Q:

12/5/2013
I am evaluating a patient who potentially had a systemic reaction to either Flagyl or Cipro; both antibiotics were administered simultaneously during an outpatient surgical procedure. While the history of reported symptoms does not sound entirely allergic to me, the infectious disease doctor and internist would like to have skin testing to both of the antibiotics. Can you suggest a protocol for skin testing to each of these antibiotics?

A:

Thank you for your inquiry.

Unfortunately, there are very little published data to my knowledge regarding either drug, and all the data on Cipro indicate that one cannot use it for skin testing because it causes reactions in low doses in normal individuals, presumably because it releases histamine directly from cutaneous mast cells. Therefore, one cannot employ cutaneous testing to ciprofloxacin (1-5).

The situation is perhaps a little better in regards to skin test protocols for Flagyl. However, it is still controversial as to whether or not skin tests to Flagyl give valid results because there are very few articles in the literature that describe patients with immediate hypersensitivity reactions to this drug. And it is not mentioned in the two classic articles that discuss skin test concentration to antibiotics (5, 6).

Below I have copied for you the references (including one for which I was able to obtain the abstract) of articles that have or may have a protocol for skin testing to metronidazole. Unfortunately, the one for which I was able to obtain the abstract (Garcia-Rubio, et al.), analogous to the situation for Cipro, found that skin testing for metronidazole was not a highly reliable method to determine the presence of allergic sensitivity. However, there is at least one other of these articles which evidently found skin testing useful (Asensio Sanchez, et al.). Unfortunately, I do not have direct access to this journal and therefore cannot give you the concentrations/protocol used. However, I am sure your local medical library can order the article for you.

In summary, therefore, skin testing to Cipro, according to the studies that I have been able to find, appears to be unreliable. There is a question as to the reliability of skin testing to Flagyl and very few cases have been reported. However, there are published protocols (see references and abstracts copied below) that you could obtain through your medical library.

Thank you again for your inquiry and we hope this response is helpful to you.

J Allergy Clin Immunol. 1991 Aug;88(2):279-80.
Metronidazole hypersensitivity and oral desensitization.
Kurohara ML, Kwong FK, Lebherz TB, Klaustermeyer WB.

Allergol Immunopathol (Madr). 2006 Mar-Apr;34(2):70-2.
Hypersensitivity reactions to metronidazole.
García-Rubio I, Martínez-Cócera C, Santos Magadán S, Rodríguez-Jiménez B, Vázquez-Cortés S.
Allergy Department, Hospital Clínico San Carlos, Madrid Spain.
Abstract
Background: Hypersensitivity reactions to metronidazole are infrequently described. However, we believe that such reactions are increasing due to growing use of the drug for the treatment of amebiasis and anaerobe infections combined with other antibiotics. The present study assesses the need for oral provocation in patients with probable hypersensitivity reactions to metronidazole.
Methods: We performed cutaneous prick tests with spiramycin and metronidazole as well as epicutaneous tests with metronidazole at different concentrations in four patients with cutaneous reactions to Rhodogil (metronidazole plus spiramicyn). Controlled oral challenges were then carried out with placebo using erythromycin, spiramycin and metronidazole except in the last patient due to a positive prick test.
Results: Only one patient showed a positive metronidazole prick test. The epicutaneous tests were negative. All patients tolerated erythromycin and spiramycin up to therapeutic doses. Oral provocation with metronidazole proved positive, the first patient presenting a delayed exanthema and the other two early erythema and itching.
Conclusions: We present four cases of cutaneous exanthemas caused by metronidazole (two early and two delayed) and probably mediated by an immune mechanism which we have only been able to demonstrate in one case. Taking into account the low sensitivity of the cutaneous tests (prick tests and epicutaneous tests), oral provocation must be considered the "gold standard" for establishing the diagnosis in many cases of hypersensitivity reactions to metronidazole.

Ann Pharmacother. 2012 May;46(5):763-4. doi: 10.1345/aph.1Q478. Epub 2012 May 8.
Immediate hypersensitivity reaction induced by metronidazole.
Seto K, Knowles SR, Weber EA.
J Investig Allergol Clin Immunol. 2008;18(2):138-9.
Anaphylaxis due to metronidazole with positive skin prick test.
Asensio Sánchez T, Dávila I, Moreno E, Laffond E, Macías E, Ruiz A, Lorente F.

Allergol Immunopathol (Madr). 2006 Mar-Apr;34(2):70-2.
Hypersensitivity reactions to metronidazole.
García-Rubio I, Martínez-Cócera C, Santos Magadán S, Rodríguez-Jiménez B, Vázquez-Cortés S.
Source
Allergy Department, Hospital Clínico San Carlos, Madrid Spain. Abstract
Background: Hypersensitivity reactions to metronidazole are infrequently described. However, we believe that such reactions are increasing due to growing use of the drug for the treatment of amebiasis and anaerobe infections combined with other antibiotics. The present study assesses the need for oral provocation in patients with probable hypersensitivity reactions to metronidazole.
Methods: We performed cutaneous prick tests with spiramycin and metronidazole as well as epicutaneous tests with metronidazole at different concentrations in four patients with cutaneous reactions to Rhodogil (metronidazole plus spiramicyn). Controlled oral challenges were then carried out with placebo using erythromycin, spiramycin and metronidazole except in the last patient due to a positive prick test.
Results: Only one patient showed a positive metronidazole prick test. The epicutaneous tests were negative. All patients tolerated erythromycin and spiramycin up to therapeutic doses. Oral provocation with metronidazole proved positive, the first patient presenting a delayed exanthema and the other two early erythema and itching.
Conclusions: We present four cases of cutaneous exanthemas caused by metronidazole (two early and two delayed) and probably mediated by an immune mechanism which we have only been able to demonstrate in one case. Taking into account the low sensitivity of the cutaneous tests (prick tests and epicutaneous tests), oral provocation must be considered the "gold standard" for establishing the diagnosis in many cases of hypersensitivity reactions to metronidazole.

References:
1) Colas C, Pola J, Zapata C, et al. Quinolones hypersensitivity: clinical and immunological aspects [Abstract]. J Allergy Clin Immunol 1993; 91:365.

2) Davila I, Diez ML, Quirce S, et al. Cross-reactivity between quinolones – report of three cases. Allergy 1993; 48:388–390.

3) Vieluf D, Russwurm R, Przybilla B, Ring J. Anaphylactoid reactions to quinolones
[Abstract]. J Allergy Clin Immunol 1991; 87:228.

4) Campi, Paolo; Pichler, Werner J. Quinolone hypersensitivity. Current Opinion in Allergy & Clinical Immunology. 3(4):275-281, August 2003.

5) Empedrad et al: Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics. Journal of Allergy and Clinical Immunology Vol. 112, Issue 3, Pages 629-630, 2003.

6) Brockow. Skin test concentrations for systemically administered drugs - EMDA/EAACI Drug Allergy Interest Group Position Paper. Allergy 2013; 68:702-712.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology