Penicillin and other beta-lactams


b-lactams: bactericidal antibiotics that act on bacteria during their growth phase by inhibiting the formation of specific peptide bonds on the bacterial wall.
 
Penicillins: natural or semi-synthetic antibiotics with a core structure consisting of a b-lactam fused to a thiazolidine (6 amino penicillanic acid) differing simply in regard to their lateral fixed chain on the 6 amino function.
 
Cephalosporins: antibiotics with a core structure consisting of a b-lactam fused to a 1.3-thiazine ring system.
 
Some anaphylactic reactions to cephalosporins are due to antibodies directed against specific side chains in these molecules rather than the b-lactam ring.
 
Incidence
Penicillins: 1/1 000 administrations, i.e. 0.7 to 10% of treatments. Responsible for 75% of anaphylactic deaths in the USA.
 
Urticaria: 4.5% of treatments. Systemic reactions: 2% of treatments. Anaphylactic shock: 0.2% of treatments. Mortality: 0.02% of treatments.
 
Cephalosporins: 1.1 to 3% cutaneous reactions.
 
Risk factors
Atopy not implicated.
 
Sensitivity to moulds not implicated.
 
Intravenous administration.
 
Mean age, 20 to 49 years.
 
Prior history of penicillin reaction (risk x 6).
 
Clinical manifestations
Immediate (< 1 h): anaphylactic shock, urticaria, angioedema, laryngospasm, bronchospasm (especially with benzylpenicillin).
 
Accelerated (1 to 72 h): mainly urticaria.
  • cutaneous: maculopapular rash, pruritis, erythema multiforme, bullous erythema, erythrodermia (especially with amino penicillin)
     
  • serum sickness
     
  • hematological: hemolytic anemia, neutropenia, thrombocytopenia
     
  • renal: acute interstitial nephropathy.

Late (> 72 h): maculopapular rash, contact dermatitis

Diagnostic methods
Cutaneous testing
 

Scratch, prick or intradermal skin tests with:

  • Polylysine penicilloyl (main component): P. P. L. 6 10-5 M.
  • Variable amounts of minor components (M. D. M.): benzylpenicillin, benzylpenicilloic acid, benzylpenilloate, benzylpenicilloylamine or benzylpenicilloate salt (now standardized on lyophilized form).

Begin with the polylysine penicilloyl prick-test. If negative do the intradermal test with polylysine penicilloyl. If negative do the prick test with minor component mixture, and if this is negative do the intradermal test with minor component mixture.
 
Results: wheal:
  • 0—3 mm: negative test
  • 3—5 mm: undetermined test
  • 5—10 mm: positive test
  • > 10 mm: strongly positive test

In case of anaphylactic shock, begin the test with M. D. M. at diluted concentrations (1/100 and 1/10).

The reported incidence of positive skin-tests for detection of IgE sensitization in patients with suspected previous history of allergy to penicillin is less than 20%.
 
Risk of anaphylactic reactions to penicillin is < 3% if skin tests for major and minor determinants are negative.
 
For drugs other than penicillin G, conduct empirical skin tests using 0.25 mg/ ml; 2.5 mg/ ml; 25 mg/ ml for prick tests, and if negative 2.5 mg/ ml and 25 mg/ ml for intradermal injection.
 
N.B.: A patch test may be positive in patients with contact dermatitis to aminopenicillin.
 
Specific IgE: RAST and ELISA for the major determinant of the most common penicillins are available. However, there are no tests for IgE antibodies to minor determinants.
 
Mechanisms
The metabolites of benzyl penicillin are haptens and can lead to the formation of antibodies by conjugating with a carrier to form a complete antigen (serum or tissue protein).
 
Reactions to penicillin may be caused by consuming milk or meat from cows treated with penicillin. Pregnant or nursing mothers treated with penicillin may induce reactions in fetuses or babies. Also occupational exposure, skin tests (theoretical).
 
Immediate IgE hypersensitivity
 
Detection of IgE antibodies against major components (especially in accelerate reactions).
 
Detection of IgE antibodies against minor components (especially in immediate reactions).
 
