1. Antibiotic Safety: From Allergy to QTc
Monique Bidell, PharmD, BCPS
Assistant Professor
Albany College of Pharmacy and Health Sciences
Albany, New York

2. Disclosures
I have no actual or potential conflicts of interest related to this presentation.

3. Objectives
Compare cardiac risks between macrolides and fluoroquinolones
Summarize the literature on vancomycin- and vancomycin/piperacillin-tazobactam- induced nephrotoxicity
Describe an evidence-based approach to assess beta-lactam cross reactivity
Overview: QTc prolongation and arrhythmia risk
Fluoroquinolones vs macrolides
Toxicities
Vancomycin-induced nephrotoxicity
Cross-reactivity
Penicillin allergy

4. When assessing risk of beta-lactam cross-reactivity:
Class to class risk assessments appear to be sufficient (Eg, penicillin and cephalosporins)
Robust data are limited to within-class assessments (eg, penicillin to penicillin)
Agent-specific assessments appear to be best (eg, amoxicillin and ceftriaxone)
Data are insufficient to easily assess cross reactivity

5.
Balancing effectiveness and safety, though in most cases our primary role is ensuring safe medication use, since we don’t always know the indication to allow us to assess the effectiveness piece

6. QT prolongation & Torsades de Pointes (TdP)
Mechanism: Potassium current (Ikr) inhibition  delays cardiac repolarization
TdP risk factors
QTc >500 msec or >60 msec change from baseline
Bradycardia
Electrolyte imbalances
Heart disease (also HFrEF, MI)
Female gender
Age >65 years
“Swiss cheese” effect
Matthew Li, PharmD and Liz G. Ramos, PharmD, BCPS. P T Jul; 42(7): 473–477.
Defintiion: prolongation = >60msec change from baseline or >450 msec
Tdp: polymorphic vent tachycardia; qtc >500 a/w 2-3 fold increase in risk
CV disease, electrolyte abnormalities (hypoK), concomitant meds
-swiss cheese model
hERG forms the major portion of one of the ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts potassium (K+) ions out of the muscle cells of the heart (cardiac myocytes), and this current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane during the cardiac action potential
The proposed cellular mechanism of drug-induced prolonged QT interval involves inhibition of the rapid component of the delayed rectifier potassium current (IKr).1 Blocking IKr leads to prolongation of the ventricular action potential duration, leading to an excess sodium influx or a decreased potassium efflux. This excess of positively charged ions leads to an extended repolarization phase, resulting in a prolonged QT interval and causing arrhythmias such as TdP. This TdP trigger is seen as a premature ventricular complex (PVC) that is generated during the prolonged repolarization phase, also known as the R-on-T phenomenon.2 In contrast to ventricular fibrillation, TdP is a unique ventricular arrhythmia because it can spontaneously end. However, it is possible for TdP to degenerate to ventricular fibrillation and cause sudden cardiac death.2

7. Azithromycin and levofloxacin
QTc prolongation themselves (& versus other class agents)
Cardiac risks: Lu et al., 2015: 15 case reports/series, 5 observational studies, 5 clinical trials
-Azithro and levo are two of the most frequently prescribed antibiotics across patient care settings
-obviously both can prolong the qtc, but the CV event risk is really what we are concerned about – caveat: most comparators are amox; sicker patients are more likely to get a fq or macro
-FQ qtc prolong risk: moxi > levo > Cipro; macrolides: azithro < others
Increased cv risk azithro vs amox: 2 large retro studies; no difference with amox: two retro
Increased cv risk levo: 1 retro

