Is it safe to use carbapenems in patients with a history of allergy to penicillin?

Manica Sodhi1, Sandra S. Axtell2,*, Joyce Callahan1 and Raja Shekar1

1 Infectious Diseases, Huron Hospital — Cleveland Clinic Health System, East Cleveland, OH; 2 Pharmacy, Hillcrest Hospital — Cleveland Clinic Health System, Mayfield Heights, OH, USA

Received 21 June 2004; returned 24 July 2004; revised 30 August 2004; accepted 11 September 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: The purpose of this retrospective study was to ascertain the clinical safety of administering carbapenems, namely imipenem/cilastatin and meropenem, in patients with a history of penicillin allergy compared with administering carbapenems in patients with no reported penicillin allergy. Carbapenems are similar in chemical structure to the penicillins and therefore are associated with a risk for allergic cross-hypersensitivity. Carbapenems are commonly avoided in patients with a reported penicillin allergy on the basis of a potential cross-hypersensitivity with penicillin, however, very few studies have been conducted describing the incidence of cross-hypersensitivity between penicillin and carbapenems.

Methods: A retrospective review was conducted in a total of 266 patients who were administered either imipenem/cilastatin or meropenem. The patients were admitted to the Cleveland Clinic Health System—Eastern Region Hospitals during the years 2001 and 2002.

Results: Fifteen of the 163 patients (9.2%) with reported penicillin allergy developed a hypersensitivity reaction to meropenem or imipenem/cilastatin whereas 3.9% of the 103 patients without penicillin allergy developed a hypersensitivity reaction to meropenem or imipenem/cilastatin. These results are not statistically significant.

Conclusions: Based on this study and other similar studies, the true incidence of cross-hypersensitivity reactions between penicillin and carbapenems may be lower than previously reported. Carbapenem use may be reasonable for penicillin allergic patients if caution is exercised.

Keywords: imipenem/cilastatin , meropenem , hypersensitivity


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Carbapenems are similar in chemical structure to penicillins and therefore are associated with a risk for allergic cross-hypersensitivity. The package inserts for both Merrem (meropenem) and Primaxin (imipenem/cilastatin) list a warning stating that "serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity that have experienced severe hypersensitivity reactions when treated with another beta-lactam. Before initiating therapy careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens."1,2 Selection of antibiotic therapy can therefore be severely limited by the medication allergies reported by the patient. Penicillin is commonly cited as a drug allergy. Patients mistakenly report reactions such as experiencing gastrointestinal upset as an allergy.36 Patients may report intolerance to penicillin from several decades ago when penicillin formulations were less pure and had more of an allergenic potential.6 Also, patients may mistakenly report symptoms of the illness they were being treated for as an allergy such as fever and yellow spots on the tonsils or a rash due to a viral infection.5,6 Allergies may also fade over time. An adult whose reaction may have occurred many years ago may no longer be allergic, although in many cases the patient's self-reported history may be unreliable.6 An accurate drug allergy history is one method to limit unnecessary avoidance of certain antibiotics including carbapenems especially when they are necessary to treat serious, life-threatening infections.

Carbapenems are commonly avoided in patients with a reported penicillin allergy on the basis of a potential cross-hypersensitivity with penicillin, however, very few studies have been conducted describing the incidence of cross-reactivity between penicillin and carbapenems. One study reported the incidence of cross-reactivity between penicillin and carbapenems as being 47%.7 The cross-reactivity was determined by the reactivity to both penicillin and imipenem/cilastin skin tests. The clinical relevance of this cross-reactivity, however, is not known. A retrospective review in neutropenic bone marrow transplant patients with reported penicillin allergy that received imipenem/cilastatin demonstrated an overall incidence of imipenem/cilastatin allergy in 9.5% of these patients. The authors concluded that the incidence of cross-hypersensitivity between penicillin and imipenem/cilastatin might be lower than previously reported.8 A recent retrospective review determined an incidence of carbapenem allergy in 11% of the penicillin allergic patients.9 Reported incidence of carbapenem-associated hypersensitivity in the general population is estimated to be 1–3%.1,2

