Patients % 17.4% Penicillin Allergy No Allergy 21.7% 8% Antibiotic Choices for Inpatients with History of Penicillin Allergy 0 Vancomycin Levofloxacin Lee CE, et al. Arch Intern Med 2000; 160: Penicillin Allergy & Use of Vancomycin Vancomycin is frequently prescribed because of patients history of penicillin allergy 51% of vancomycin prescriptions (2 tertiary care hospitals in Ontario, Canada) 1 31% of vancomycin prescriptions (Parkland Hospital, Dallas, TX) 2 31% of vancomycin prescriptions (64 non-psychiatric Oregon hospitals) 3 1. Kwan T et al. Clin Invest Med 1999; 22: Solensky R et al. Ann Allergy Asthma Immunol 2000; 84: Cieslak PR, et al. Infect Control Hosp Epidemiol 1999; 20:

8 Vancomycin Resistant Enterococcus (VRE) and Use of Broad-Spectrum Antibiotics Risk factors for VRE acquisition in MICU: Pre-MICU Antibiotic Odds Ratio (95% CI) P Value Vancomycin 5.1 ( ) 0.02 Cephalosporins 6.0 ( ) 0.03 Quinolones 8.6 ( ) Penicillins + β-lactamase inhibitors 1.8 ( ) 0.24 Martinez JA, et al. Arch Intern Med 2003; 163: Risk Factors for C. difficile in hospitalized patients Antibiotic use during 6 weeks prior Odds Ratio (95% CI) P Value to diagnosis of C. difficile Fluoroquinolones 3.9 ( ) <0.001 Cephalosporins 3.8 ( ) <0.001 Clindamycin 1.6 ( ) NS Penicillins + β-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:

9 Azithromycin and Risk of Cardiovascular Death Ray WA, et al. N Engl J Med 2012; 366: Penicillin Allergy in Hospitalized Patients Retrospective study ( ) of all hospitalized patients at Southern California Kaiser Foundation hospitals 11.2% (51,807/462,225) labeled penicillin allergic in EMR Patients labeled penicillin allergic (cases) matched 1:2 with patients not labeled as penicillin allergic (controls) Macy E, et al. J Allergy Clin Immunol 2014; 133: Antibiotic Antibiotic Use in Hospitalized Patients with Penicillin Allergy Cases (Penicillin Allergy) Controls (No Penicillin Allergy) P Value Quinolones 25% 14.3% < Vancomycin 21.2% 12.4% < Clindamycin 24.4% 5.7% < Macy E, et al. J Allergy Clin Immunol 2014; 133:

10 Consequences of Penicillin Allergy Cases (penicillin allergy ) vs controls (no penicillin allergy): 30.1% (95% CI, %) more VRE 23.4% (95% CI, %) more C. difficile 14.1% (95% CI, %) more MRSA 0.59 day longer mean hospital stay (95% CI, ) Macy E, et al. J Allergy Clin Immunol 2014; 133: Antibiotic Costs in Penicillin-Allergic Patients Study Cost: H/O Penicillin Allergy Cost: No Pcn Allergy P Value Kraemer MJ (1987) 1 $4.6 $1.75 <0.001 MacLaughlin EJ (2000) 2 $28.6 $ Sade K (2003) 3 $81.7 $ Sade K (2003) 4 $43.0 $31.0 < Irawati L (2006) 5 Aus$ Aus$ N/A Borch JE (2006) N/A Picard M (2013) 5 Can$ Can$ N/A Satta G (2013) N/A 1. 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 5. Average antibiotic cost per hospitalization 10

11 Before prescribing broad-spectrum antibiotics to a patient thought to be penicillin-allergic, evaluate the patient for true penicillin allergy (IgE-mediated) by conducting a history and physical, and, when appropriate, a skin test and challenge dose. 11

12 Penicillin Skin Testing Effect on Antibiotic Use Study % Pcn ST-Negative Antibiotic Use (% of Patients) Harris AD (1999) 86% Vancomycin 25% 0% Quinolones 27% 14% Clindamycin 23% 0% Nadarajah K (2005) 92% Vancomycin 77% 8% Quinolones 26% 3% Clindamycin 9% 2% Park M (2006) 96% Vancomycin 30% 16% del Real GA (2007) 88% Vancomycin 37% 16% Quinolones 36% 13% Clindamycin 15% 5% 3 rd Gen Cephalosporins 8% 2% Frigas E (2008)? Vancomycin 28% 10% Rimawi RH (2013) 100% Vancomycin 9.6% 0% Quinolones 27% 0% Clindamycin 9.6% 0% Chen JR, et al. J Allergy Clin Immunol Pract 2017; 5: Chen JR, et al. J Allergy Clin Immunol Pract 2017; 5:

13 Chen JR, et al. J Allergy Clin Immunol Pract 2017; 5: % (67/70) of patients skin test-negative Park MA, et al. Int Arch Allergy Immunol 2011; 154: Park MA, et al. Int Arch Allergy Immunol 2011; 154:

14 Penicillin Allergenic Determinants Penicillin 95% 5% Major Determinant (Penicilloyl) Skin Test Reagent Penicilloyl-polylysine (PPL) = Pre-Pen Minor Determinants (Penicilloate, Penilloate) Skin Test Reagents Penicilloate Penilloate Penicillin G MDM Structures of Penicillin Breakdown Products Penicillin Skin Test Reagents Penicillin Reagent Penicilloyl polylysine (6x10-5 M) Penicillin G (10,000 U/ml) Penicilloate/penilloate (0.01M) Amoxicillin (3-25 mg/ml) Ampicillin (3-25 mg/ml) Availability Commercially available as Pre- Pen (premixed solution) Commercially available, requires dilution (off-label) Not commercially available in US, requires synthesis IV form not commercially available in US Commercially available (IV form), requires dilution (off label) 14

15 Penicillin Skin Testing PPV Based on limited number of patients due to ethical concerns PPV = ~ 50% (range %) 1-7 primarily based on PPL+ patients PPV = 75% in patients ST+ to only penicilloate or penilloate 8-10 One outlier study: PPV 10% 11 Only patients with mild reactions > 3 years prior Skin test-positive rate = 43% 1. Sogn DD, et al. Arch Intern Med 1992; 152: Chandra RK, et al. Arch Dis Child 1980; 55: Green GR, et al. JACI 1977; 60: Solley GO, et al. JACI 1982; 69: Adkinson NF, et al N Engl J Med 1971; 46: Macy E and Burchette RJ. Allergy 2002; 57: Caubet JC, et al. JACI 2011; 127: Levine BB, Zolov DM. J Allergy 1969; 43: Levine BB, et al. Ann New York Acad Sc 1967; 145: Macy E, Ho NJ. Perm J 2011; 15: Goldberg A, et al. Ann Allergy Asthma Immunol 2008; 100: Penicillin Skin Testing Negative Predictive Value United States 1-7 >95% and reactions generally mild Europe % and reactions sometimes severe 1. Sogn DD, et al. Arch Intern Med 1992; 152: Gadde J, et al. JAMA 1993; 270: Mendelson LM. JACI 1984; 73: Macy E, et al. JACI 2003; 111: del Real GA, et al. Ann Allergy Asthma Immunol 2007; 98: Fox SJ and Park MA. JACI Pract 2014; 2: Macy E, et al. JACI Pract 2013; 1: Torres MJ, et al. Allergy 2001; 56: Bousquet PJ, et al. Allergy 2007; 62: Bousquet PJ, et al. Allergy 2008; 38: Bousquet PJ, et al. JACI 2005; 115: Demoly P, et al. Allergy 2010; 65: Matheu V, et al. JACI 2005; 116: Matheu V, et al. J Investig Allergol Clin Immunol 2007; 17: Penicillin Skin Testing Which Skin Test Reagents? VS MDM Solensky R and Macy E. J Allergy Cllin Immunol Pract 2015; 3:

16 Amoxicillin/ampicillin-Specific Reactors (US) Reference (Year) # History- Positive Patients # ST- # Positive % Positive to Only Amox/Amp: Positive to Only ST+ Patients Patients Amox/Amp All Patients Macy E (1997, 2002) /161 = 3.1% 5/1429 = 0.35% Mendelson LM (pers. communication) /257 = 2.7% 7/5006 = 0.14% Park MA (2007) /64 = 3.1% 2/1759 = 0.11% Lin E (2010) /243 = 5.8% 14/1068 = 1.3% Fox SJ (2014) /66 = 15% 10/778 = 1.3% Macy E (2014) /4 = 0% 0/500 = 0% Amoxicillin/ampicillin-Specific Reactors (Europe) Reference (Year) # of History- Positive Patients # of ST- Positive Patients # Positive to Only Amox/Amp % Positive to Only Amox/Amp: ST+ Patients All Patients Torres MJ (2001)? /203 = 45% Bousquet PJ (2005) 824* /88 = 50% 44/824 = 5.3% Matheu V (2007)? /69 = 25% Romano A (2009)? /300 = 38% * Includes cephalosporin reactors Future of Penicillin Skin Testing? Components PPL ampule MDM vial Amoxicillin reagent vial Additional kit items Saline diluent for MDM Water diluent for amoxicillin Histamine 16

17 Penicillin Allergy: Resensitization Resensitization = re-development of penicillin allergy in patients who have lost their sensitivity Initial argument against elective penicillin skin testing Resensitization after oral penicillin = very low and comparable to rate of sensitization Resensitization after parenteral penicillin =? slightly higher than rate of sensitization Resensitization After Oral Penicillins Study Type Patients Antibiotic Repeat ST Resens Rate Mendelson LM (1984) Prospective Peds Penicillin YES 2/219 (1%) Parker PJ (1991) Prospective Adults Penicillin YES 0/3 (0%) Pichichero ME (1998) Prospective Peds Various -lactams YES 26/189 (14%) Macy E (1998) Retrospective Both Various Pcn s NO 0/69 (0%) Solensky R (2002) Prospective Adults Penicillin YES (x3) 0/46 (0%) Macy E (2003) Prospective Adults Various Pcn s YES 1/33 (3%) Macy E (2003) Retrospective Both Various Pcn s NO 38/405 (9%)* Bittner A (2004) Retrospective? Amox NO** 0/3 (0%) Ponvert C (2007) Retrospective Peds Various -lactams NO*** 2/93 (2.1%) Hershkovich J (2009) Prospective Peds Various -lactams YES 2/98 (2%) * Most reactions not allergic ** One patient repeat ST-negative *** Five patients repeat ST/oral challenge-negative Penicillin Resensitization Drug Allergy: An Updated Practice Parameter Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105: e78 17

18 Penicillins/Cephalosporins Cross-reactivity R-group side chains β-lactam Ring 2. Thiazolidine Ring 3. Dihydrothiazine Ring Cephalosporin Challenges in Patients with History of (Unproven) Penicillin Allergy Reference (Year) Cephalosporin Reaction Rate Comments + History Pcn Allergy 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) N/A Reactions convincing MacPherson RD (2006) 0% (0/84) N/A Crotty DJ (2015) 3.8% (7/186) N/A 3/7 reactions immediate Beltran RJ (2015) 0.7% (1/153) N/A Reaction = urticaria 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 Ahmed KA (2012) 21 0 No TOTAL (2.9%) 18