8. Agent Study Outcome; population Estimate
Azithromycin
Ray et al. 2012
CV death; Medicaid
Amox (D1-5): HR 2.49 (1.38, 4.50)
Levo (D1-5): HR 1.27 (0.66, 2.47)
Svanstrom et al. 2013
CV death; general
Pen V (D1-5): RR 0.93 (0.56, 1.55)
Rao et al. 2014
Arrhythmia; Veterans
Amox (D1-5): 1.77 (1.20, 2.62)
Levo (D1-5): 0.73 ( )
Mortensen et al. 2014
CV events; Veterans
Other abx: OR 1.01 ( )
Levofloxacin
Amox (D1-5): HR 1.99 (0.93, 4.23)
Amox (D1-5): HR 2.43 (1.56, 3.79)
Adapted from Lu et al. 2015
Cohort studies; Rao was a weighted HR-did not adjust for infection indication—inpatient and outpatient, older pop vs Ray
Ray—propensity score matching; outpatient population
*yes – only during current use, not after use; no on propensity score matching
Rao: also only during current use (d1-5)
Ray et al 2012: no sig diff between azithro and levo HR 1.27, 95% CI
Amox, amoxillin; levo, levofloxacin; abx, antibiotics; pen V, penicillin; D1-5, days 1-5

9. Considerations Populations (co-morbidities, severity of illness)
Correlation vs causation
Non-randomized design
-healthy patients don’t even consistently have prolonged qtc
-different infections (pneumonia severity, if that was the indication); most studies were observational; even in clinical trials there wasn’t much qt prolongation; this is obviously an important
-**duration of treatment – risk is as long as pt gets the drug. So possible increased risk with levo bc tends to be longer than 5 days
-ray and rao both retrospective and non-randomized

10. Fluoroquinolone arrhythmia risk factors
Cardiovascular Disease
45-85 events/100,000 patients
No Cardiovascular Disease
5-44 events/100,000 patients
Elderly also a RF; use of concomitant medications—don’t use with antiarryhtmics, caution with electrolyte disturbances
AMDAC and DSaRM Advisory Committee. FDA Briefing Information, 2015.

11. Management Correct modifiable risk factors (e.g., replete K, Mg)
Monitoring
Modifiable risk factors
EKG at baseline, periodically during treatment depending on risk assessment
Patients: signs/sxs of dizziness, palpitations, syncope

12. Patient #1 60 yo F presents w/ chills, lightheadedness, hemoptysis
PMH: afib (on sotalol), HFpEF, CAD, COPD
All: cefdinir (nausea)
Afebrile, BP 87/52101/62, HR 78, 5L NC, respiratory alkalosis on ABG, WBC 13.3
Urine legionella Ag+, Scr 0.69
QTc 500 (SR, LBBB)
Ceftriaxone 1g IV q24h, doxycycline 100mg IV q12h
CXR bibasilar opacities
Urine ag: positive even after abx, serogroup 1, culture takes several days on a charcoal plate
HR 97, QRSd 154, QT 393
All: tramadol-SOB, hydrocodone-rash, cefdinir-nausea, codeine-nausea
-management: correct modifiable risk factors, like K, Mg; increased monitoring—EKG at baseline, during treatment; ask patients to report signs/sxs of dizziness, palpitations, syncope

13. Vancomycin nephrotoxicity
Acute tubular necrosis?
Risk factors
Daily doses >4 grams
Trough levels >20 mcg/ml
Therapy >6 days
Concurrent nephrotoxins
Pre-existing renal disease
Obesity
Severe illness
Negative consequences
Mergenhagen and Borton. J Pharm Practice 2014;27(6):545-53
-mechanism is still not well defined; may be a component of oxidative stress that causes tubular necrosis
-AKI a/w 4-fold increase in mortality in hospitalized patients; one study cited 11%
Antimicrob Agents Chemother Feb;57(2): doi: /AAC Epub 2012 Nov 19.
Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.
van Hal SJ1, Paterson DL, Lodise TP.
The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥ 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of <15 mg/liter. The relationship between a trough of ≥ 15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥ 15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