The objective of this retrospective study was to ascertain the clinical safety of administering carbapenems, namely imipenem/cilastatin and meropenem, in patients with a history of penicillin allergy compared with administering carbapenems in patients with no reported penicillin allergy to help clinicians make better informed decisions regarding the choice of antibiotics for patients with a history of penicillin allergy.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A retrospective chart review was conducted in a total of 266 patients who were administered either imipenem/cilastatin or meropenem. The patients were admitted to the Cleveland Clinic Health System—Eastern Region Hospitals during the years 2001 and 2002. The review consisted of 163 patients with reported penicillin allergy as well as 103 patients without reported penicillin allergy. The details of penicillin allergy were collected. Allergy to imipenem/cilastatin and meropenem was based on the appearance of a hypersensitivity reaction, which resolved upon discontinuation of the carbapenem. A hypersensitivity reaction was defined as developing a rash, hives, fever, angio-oedema, bronchospasm or pruritis that led to the discontinuation of the carbapenem. Other antibiotic allergies were noted and also the number of days the carbapenem was administered before the development of the reaction.

Charts of 163 patients with no reported penicillin allergy who received either imipenem/cilastatin or meropenem were identified to serve as controls. Sixty of the patients identified without penicillin allergies were not included due to the unavailability of the charts or not meeting inclusion criteria. These patients were matched in time (admission to the hospital ± 3 days of the case patient) and age (± 5 years of the case patient) to patients with reported penicillin allergy. Patients needed to receive at least 1 day of treatment with a carbapenem to be included.

Analysis of the data was accomplished using the Student's t-test to compare mean ages and the z statistic to compare proportions. Results were deemed statistically significant if P < 0.05 and ß=0.2. Statistical analysis was completed using Primer of Biostatistics.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fifteen of the 163 patients (9.2%) with reported penicillin allergies developed a hypersensitivity reaction to a meropenem or imipenem/cilastatin whereas 3.9% of the 103 patients without penicillin allergy developed a hypersensitivity reaction to meropenem or imipenem/cilastatin. The z score was 1.390 and P=0.164, thus there was no statistically significant difference between the two groups. Results are listed in Table 1.


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Table 1. Comparisons of patients with reported penicillin allergy and without penicillin allergy

 
Among the 15 penicillin allergic patients that developed a hypersensitivity reaction, 11 manifested a maculopapular rash as the reaction to the carbapenem. Only one of the patients developed facial oedema and lip swelling in addition to the maculopapular rash. One patient developed pruritis and another patient developed drug fever in addition to a rash. The drug fever was viewed as an adverse drug reaction rather than an allergic reaction. Among the patients with no reported penicillin allergy, three developed a maculopapular rash and one developed a drug fever in addition to a rash. Development of a hypersensitivity reaction invariably led to the discontinuation of the carbapenem. The reactions resolved upon discontinuation of the carbapenem. Reactions occurred on an average of 3.6 days into treatment for the penicillin allergic patients and 5.5 days for patients without penicillin allergies.

Patients with multiple drug allergies including penicillin are inherently more apt to have an allergic reaction to the carbapenem. This tendency was most notable in patients with both penicillin and cephalosporin allergies. Fifty-seven percent (4/7) of the patients with both allergies also had an allergic reaction to the carbapenem. Statistical significance could not be determined.

