What is the allergy cross-reactivity risk between meropenem and ampicillin?

In patients with true allergy to penicillin, what is the chance of cross-reactivity with meropenem?

Comment by InpharmD Researcher

While data specific to cross-reactivity between meropenem and ampicillin is lacking, existing guidelines suggest that carbapenems can be administered to patients with a history of penicillin or cephalosporin allergy without the need for additional testing, even in cases of prior anaphylactic reactions. The overall incidence of carbapenem allergy is low, with clinical cross-reactivity rates between carbapenems and penicillins generally reported to be less than 1%. This suggests that meropenem may be safely used in patients with reported penicillin allergies, though a graded drug challenge may be considered for patients with significant anxiety or those with multiple drug allergies.

Background

The American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) developed the 2022 practice parameter update on drug allergies, which addresses the topic of beta-lactam cross-reactivity. It was highlighted that guidance on administering carbapenems to patients with penicillin allergy has changed since the previous drug allergy practice parameter update. Though not specific to ampicillin, the panel suggests that in patients with a history of penicillin or cephalosporin allergy, carbapenems may be administered without testing or additional precautions, even in cases where the previous reaction was anaphylactic (conditional recommendation, moderate certainty of evidence). [1]

The reported incidence of carbapenem allergy ranges from 0.3% to 3.7%. Clinical cross-reactivity between carbapenems and other beta-lactams is low, with multiple review articles reporting a cross-sensitivity risk of less than 1% between penicillins and carbapenems in patients with a positive penicillin skin test. A systematic review of 10 studies and 12 case reports, which included 838 patients with suspected or confirmed IgE-mediated penicillin allergy, found carbapenem reactions in 4.3% of cases (95% confidence interval [CI] 3.1% to 5.9%). Among those with positive skin test for penicillin (n= 295), only 1 had an IgE-mediated reaction (0.3%; 95% CI 0.06% to 1.9%). Another meta-analysis of 11 studies (n= 1,127) reported a cross-reactivity rate of 0.3% (95% CI 0.08% to 1.19%) to meropenem in penicillin-allergic patients. A prospective study involving 212 patients with confirmed penicillin allergy also showed all subjects tolerated carbapenems (Table 2). It was suggested that in most cases, carbapenems can be administered to patients with penicillin or cephalosporin allergy, except in those with severe delayed cutaneous or organ-involved reactions. For select patients, such as those with multiple drug allergies or significant patient anxiety, a graded drug challenge may be preferred. [1], [2], [3], [4], [5]

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

In patients with true allergy to penicillin, what is the chance of cross-reactivity with meropenem?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-6 for your response.

Safety of Meropenem in Patients Reporting Penicillin Allergy: Lack of Allergic Cross Reactions
Design	Prospective, observational study N= 110
Objective	To assess the safety of meropenem in patients with reported penicillin allergies, including those with anaphylactic reactions, without penicillin skin testing
Study Groups	Anaphylactic group (n= 51) Non-analphylactic group (n= 59)
Inclusion	Patients with serious systemic infections and a history of penicillin allergic reactions
Exclusion	Patients who received meropenem for less than a week; patients who received meropenem in combination with another antibiotic (except for those with Clostridium difficile colitis treated with metronidazole/vancomycin)
Methods	Patients treated with meropenem were included into anaphylactic or non-anaphylactic group depending on if they reported definitive anaphylactic reactions including: hives, laryngospasm, angioedema, and bronchospasm/hypotension/shock. Patients were treated with meropenem (1 g intravenously [IV] Q8H and adjusted for renal function) for 1-4 weeks and monitored daily for allergic reactions by infectious disease physicians. No penicillin skin testing was performed.
Duration	Follow-up: 12-months after meropenem treatment
Outcome Measures	Primary: incidence of allergic reactions to meropenem Secondary: tolerance of prolonged meropenem therapy
Baseline Characteristics	In both groups, there were comparable gender and age distributions, type and severity of infections, meropenem doses and durations. Meropenem doses ranged between 2 g IV Q8H to 500 mg IV Q24H.
Results	Endpoint	Anaphylactic group (n= 51)	Non-anaphylactic group (n= 59)
	Allergic reactions	0	0
Study Author Conclusions	In this study of 6,000 courses of meropenem therapy, there was not a single anaphylactic reaction in patients with known/unknown allergic reactions to penicillin, including anaphylactic reactions. These data and our previous clinical experience indicate that meropenem can be used safely in patients reporting a history of penicillin allergy, particularly those with anaphylactic reactions, and without penicillin skin testing.
InpharmD Researcher Critique	Determination of allergy status was based on patient self-reporting of allergic reaction. Therefore, the number of true penicillin allergy in the patient population is unknown. No statistical analysis was performed to determine the population needed to detect meaningful cross-reactivity. Therefore, the conclusion is that 51 patients with self-reported IgE-mediated allergy to penicillin did not experience an allergic reaction to a standard dose of meropenem.