14. Vancomycin-piperacillin/tazobactam (VPT) nephrotoxicity
Hammond et al: 2017 Meta-analysis (14 studies)
Population
Unadjusted analysis
Adjusted analysis
All studies
OR 3.12 (2.04, 4.78) p<0.001
OR 3.11 (1.77, 5.47) p<0.001
Vanco + other BL
OR 3.60 (2.28, 5.68) p<0.001
OR 3.31 (2.13, 5.12) p<0.001
Vanco + cefepime
OR 2.63 (1.62, 4.28) p<0.001
OR 3.78 (2.48, 5.78) p<0.001
Vanco alone*
OR 3.16 (0.67, 14.91) p=0.146
OR 2.50 (0.41, 15.44) p=0.323
Critically ill
OR 3.83 (1.67, 8.78) p=0.002
OR 2.83 (0.74, 10.85) p=0.128
Non-critically ill
OR 2.44 (1.40, 4.27) p=0.002
OR 3.04 (1.49, 6.22) p=0.002
Acute tubular necrosis vs acute interstitial nephritis
-adults and children; incidence ranged from 11-49% in the 14 studies (2800 patients); Luther was 15 studies and 17 abstracts w/25k patients—overall incidence was 22% VPT vs 13% comparators in Luther
Vanco believed to cause ATN; semi syn pcns tend to cause AIN—some type of combo injury since both accumulate in proximal renal tubules (Pcns accumulate throughout the nephron)
-vs vanco alone NS; critical illness NS in adjusted analysis (Luther – increased risk in ICU appeared consistent across treatments not just VPT)
-could not perform a complete adjustment based on inherent limitations of studies
*Meta-analysis by Luther et al. (2018) found increased risk of VPT-AKI vs vancomycin alone (OR 3.40, 95% CI )

15. VPT nephrotoxicity (Hammond et al. cont’d)
Considerations:
Retrospective observational studies
Heterogeneity: I2 78% in adjusted analysis (E.g. definitions of AKI)
Vancomycin duration
Concurrent nephrotoxin data
Per Luther et al., NNH=11
Vancomycin duration data unavailable for 6/11 studies; concurrent nephrotox and durations unavailable for 5 studies
-different definitions of AKI (rifle, akin, vanco guideline)
-findings too generalized to give us details on modifiable risk factors

16. Navalkele et al. 2017 VPT vs vanco-cefepime (VC) nephrotoxicity
Retrospective, matched cohort study (n=558)
Illness severity, ICU, duration of combo therapy, vancomycin dose, number of concomitant nephrotoxins
Combo therapy for ≥48 hours; excluded Scr >1.2
Primary outcome: incidence of acute kidney injury (AKI)
RIFLE, AKIN, vancomycin consensus guidelines
-meta analysis have their limitations because you can only get so granular
279 patients per treatment group

17. Navalkele et al. 2017 (cont’d)
279 VPT-VC pairs
Mean age: / years
Comparable:
Age, length of ICU stay, Charlson comorbidity index, baseline Scr, nephrotoxins, vancomycin (load, dose, pre-AKI troughs)
More in VPT: septic shock, skin & soft tissue
More in VC: hypertension, enterobacteriaceae

18. Navalkele et al. 2017 (cont’d)
Outcomes
MV analysis: VPT independently associated with RIFLE-defined AKI (HR 4.3, 95% CI , p<0.0001)
Definition
Findings
Hazard ratio
RIFLE
VPT 29% (81/279) vs VC 11% (31/279)
HR 4.0, 95% CI , p<0.0001
AKIN
VPT 32% vs VC 14%
HR 3.5, 95% CI , p<0.0001
Vancomycin guidelines
VPT 24% vs VC 8.2%
HR 4.4, 95% CI , p<0.0001

19. Navalkele et al. 2017 (cont’d)
Outcomes
Median onset of AKI: VPT 3 days (IQR 2-5 days) vs VC 5 days (IQR 3-7 days)
Median length of stay: VPT 8 days vs VC 6 days (p=0.01)
Vancomycin trough (<15 mcg/ml vs ≥15 mcg/ml)
VPT: no association
VC: AKI 1% (1/76) for <15 mcg/ml vs 13% (20/160) for ≥15 mcg/ml (p=0.003)
Considerations: pre-AKI troughs; 20% ICU; excluded baseline renal insufficiency
Broke down troughs further into <15, 15-20, >20 and this was further characterized in a stepwise fashion (1%, 5%, 21%)
-pro: pre-AKI troughs limited potential for bias
-limitation: 20% of pts were ICU so not as applicable to that population
-faster onset also showed in Luther et al 2018 meta analysis though not statistically significant