Detection of IgE antibodies against side chains in some patients allergic to cephalosporins.
 
IgE-mediated reactions are responsible for anaphylactic shock, angioedema as well as some forms of urticaria.
 
Cytotoxic mechanisms
Detection of IgG antibodies against erythrocytes and neutrophils.
This mechanism is responsible for hemolytic anemia and leukoneutropenia.
 
Hypersensitivity due to immune complexes
 
Implicated in serum sickness as well as in some forms of urticaria and maculopapular rash.
 
 
Delayed cell-mediated hypersensitivity
 
Responsible for contact dermatitis and some form of maculopapular rash.
 
Two particular problems:
  • Ampicillin rash (5 to 8% of patients treated). Non- immunological mechanism: the amine function of aminopenicillins causes changes in leukocyte function (especially lymphocytes), particularly if there is a concurrent disease (viral infection, chronic lymphoid leukemia).
     
  • Cross sensitivity between penicillin and cephalosporins: 8 to 10% risk of allergy to cephalosporins in patients allergic to penicillin.
Management
Patients with a positive history of penicillin allergy and negative skin-tests for major and minor determinants have a risk of < 3%.
 
Patients with a positive history and a positive skin-test response to penicillin have a 50% or greater risk of repeat reaction after administration of penicillin.
 
Patients with a positive history of penicillin allergy but with negative skin-tests to major and minor determinants may receive a cephalosporin at no greater risk than the general population.
 
Patients with a positive history of penicillin allergy and positive skin-tests to penicillin determinants have a 5-10% risk of clinical reactions to cephalosporins. An alternative antibiotic class should be proposed or provocation-desensitization with the cephalosporin if needed.
 
The negative predictive value of skin-tests with cephalosporins is unknown.
 
Example of penicillin desensitization:
0 min:100 U orally (penicillin V)
15 min:200 U orally
30 min:400 U orally
45 min:800 U orally
1 h:1 600 U orally
1 h 15:3 200 U orally
1 h 30:6 400 U orally
1 h 45:12 800 U orally
2 h:25 000 U orally
2 h 15:50 000 U orally
2 h 30:100 000 U orally
2 h 45:200 000 U orally
3 h:400 000 U orally
3 h 15:200 000 U subcutaneous (penicillin G)
3 h 30:400 000 U subcutaneous
3 h 45:800 000 U subcutaneous
4 h:1 000 000 U intramuscular

References

  1. Nicklas R.A, "Bêta-lactam antibiotics", J. Allergy. Clin. Immunol., 1998 ; 101: S498-501
  2. Birnbaum J, Vervloet D, "Allergie aux penicillines", Rev. fr. Allergol., 1997 ; 37: 29-35
  3. Bernstein I.L, Storms W.W, "Practice parameters for allergy diagnostic testing", Ann. Allergy. Asthma. Immunol, 1995 ; 75 (6.2): 543-625
  4. Adkinson N.F Jr, "Tests for immunological drug reactions", In: Rose NR, de Marco EC ed. Manual of clinical laboratory immunology. 4th ed. Washington: American society of microbiology, 1992: 717-22
  5. Blanca M, Vega J.M, Garcia J, Carmona M.J, Terado S, Avila M.J, Miranda A, Juarez C, "Allergy to penicillin with good tolerance to other penicillins. Study of the incidence in patients allergic to betalactams", Clin. Exp. Allergy, 1990 ; 20: 475-81
  6. Redelmeier D.A, Sox H.C Jr, "The role of skin testing for penicillin allergy", Arch. Intern. Med., 1990 ; 150: 1939-45.
  7. Saxon J, "Immediate hypersensitivity reactions to b-lactam antibiotics", Ann. Int. Med., 1987 ;107: 204-15.
  8. Stark B.J, Earl H.S, Gross G.N, Lumry W.R, Goodman E.L, Sullivan T.J, "Acute and chronic desensitization of penicillin allergic patients using oral penicillin", J. Allergy Clin. Immunol., 1987 ; 79 (3): 523-32.

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.