19 Penicillin/Cephalosporin Side Chains Cephalosporins with Identical Ampicillin R1-group Side Chains Cefaclor Cephalexin Cephradine Cephaloglycin Loracarbef Amoxicillin Cefadroxil Cefprozil Cefatrizine Cephalosporin Reactions in Patients Selectively Allergic to Amoxicillin/Ampicillin Reference (Year) Selective Allergy To Cephalosporin with Identical Side Chain Cephalosporin Reaction Rate Audicana M (1994) Ampicillin Cephalexin 1/10 (10%) Sastre J (1996) Amoxicillin Cefadroxil 2/16 (12%) Miranda A (1996) Amoxicillin Cefadroxil 8/21 (38%) TOTAL 11/47 (23%) Non-IgE-mediated Penicillin/Cephalosporin Cross-reactivity Limited data on delayed maculopapular eruptions rate of cross-reactivity similar to IgE-mediated allergy No data on Serum sickness-like reactions Stevens-Johnson syndrome/toxic epidermal necrolysis Drug rash with eosinophilia and systemic symptoms (DRESS) 19

20 Cephalosporin Administration to Patients with a History of Penicillin Allergy: AAAAI Workgroup Report No penicillin skin testing, if exclude severe reaction histories Administer cephalosporin via full dose or graded challenge Consider cephalosporin skin testing In amox/amp reactors, avoid cephalosporins with identical R1 group side chains Penicillin skin test-positive Administer cephalosporin via graded challenge or desensitization Consider cephalosporin skin testing Carbapenem Challenges in Penicillin ST+ Patients Reference (Year) # of Patients # of Reactions Carbapenem Given Comment Romano A (2006) Imipenem One patient imipenem ST+ Romano A (2007) Meropenem One patient meropenem ST+ Atanaskovic (2008) Meropenem One patient meropenem ST+ Atanaskovic (2009) Imipenem One patient imipenem ST+ Gaeta F (2015) Imipenem Meropenem Ertapenem TOTAL Patients challenged with all 3 carbapenems No patients carbapenem ST+ All challenged patients also skin test-negative to carbapenems Carbapenem skin test-positive patients not challenged Allergy to Cephalosporins Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105: e78 20

21 Cephalosporin Allergy: Skin Testing/Challenges 102 patients (14-81 Y/O) with IgE-mediated reactions to cephalosporins (80/22 M/F) (Italy) Median time since reaction = 2.5 months (range months) Reaction history 83% anaphylaxis (⅔ hypotension and ⅜ LOC!) 9% urticaria 8% other Skin testing with 11 different cephalosporins (2-20 mg/ml) Challenges with alternate cephalosporins Romano A, et al. J Allergy Clin Immunol 2015; 136: Group # of Patients Pattern of Cephalosporin Positivity A 73 Ceftriaxone Cefotaxime (41 only culprit, Cefuroxime Cefepime 32 > culprit) Ceftazidime Cefodizime B 13 Cephalexin Cefaclor Cefadroxil (11 only culprit, 2 > culprit) C 7 Cefazolin Cefamandole (6 only culprit, Cefoperazone Ceftibutin 1 > culprit) Cephalosporin Challenges* Cefaclor Cefazolin Ceftibutin Cefuroxime Ceftriaxone Cefazolin Ceftibutin Cefaclor Cefuroxime Ceftriaxone Cefazolin** Ceftibuten D 9 2 different groups Various - based on ST Total 102 * All cephalosporin challenges negative ** Patients who reacted to cefazolin not challenged with cefazolin Romano A, et al. J Allergy Clin Immunol 2015; 136: Cephalosporin Allergy Natural History Group 1 = Reaction < 1 year before evaluation Group 2 = Reaction > 1 year before evaluation Romano A, et al. Allergy 2014; 69:

22 Macrolides (I) 73 consecutive pediatric patients referred for suspected clarithromycin allergy (Florence, Italy) Urticaria (62%), angioedema (18%), M-P rash (19%) Immediate (27%), delayed (67%), undetermined (6%) All patients underwent skin testing with IV clarithromycin 64/73 patients underwent clarithromycin challenges, irrespective of skin test results (9 refused) 5 days (7.5 mg/kg bid) Initial dose single blinded Initial dose given via 4 step graded challenge (1/100, 1/10, 2/10, 7/10) Mori F, et al. Ann Allergy Asthma Immunol 2010; 104: Macrolides (I): Results 4 reactions: 2 immediate (urticaria, urticaria/ae) 2 delayed (M-P rashes on days 3 & 4) Mori F, et al. Ann Allergy Asthma Immunol 2010; 104: Macrolides (I): Results Skin Test Positive Skin Test Negative Challenge Positive Challenge Negative Sensitivity = 75% Specificity = 90% PPV = 33% NPV = 98% Mori F, et al. Ann Allergy Asthma Immunol 2010; 104:

23 Macrolides (II) 45 consecutive pediatric patients referred for suspected clarithromycin allergy (Ankara, Turkey) Reactions = urticaria, maculopapular exanthem, angioedema No breakdown of immediate vs delayed reactions 20/45 patients underwent prick and ID skin testing mg/ml (1:100,000 dilution from full strength) mg/ml (1:10,000 dilution from full strength) 0.05 mg/ml (1:1,000 dilution from full strength) All patients underwent clarithromycin challenges, irrespective of skin test results Initial dose (10 mg/kg, non-blinded) given via 4-5 step graded challenge (1 mg, 5 mg, 25 mg, 100 mg, 500 mg) Only delayed reactors continued clarithromycin for 5 days Cavkaytar O, et al. JACI Pract 2015; 4: Macrolides (II): Results Antibiotic Non-irritating Skin Test Concentrations IV Antibiotic Full Strength Conc (mg/ml) Highest Nonirritating Conc Dilution from Full Strength Tobramycin 40 4 mg/ml 1:10 Ticarcillin mg/ml 1:10 Clindamycin mg/ml 1:10 Gentamycin 40 4 mg/ml 1:10 Trimethoprim-sulfa 80 (sulfa) 0.8 mg/ml 1:100 Levofloxacin mg/ml 1:1,000 Erythromycin mg/ml 1:1,000 Nafcillin mg/ml 1:10,000 Vancomycin mg/ml 1:10,000 Azithromycin mg/ml 1:10,000 Empedrad RB, et al. J Allergy Clin Immunol 2003; 112:

24 Quinolones 218 consecutive patients (75/140 M/F) referred for history of recent (< 1 year) allergic reactions to quinolones (Spain) 152 immediate reactors (53% urticaria/angioedema, 47% anaphylaxis) 66 delayed reactors BAT in all immediate reactors No skin testing or patch testing All patients (except if BAT positive) challenged with culprit quinolone 2 day course First dose single-blinded, given via 5 step graded challenge Blanca-Lopez N, et al. Clin Exp Allergy 2013; 43: Patients 152 Immediate reactors 66 Delayed reactors 24 BAT+ No challenge 125 Challenged 3 positive challenge 63 negative challenge 42 positive challenge 83 negative challenge Blanca-Lopez N, et al. Clin Exp Allergy 2013; 43: Case History 50 Y/O female: Age 21: anaphylaxis to IM penicillin Age 30: SJS on PO TMP/SMX Age 46: urticaria on IV ciprofloxacin Age 47: cutaneous pruritus, nausea day 1 of PO azithromycin Age 49: cutaneous pruritus, nausea day 1 of clindamycin and doxycycline PCP and patient worried about running out of antibiotic choices 24

25 Case History (cont) 1) Penicillin skin test negative oral challenge negative 2) Levofloxacin skin test negative oral graded challenge negative 3) Azithromycin skin test negative oral challenge negative 4) Avoid sulfonamide antibiotics indefinitely 5) Defer evaluation of clindamycin and doxycycline allergies Summary Penicillin allergy is associated with vancomycin, quinolones, clindamycin, 3 rd gen cephalosporins VRE, C. difficile, MRSA medical costs and length of hospitalization Evaluation of penicillin allergy with skin testing Combats drug resistance and access to safe and cost-effective antibiotic treatment Allergic cross-reactivity between penicillins and cephalosporins/carbapenems is minimal Allergy to cephalosporins, macrolides and quinolones wanes and often resolves 25