20. Management Antimicrobial stewardship Monitor Scr
Assess need for combo therapy daily/antibiotic time outs
Treatment guidelines
Antibiotic restrictions
Monitor Scr
Assess other risk factors

21. Patient #2 62 yo M presents with coughing and SOB
PMH: HFrEF (EF 40%), afib, T2DM; recent hospitalization
Afebrile, BP 102/74, HR 90; WBC 10; Scr 1.0
Meds of note: bumetanide, lisinopril
Vancomycin 1250mg (16.5 mg/kg) IV q12h, pip/tazo 3.375g q6h started in ED
Scr on hospital day 1: 1.7

22. Types of reactions
Immediate* (generally <60 min) vs. non-immediate (>60 min)
Type I* vs. Types II-V
Type A vs. Type B*
(immunologic, idiosyncratic)
*IgE-mediated
BMJ 2017;358:j3402 doi: /bmj.j3402
BMJ: immediate- <1 to 6 h, generally <1h after exposure, often IgE-related (urticarial, pruritis, angioedema, anaphylaxis)
-non-imm: commonly days later, from release of cytokines by activated T cells, maculopapular/morbilliform rashes
Depestel:
Type I = immediate (1h-72h); IgE;
II-IV (IgG or IgM): SJS, TEN, interstitial nephritis, vasculitis, serum sickness, hemolytic anemia, contact dermatitis, morbilliform rashes, maculopapular rashes
Type A: 75% of ADRs (adverse effects, toxicities due to pharmacology); type B: immunologic (IgE) vs idiosyncratic
Non-type I serious: stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, vasculitis, serum sickness, hemolytic anemia, neutropenia, thrombocytopenia
-idiosyncratic can involve drug metabolism and alteration of pathways that can be situation specific: for example, sulfonamides usually undergo acetylation; in the case of some viral infections like CMV or HIV this can drive the pathway to become more oxidative, which produces a more reactive compound that may ilicit an allergic response (Depestel)
-type I: can be immediate (second exposure); can occur during prolonged initial exposure; can have a ‘late phase’ reaction hours after the immediate reaction that can cause resp and cardiac sxs (mediated by cytokines, ILs, eosinophils)
-release of histamines, prostaglandins, leukotrienes can cause bronchoconstriction, hives, vascular dilatation, edema, cardiogenic shock

23. What percent of the population reports a PCN allergy versus is truly allergic?
20-30%; ≤5%
20-30%; ≤1%
10-20%; ≤5%
10-20%; ≤1%
10%, <=1%
(10% community, up to 20% hospitalized)
Per JAMA: estimated million people are labeled as allergic to pcn
Risk factors
Repeated exposure, female, increased age, family history
IgE against benzylpenicilloyl structural group (a hapten)
Skin testing
Types of assessments: patch test (abrasion), intradermal, RAST IgE blood test
BMJ: -no one test that can diagnose or exclude beta-lactam hypersensitivity—a combo approach is required
-age: I think we often think of children as being more likely to exhibit a reaction particularly a rash; the thought is that actually the risk of allergy remains very low and any sort of urticarial or maculopapular rash that occurs may actually be as a result of viral infections that are mistreated with abx; one review indicated that <7% of children with a delayed rash after PCN had a recurring rash on rechallenge
-negative consequences; use of non-beta lactams that are second line agents have their own problems—less effective agents for infections for which beta lactams are first line (vanco and MSSA BSI); more toxicities (vanco (nephrotox), FQs); increased use of broad spectrum agents; costlier meds; meds more a/w antibiotic resistance
-hapten: low molecular weight chemical that conjugates with a carrier such as polylysine resulting in formation of an Ag with the hapten’s specificity. The BPO hapten is the major antigenic determinant in pcn-allergic patients. Pre-pen test determines presence of penicilloyl IgE Abs which are necessary but not sufficient for acute allergic reactions due to the major penicilloyl determinant. Non-BPO haptens are designated as minor determinants, since they less frequently elicit an immune response. Pre-pen does not reaction with IgE abs directed against non-BPO haptens. A negative skin test is a.w incidence of immediate allergic rxn of <5% after admin of pcn; incidence may be more than 50% in a history-positive patient with a positive skin test. Whether a negative skin test predicts a lower risk of anaphylaxis is not established. The clinical value of pre-pen skin tests alone in determining thr risk of giving semi-syn pcns (amp, meth, naf, ox, amox, ceph, penems) is not known.
-positive skin test, done; negative skin test, oral challenge