The nature of the previous penicillin allergy was reviewed to compare differences or similarities with the carbapenem hypersensitivity reaction. Seven (12.3%) out of 57 patients who reported rash as a reaction to penicillin also developed a reaction to the carbapenem. Five of these patients developed a rash as a reaction to the carbapenem, whereas one of them developed facial oedema and lip swelling. Interestingly, only one out of the 10 patients who reported anaphylaxis with penicillin administration developed a reaction to the carbapenem. This patient developed a maculopapular rash as a reaction to the carbapenem.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients with a history of penicillin allergy had a 9.2% incidence of a carbapenem allergic reaction compared with 3.9% of the patients with no penicillin allergy. These results are not statistically significant. Only one of the patients with a history of anaphylaxis to penicillin had an allergic reaction to the carbapenem and this patient developed a maculopapular rash. These results are similar to two previously published retrospective reviews that demonstrated an overall incidence of imipenem/cilastatin allergy between 9.5% and 11%.8,9 The true incidence of cross-hypersensitivity between penicillin and the carbapenems may therefore be lower than what is reported in the product package inserts which list 47%.1,2,7

Carbapenem use seems reasonable in penicillin allergic patients if there is a valid indication for the antibiotic. A possible trend towards a higher incidence rate of a carbapenem reaction was observed in penicillin allergic patients with multiple antibiotic allergies most notably to cephalosporins. It may be prudent to use caution when prescribing carbapenems in patients with multiple antibiotic allergies. Fifty-four percent of our penicillin allergic patients had unknown types of reactions due to incomplete histories documented in the chart. There was a potential that some of the reported penicillin allergic patients actually were not truly allergic. This reflects actual clinical practice where listed allergies are usually treated as fact regardless of their actual nature.

Retrospective studies inherently have their limitations due to the dependence on the quality of documentation in the medical records. Penicillin allergy histories and descriptions of hypersensitivity reactions relied on the details documented in the medical record. A prospective study would allow for more accurate and complete assessment of the allergy history and allergic reaction description. In this retrospective review, typically only one antibiotic was discontinued when a reaction was noted which increased the likelihood of correctly identifying the causative agent.

Conclusions

Very limited data are available concerning the incidence of cross-hypersensitivity of carbapenems in patients with penicillin allergies. A prescriber may commonly avoid prescribing a carbapenem and then may be unnecessarily left with very few alternatives. Selecting antibiotics in severely ill patients with a history of penicillin allergy can be a very difficult task. Based on this and other similar studies,8,9 the true incidence of cross-hypersensitivity between penicillin and the carbapenems may be lower than that previously reported and less concerning than previously thought. Carbapenem use may be reasonable for patients with penicillin allergies if caution is exercised.


    Footnotes
 
* Corresponding author. Tel: +1-440-312-4396; Fax: +1-440-312-7104; Email: saxtell{at}cchseast.org


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Primaxin package insert. (2001). Merck & Co., Inc., Whitehouse Station, NJ, USA.

2 . Merrem package insert. (2002). AstraZeneca Pharmaceuticals, Wilmington, DE, USA.

3 . Salkind, A. R., Cuddy, P. G. & Foxworth, J. W. (2001). Is this patient allergic to penicillin? Journal of the American Medical Association 285, 2498–505.[Abstract/Free Full Text]

4 . Kerr, J. R. (1994). Penicillin allergy: a study of the incidence as reported by patients. British Journal of Clinical Practice 48, 5–7.[ISI][Medline]

5 . Oswald, N. T. A. (1983). Penicillin allergy: a suspect label. British Medical Journal 287, 265–6.[ISI][Medline]

6 . Surtees, S. J., Stockton, M. G. & Gietzen, T. W. (1991). Allergy to penicillin: fable or fact. British Medical Journal 302, 1051–2.[ISI][Medline]

7 . Saxon, A., Adelman, D. C., Patel, A. et al. (1988). Imipenem cross-reactivity with penicillin in humans. Journal of Allergy and Clinical Immunology 82, 213–7.[ISI][Medline]

8 . McConnell, S. A., Penzak, S. R., Warmack, T. S. et al. (2000). Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with history of penicillin allergy. Clinical Infectious Diseases 31, 1512–4.[CrossRef][ISI][Medline]

9 . Prescott, W. A., DePestel, D. D., Ellis, J. J. et al. (2004). Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clinical Infectious Diseases 38, 1102–7.[CrossRef][ISI][Medline]





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