Are there protocols for skin testing to cipro, metronidazole and macrodantin?


Thank you for your inquiry.

Unfortunately there are no studies of which I am aware of large numbers of patients that have been designed to develop a skin test protocol to these antibiotics. However, there are a number of case reports in which the authors have published protocols used to test for immediate hypersensitivity to all three agents. I have copied these references for you below.

The “Ask the Expert” website has previously dealt with skin testing protocols to both nitrofurantoin and ciprofloxacin. I have copied in its entirety our response to the question regarding nitrofurantoin that was posted on 7/17/2012. The “Ask the Expert” response to ciprofloxacin was accompanied by skin testing to three other drugs and a little too lengthy to copy here, but I have noted the site for you. The date the response was posted was 2/29/2012. I have also copied below the concentration of the drug to be used in skin testing as posted on this entry.

Finally, you will see below references to skin testing protocols used to test to metronidazole. In addition, I have copied below a link to an article which you can obtain at no charge regarding testing to metronidazole.

As you can see, there may be more than one concentration used to test for each one of these drugs. Unfortunately, as noted, these concentrations have not been tested in large numbers of patients, and therefore which concentration to employ remains up to your clinical judgment. Nonetheless, you will obtain through these references, and reviewing the previous “Ask the Expert” entries, concentrations which have been previously published.

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

Tests to nitrofurantoin
Ask the Expert - 7/17/2012
Is there a protocol to allergy test to Nitrofurantoin (Macrobid)?

Thank you for your inquiry.

There have been isolated, but not well standardized, attempts to skin test to nitrofurantoin. The first of these that I could find with a search of the literature was a German article. The reference is copied for you below.

There was another case report of an attempt to skin test to nitrofurantoin. This attempt was unsuccessful because the author could not get the capsule contents to dissolve in saline. I have copied the link to this brief report below as well.

Finally, there is an article in the British Journal of Dermatology which looked at various in vivo methods to test for patients with suspected drug allergies to multiple agents. Nitrofurantoin was included amongst these drugs, and prick tests were done with what appears to be a 1:1 dilution with saline. Then it appears also that some intradermal tests were done with further tenfold dilutions of this drug. However, as noted, these references report only small numbers of patients, and the protocols employed have not been well standardized.

Should you wish to proceed with skin testing, the most helpful of these three references would be the one appearing in the British Journal of Dermatology.

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

Dtsch Med Wochenschr. 1972 Feb 18;97(7):256-7.
[Anaphylactic shock following oral administration of nitrofurantoin and demonstration of reagins using the heterologous intracutaneous test (Prausnitz-Küstner)]. [Article in German]
Tykal P, Wilms H.
Nitrofurantoin Allergy
Gary Stadtmauer, MD, Allergy & Clinical Medscape.
The usefulness of skin tests to prove drug hypersensitivity
K. Lammintausta. British Journal of Dermatology, Volume 152, Issue 5, pages 968–974, May 2005.

Allergy. 2012 May;67(5):647-52. doi: 10.1111/j.1398-9995.2012.02807.x. Epub 2012 Mar 22.
Nonirritant intradermal skin test concentrations of ciprofloxacin, clarithromycin, and rifampicin.
Brož P, Harr T, Hecking C, Grize L, Scherer K, Jaeger KA, Bircher AJ.
Department of Angiology, University Hospital, Basel, Switzerland.
Background: Intradermal skin testing of the clinically important antibiotics ciprofloxacin, clarithromycin, and rifampicin in the case of suspected allergies to antibiotics is poorly standardized. For clinical practice, standardized procedures and protocols are desired.
Methods: Fifteen healthy volunteers were tested with different concentrations of the antibiotics as well as with appropriate controls. Test readings included wheal area measured by digital image analysis and blood flow increase measured by laser Doppler flowmetry (LDF). To reduce interpersonal variability, test results were normalized with the individual controls using a novel protocol.
Results: Nonirritating concentrations of the three antibiotics (ciprofloxacin ~0.0067 mg/ml, clarithromycin ~0.05 mg/ml, rifampicin ~0.002 mg/ml) could be defined for healthy volunteers. Laser Doppler flowmetry generates comparable results to wheal area measurement. Normalization of the test results is necessary and can be applied in a practical algorithm.
Conclusions: Standardized skin testing to detect sensitization to broadly used nonbetalactam antibiotics was presented and should be applied in truly sensitized patients. This approach should help to minimize the inter- and intraindividual differences in reactivity.

Ask the Expert 2/29/2012
Anaphylactic reaction occurring during the administration of three antibiotics: ciprofloxacin, Zosyn, and vancomycin

Ciprofloxacin prick test at 0.02 mg/ml, intradermal test at 0.02 mg/ml

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.
Allergy Department, Hospital Clínico San Carlos, Madrid Spain.
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.

Immediate Hypersensitivity Reaction Induced by Metronidazole

Phil Lieberman, M.D.

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