Antibiotic and latex allergy

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Antibiotic and latex allergy

• Dr Alexandra Croom
• Consultant Allergist
• Glenfield Hospital, Leicester

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Epidemiology

• Adverse Drug Reactions
• 20 type B idiosyncratic
• Approx half of these immune mediated
• Most reactions cutaneous
• Urticaria
• Maculopapular rash
• EN, TEN, SJS
• 10 Europeans think they have drug allergy most
  commonly penicillin
• SPT suggests actual figure may be 5 (although up
  to 25 in some selected populations)

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Immune reactions to antibiotics based on Gell
and Coombes classification
Based on Gruchalla N Engl J Med 2006 on-line
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Immune reactions to antibiotics based on Gell
and Coombes classification
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History
Skin prick testing
Intradermal testing
Challenge/provocation
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History taking in antibiotic allergy

• History of event often lost in sands of time
• Important to consider
• Nature of symptoms and their timing
• Risk factors
• Drug-related route of administration, how many
  previous courses and rate of repetition
• Host-determined gender, co-morbidity, family
  history, atopy

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Antibiotic allergy in cystic fibrosis

• Incidence of ADRs to antibiotics increased
  4.5-25 in adults with CF
• Immediate reaction in 1.9 of antibiotic courses
• Dependent on which antibiotic being used
• piperacillin highest risk
• azithromycin no greater than placebo

Parmar Thorax 2005 Koch Rev Infect Dis 1991
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Why is incidence higher in cystic fibrosis?

• Antibiotics given intravenously
• Number of course of antibiotics received
• Danish study 121 patients received 2800 courses
• Haptenisation (formation of allergenic
  determinant) enhanced by presence of
  infection/inflammation
• Atopic children with CF more likely to be
  colonised by pseudomonas

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Looking for drug specific IgE skin prick testing
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Skin prick testing
Lancet through allergen test solution
Weal formation
Preformed allergen specific IgE
Itch
Release of histamine
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Skin prick testing

• For aeroallergens quick, cheap and safe
• Not so straightforward for antibiotics
• only well validated for penicillin
• risk of anaphylaxis during prick testing for
  penicillins
• 5/147 patients with penicillin allergy had
  systemic reaction following skin prick testing
• more likely if initial reaction was anaphylaxis
• stop ß blockers prior to testing and optimise
  asthma management
• perform in supervised clinical environment

Minh J Allergy Clin Immunol Feb 2006
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Intradermal testing

• Allergen solution introduced intradermally
• Dilute solutions required
• Increased sensitivity use when SPT negative
• Increased risk of systemic reactions
• Painful

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Allergens in antibiotic allergy

• Allergens arise 2 ways
• Drugs low molecular weight lt1000 Da - to become
  immunogenic need to covalently bind to HMW
  proteins (allergens present in parent drug)
• Novel allergens may be generated through
  metabolism prior to haptenisation (allergens not
  present in parent drug)

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Gruchalla J Allergy Clin Immunol 2001
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Skin testing for penicillin allergy

• Replaced Allergopen after withdrawal in 2006
• Contains
• BPO (major determinant)
• PPL (minor determinant mix)
• Used in conjunction with SPTs using solutions of
  amoxycillin and ampicillin

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Testing for penicillin allergy

• lt20 of those who report penicillin allergy have
  positive skin prick tests
• Negative testing indicates previous reaction not
  IgE mediated or drug specific antibodies lost
• Readminstration is safe if SPTS using major and
  minor determinants are negative rate of reaction
  is 4 (same as general population rate)

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Evolution of skin test sensitivity with time

• 5 year prospective study
• BPO/MDM positive
• 25/31 positive 12/12
• 18 positive at 36/12 (2 lost to follow up)
• 12 positive at 60/12 (1 lost to follow up)
• Amoxycillin positive
• 12/24 positive at 12/12
• 6 positive at 36/12 (1 lost to follow up)
• 0 positive at 60/12 (1 lost to follow up)

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Specific IgE assays for penicillin allergy

• Poor predictive value
• Do not contain minor determinants
• Negative result does not exclude allergy
• Positive result confirms allergy and prevents
  unnecessary skin prick testing

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Prescribing imipenem in patients with ß lactam
allergy

• First reports of cross reactivity (9/19) between
  imipenem and penicillins published 1988 (Saxon J
  Allergy Clin Immunol)
• Romano et al (NEJM 2006)
• 112 patients with history of immediate reactions
  to ß lactams and positive skin prick tests
• 1/112 skin prick test positive with imipenem
• 110/111 with negative skin prick tests underwent
  graded IM challenge with imipenem no reactions

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Tolerability of meropenem in patients with
penicillin allergy prospective study

• 104 participants, 14-83 y, history of immediate
  response to penicillins
• 104/104 positive skin test to at least one
  penicillin reagent
• 1/104 reacted to meropenem
• Initial reaction anaphylaxis after amoxycillin
  and clavulinic acid combination
• Reacted to all penicillin reagents on skin
  testing including imipenem

Romano et al Annals Internal Med 07
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Giving cephalosporins to patients with history of
penicillin allergy

• Increased risk of reactions to cephalosporins if
  penicillin allergic
• 6/135 patients with penicillin allergy
• 2/351 with no history of penicillin allergy
• Increase risk of fatal anaphylaxis if
  cephalosporins given where history of penicillin
  allergy
• 6/12 deaths due to antibiotics related to 1st
  dose cephalosporins 3/6 history of penicillin
  allergy

Kelkar N Engl J Med 2001, Pumphrey Lancet 1999
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Giving cephalosporins to patients with history of
penicillin allergy