24. Penicillin skin testing (inpatient)
Benefits:
60-90 minutes
Negative predictive value >95%
Increases beta-lactam usage
Cost savings
Safe in children, pregnant women
Limitations:
Clinical utility
IgE reactions only
Interference with antihistamines
Contraindicated with SJS, TEN, others
-only identifies IgE—so if you have a rash, it doesn’t help you
-drug interactions with antihistamines
-decreased healthcare costs
Ref^, also Sacco et al. Allergy Sep;72(9): doi: /all Epub 2017 Apr 26.

25. Cross-reactivity PCN-PCN PCN-cephalosporin PCN-carbapenem
Cephalosporin-carbapenem
Cross-reactivity study limitations: geography, ADRs vs allergies, product purity
-Romano (limitations) – European studies report a higher anaphylaxis rate than US studies; some studies include ADRs like all rashes; first gen cephs were contaminated with PCN
-pcn-ceph, pcn-cbm, ceph-cbm (campagna J emerg med 2012, kula CID 2014)
-between classes is arguably an outdated concept; makes most sense to look at the evidence in support of cross reactivity between specific agents… how many patients even get PCN these days anyways? (look at PCN side chain)
-confounder of older studies: ceph used to be contaminated with penicillin; non-IgE reactions lumped in with ‘allergy’ definition

26. PCN-PCN cross-reactivity in (+)skin test patients (Solley et al.)
Antibiotic
Reaction
Treatment
Onset
Penicillin G
Urticaria
Carbenicillin
Mild urticarial
12-24 hr
Methicillin
Morbilliform rash, AIN
2 weeks
Nafcillin
24-48 hr
Angioedema
6 days
Unknown
None -
Rash
Morbilliform rash
Hypotension
Methicillin, oxacillin
-all 8 patients were re-challenged in a graduated fashion; this “desensitization” may have prevented any immediate allergic reactions
-”50%” cross reactivity; both immediate and delayed reactions—very muddy
-50% cross reactivity among PCN rechallenge in setting of a +skin test; overall reaction rate was low (4%) in collective cohort with negative skin tests -
-does it make sense based on side chain or structure? No; one patient got methicillin twice

27. Implications of a ‘side chain’ approach
Experimental and clinical data suggest role of side chain immunogenic epitopes & specific IgE antibodies
If side chains drive IgE response:
Skin testing with benzylpenicillin may have negative response
Patients may tolerate penicillins not possessing the relevant side chain determinants
Silviu 1993
-experimental data: (ampicillin, amoxicillin)
-studies have found that pts allergic to beta lactams may possess IgE Abs specific for the side chains

28. Penicillin Cephalosporin 6 7 3 O NH R C N COOH O S NH R C N
Depestel, Anne’
How do carbapenems differ?
Cephalosporin 3

29. DePestel et al. Amox Amp Cefep Ceftriax Cefotax Cephal 6 6/7 7
Amox: amoxicillin; Amp: ampicillin; Cefep: cefepime; Ceftriax: ceftriaxone; Cefotax: cefotaxime; Cephal: cephalexin

30. Silviu-Dan et al. (1993)
112 patients in Allergy and Clinical Immunology Clinic (Winnipeg; )
Clearly defined allergy to penicillin or derivatives
Intradermal testing: benzylpenicillin derivatives, >=1 semisynthetic penicillin