• Controversial
• indiscriminate administration cannot be
  recommended especially for patients with life
  threatening reactions
• may be attractive if allergy to penicillin is
  mild, indication for use of that drug is strong,
  skin testing is impracticable, treatment for
  reactions is readily available

Gruchalla N Engl J Med 2006, Kelkar N Engl J Med
2001
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Allergy to non-beta lactam antibiotics

• Presumed IgE mediated reactions documented 1-3
  of prescribed courses
• No large scale validation of skin testing
• Allergenic determinants may be metabolites and
  thus absent from solutions of parent drug
• If low non-irritative concentrations used and
  positive response provoked may indicate IgE
  responsible
• Negative skin tests do not exclude the presence
  of drug specific IgE should drug be absolute
  requirement next step would be incremental
  administration to induce tolerance

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Non-Ige mediated reactions with antibiotics
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Maculopapular rash after penicillins

• 195 patients with cutaneous reactions after
  penicillins
• Evaluated with
• SPT intradermal testing
• patch testing
• oral challenge (if appropriate)
• 60/195 maculopapular rash
• 33/60 positive patch tests
• 18/30 agreed to rechallenge with culprit drug
  all reacted with rash developing 6-24 hrs after
  drug given

Romano Ann Allergy Asthma Immunol 1998
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Maculopapular rash after penicillins

• 30/33 reacted to ampicillin or amoxycillin 3/33
  reacted to Pen G
• No patients reacted to MDM or PPL
• Conclusion that reactions triggered by side chain
  binding and not beta lactam structure
• ? MHC restricted HLA A2 and DRW52
  over-represented

Romano Ann Allergy Asthma Immunol 1998
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Ampicillin
Amoxicillin
Penicillin G
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Red man syndrome and vancomycin

• Pruritus, erythema, flushing and hypotension
• 50-90 of patients treated experience some
  histamine release most mild
• Histamine release is non-specific and related to
  rate of infusion
• Antihistamines will alleviate symptoms
• Some cases of IgE mediated reactions (including
  anaphylaxis) to vancomycin are reported with
  positive SPTs (but false positives common with
  vancomycin concentrations gt 10µg/ml)

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Desensitisation in antibiotic allergy

• Possible with all antibiotics
• Risk only justified when drug in question is sole
  treatment option
• Mechanism not fully understood
• Tolerance achieved in hours

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Who to test?

• ALL?
• NONE?
• SOME?

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Who to test?

• ALL?
• Tests not good enough for that
• NONE?
• As is often the case
• SOME?
• Those with a current need for specific
  antibiotics
• Those with a predictable need for specific
  antibiotics in the future
• Confirmation of a recent serious reaction

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Antibiotic allergy summary

• Misconceptions about antibiotic allergy affect
  clinical practice
• Testing can inform rational prescribing
• Testing is safe (in specialist hands
  www.bsaci.org.uk for drug allergy clinics)
• When antibiotic allergy is present
  desensitisation is effective at producing
  tolerance and allowing treatment

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Latex allergy

• Obtained from tree - hevea brasiliensis
• Original reports of latex allergy from Germany in
  1930s
• First modern day reports of latex allergy early
  1980s

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Epidemiology of latex allergy

• Few studies of incidence none of incidence over
  time
• Prevalence studies predominantly in at risk
  groups
• Serological studies on blood donors 3.3-7.6 of
  population studied sensitisation rates higher in
  men

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Epidemiology of latex allergy risk factors

• Spina bifida (OR 6.73)
• Multiple surgery (OR 1.14 per op)
• Atopic predisposition (OR 3.37)
• Occupational exposure
• HCWs
• Rubber industry
• Electronic industry
• Hidden - textiles

Hochleitner J Urol 2001
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Latex allergy and HCWs
7 March 1994
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Latex allergy and HCWs

• Increased prevalence of HCWs sensitisation to
  latex attributed to glove use
• Sensitisation rates 8-17
• Sensitisation enhanced by
• Glove protein content
• Whether powdered or not
• Exposure duration

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Reducing allergy in HCWs

• In 1997 Germany passed legislation to make use of
  low-allergen, powder free NRL gloves mandatory
• Prior to that about 80 gloves were powdered
• Incidence of latex-related contact urticaria was
  monitored by statutory system of health insurance
  and reporting of suspected occupational disease

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Allmers et al J Allergy Clin Immunol 2004
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Latex allergens

• Levels of allergens may be affected by growing
  and manufacturing methods
• Majority of allergens are defence proteins
  production enhanced when tree under stress
• Risk group reflected in allergen profile

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Kurup et al Clinical Molecular Allergy 2005
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Kurup et al Clinical Molecular Allergy 2005
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Diagnosing latex allergy

• Standardised skin prick test solutions available
• Results correlate with spIgE assays
• Anaphylaxis reported with latex skin prick
  testing
• False negatives occur if a good history of
  acute type symptoms provocation test essential

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Desensitisation in latex allergy

• Subcutaneous immunotherapy (SCIT)
• Leynadier J Allergy Clin Immunol 2000
• Sastre J Allergy Clin Immunol 2003
• Tabar Int Arch Allergy Immunol 2006
• Sublingual immunotherapy (SLIT)
• Cistero Bahima J Invest Allergol Clin Immunol
  2004
• Bernadini Curr Med Res Opin 2006
• Nettis Br J Dermatol 2007

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Conclusions

• Latex allergy is a phenomenon of last 3 decades
• Much of it was/is preventable
• Improved understanding of latex allergens has
  enhanced diagnostics
• Effective treatment is currently available for
  those most at risk of re- exposure

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Conclusions

• Latex allergy is a phenomenon of last 3 decades
• Much of it was/is preventable
• Improved understanding of latex allergens has
  enhanced diagnostics
• Effective treatment is currently available for
  those most at risk of re- exposure - but not in
  the UK

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