31. 8 10 3 Silviu-Dan et al. Amp-MDM: 8 BPO-PL: 4 Amox-MDM: 1 BP-MDM: 4
BPO-PL+Amp-MDM: 1
BP-MDM+Amox-MDM: 1
BP-MDM+Clox-MDM: 1
Silviu-Dan et al.
Amp-MDM: 8
Amox-MDM: 1
Clox-MDM: 1
BPO-PL: 4
BP-MDM: 4 8 10 3
BPO-PL = pre pen skin test
Amp: ampicillin; Amox: amoxicillin; BP: benzylpenicillin; BPO-PL: benzylpenicilloyl polylysine; Clox: cloxicillin; MDM: minor determinant mixture (equal parts part drug, penilloate and penicilloate analogs)

32. Side chains!
Silviu-Dan et al.
Patients with Amp allergy: (+) skin test for Amp-MDM, (-) for Amox-MDM
Found in other studies too (Blanca et al., de Haan et al.)
Polymer lengths for these can vary  alter antigenicity?
More (+) skin test with Amp-MDM than anticipated
Lyophilized semisynthetic preparations  more efficient mast cell degranulation?
“diamino PCNs such as amp and amox are able to form linear polymers of various lengths, with potentially an increase in multivalent antigenicity”—this property is not common to all PCNs; can even vary from lot to lot
-De Haan showed that IgE can distinguish between amp and amox, which we wouldn’t necessarily expect it to because of the position 6 substitution
-amp was used instead of amox

33. Take home points (don’t forget the salt)
PCN-1st, 2nd generation ceph: ≤10%
PCN-3rd, 4th generation ceph: <2%
Similar side chains: up to 40%
PCN-ceph
Ceph-ceph
Similar side chains:
Pcn, amp, amox, cephalexin
Ceftriax, cefurox, ceftaz, cefepime
Ceftaz, aztreonam
Many studies have evaluated pcn-ceph
JAMA
Romano:
-1st-2nd: 10%, 3rd: 2-3% (though trace amounts of BP in early batches may confound this); meta-analysis ( ) found OR 4.8 for all first gens, no increased risk with second or third gens
-(+)skin test with cephs ranging 0-15%
-delayed (T-cell): % with ceph (side chain rule “applies” for T cell too but still not perfect)
-in several studies, positive cross reactivity with ceph upon pcn skin test ranges from 0-31%
Depestel; antunez 2006
-purely based on chemical structure, not necessarily clinical data
-antunez 2006 J all clin imm  24 patients, 9 had 2+ ceph cross-reactivity
-review article: Romano 2016 Curr All Asthma resp
Take home: skin, PO and IV challenges show a LACK of allergic reaction with dissimilar side chains, though there is limited data within the PCN class
To do: get a specific med with the reaction, not just the class; use dis-similar agents; document when someone tolerates a beta-lactam
-limited data/polls suggest that prescribers are worried about legal liability, which we may not consider as critically
Cefazolin = no similarities

34. PCN-carbapenem
Immediate hypersensitivity (n=212): all (-) skin tests with imipenem/cilastatin, meropenem, ertapenem; 211 challenges all (-)
T-cell mediated (n=57-204): 0-5%
Cross reactivity: ~1% (imipenem, meropenem)
Similar with ceph-carbapenem (limited data)
Gaeta et al. (first one) J Allergy Clin Immunol 2015;135:972 [most patients 70% had anaphylaxis]; Romano (four studies assessed T cell)
5% was only found it one study and it was believed due to the methodology related to the skin patch testing method they used
Most studies done with imi

35. Assessment & management of allergies
Patient history: specific agent, nature of event/severity, timing, onset, course/resolution, current meds, previous ADRs and outcomes
Skin testing
Desensitization (90-95% success rate) or graded dose challenge
Depestel
-exception to desens/contraindication: SJS or TEN
Pen skin testing: J all clin immune pract 2017
-Wall AJHP 2004—pharmacy dept in Iowa is doing pcn skin testing; spend 1h to assess and test; decreased vanco and fq use
-national pcn allergy day is sept 28, the day that alexander fleming discovered pcn in 1928
AAAAI Statement before the Presidential Advisory Council on Combatting Antibiotic-Resistant Bacteria (PACCARB), May 3-4, 2017:
“One of the often overlooked factors contributing to antibiotic resistance is unverified penicillin allergy”
“AAAAI urges the new administration to recognized the growing threat of antimicrobial resistance by encouraging penicillin allergy testing among federal health agencies…”
Emerging role for pharmacists?
The American Academy of Allergy, Asthma & Immunology (AAAAI) advocates for the increased use of penicillin allergy testing to mitigate the emergence and spread of antibiotic resistance and to ensure the continued availability of effective therapeutics for the treatment of bacterial infections. As clinicians dedicated to the advancement of the knowledge and practice of allergy, asthma and immunology for optimal patient care, the AAAAI recommends patients who believe they have a penicillin allergy or who have documentation in their health record regarding a penicillin allergy should undergo skin prick testing to verify if they are truly allergic to penicillin, before an alternative non-penicillin antibiotic is prescribed. As many as nine of 10 patients who are tested actually do not have an allergy to penicillin. According to published research, without testing, an unverified history of penicillin allergy can contribute to longer hospitalizations, higher costs, greater risk for adverse effects of alternative (non beta lactam) antibiotics, and increased rates of serious antibiotic resistant infections such as C.difficile and methicillin-resistant Staphylococcus aureus (MRSA). Penicillin allergy testing is safe, effective, and can be performed even in critically ill patients and pregnant women. As part of the American Board of Internal Medicine Choosing Wisely® program, the AAAAI recommended in 2014 that physicians should not overuse non-beta-lactam antibiotics in patients with a history of penicillin allergy, without an appropriate evaluation.   The AAAAI has included in its Quality Clinical Data Registry a quality measure on appropriate removal or confirmation of indication of penicillin allergy from a patient’s medical record. A variation of this measure has been shared with a national work group developing quality measures designed to combat antimicrobial resistance. The AAAAI advocates that federal policies to address the growing threat of antimicrobial resistance should: • Establish a national strategy working through the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and other Federal agencies to encourage penicillin allergy testing to reduce the large number of patients mislabeled as allergic to penicillin; • Develop and adopt quality measures, Medicare Conditions of Participation (CoPs), and other federal health and safety standards that target a variety of settings to encourage correct identification of penicillin allergies; and • Implement the recommendations contained within the Report from the National Institute of Allergy and Infectious Diseases Workshop on Drug Allergy.   In addition, the AAAAI continues to promote the increased use of penicillin allergy testing in traditional and social media. The AAAAI Board of Directors identified penicillin allergy testing as an advocacy priority stating, “Without such testing, there is an unrealized opportunity to improve healthcare outcomes and reduce rising rates of antibiotic resistance.”

36. Patient case #3 75 yo M presents w/ malaise, fevers x 2 days
PMH: ESRD on HD, T2DM, chronic LE wound, CAD
Allergies: penicillin (unknown)
Empiric vancomycin & levofloxacin
Blood cultures  GPC clusters  MSSA
Antibiotics plan?

37. When assessing risk of beta-lactam cross-reactivity:
Class to class risk assessments appear to be sufficient (Eg, penicillin and cephalosporins)
Robust data are limited to within-class assessments (eg, penicillin to penicillin)
Agent-specific assessments appear to be best (eg, amoxicillin and ceftriaxone)
Data are insufficient to easily assess cross reactivity

38. Summary
Limited data suggest that azithromycin and levofloxacin have comparable CV risks
Study limitations; patient factors appear to be most important
Vancomycin & piperacillin/tazobactam carry an increased risk of AKI
Duration appears to be a prominent risk factor
When assessing penicillin and cephalosporin cross-reactivity, a specific agent approach seems best
Class approach appears outdated, though penicillin-carbapenem seems okay