References:

Cunha BA, Hamid NS, Krol V, Eisenstein L. Safety of meropenem in patients reporting penicillin allergy: lack of allergic cross reactions. J Chemother. 2008;20(2):233-237. doi:10.1179/joc.2008.20.2.233

Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins
Design	Prospective study N= 212
Objective	To assess the cross-reactivity and tolerability of aztreonam and 3 carbapenems (imipenem-cilastatin, meropenem, and ertapenem) in patients with documented IgE-mediated hypersensitivity to penicillins
Study Groups	All study subjects (N= 212)
Inclusion criteria	Age >15, history of immediate IgE-mediated reaction to penicillins, positive skin test result to at least 1 penicillin reagent
Exclusion criteria	Pregnancy, use of β-blockers, and severe cardiovascular, renal, or respiratory compromise
Methods	Patients were recruited to receive a penicillin skin test on 2 different days. Subjects with a positive skin test to penicillin initially received a prick of the study drugs on the volar forearm skin with aztreonam 2 mg/mL in normal saline (NS), imipenem-cilastatin 0.5 mg/mL in NS, meropenem 1 mg/mL in NS, and ertapenem 1 mg/mL in NS. Readings were performed 20 minutes after injection. Positive results consisted of wheal 3 mm or more with erythema. Drug challenges were performed in all patients who displayed negative results in skin testing, with aztreonam administered intramuscularly and carbapenems administered intravenously; initial test doses were administered at one-hundredth (0.01 g of aztreonam and ertapenem) or one-tenth (0.1 g of aztreonam and ertapenem; 50 mg imipenem plus 50 mg of cilastatin or 0.1 g of meropenem) of therapeutic dose followed by a full dose one hour later. Additional challenge doses were only administered upon confirmation of negative result. Patients with positive skin test responses to aztreonam or carbapenems were not challenged due to potential sensitization.
Duration	January 2007 to December 2013
Outcome Measures	Tolerability of aztreonam and carbapenems in penicillin-allergic, cross-reactivity rates
Baseline Characteristics		All study subjects (N= 212)
	Age, years	47.4 ± 16.3
	Women	135 (63.7%)
	Time since last drug reaction, months	2
	Responsible beta-lactams for all reactions Amoxicillin Ampicillin Piperacillin Bacampicillin Benzylpenicillin Ceftriaxone Cephalexin Cefaclor Ceftazidime	237 (84.6%) 20 (7.2%) 10 (3.6%) 3 (1.1%) 3 (1.1%) 3 (1.1%) 1 (0.4%) 1 (0.4%) 1 (0.4%)
	Total number of documented beta-lactam reactions Diagnosed anaphylactic reaction Urticaria/angioedema	279 163 (76.9%) 49 (23.1%)
	Experience only one reaction	150 (70.7%)
	Distinct reaction to same or different penicillins in separate episodes	62 (29.2%)
Results	Endpoint	All study subjects (N= 212)
	Positive skin test results to study drugs	0
	Tolerated challenging of study drugs (95% confidence interval)	100% (98.2% to 100%) (1 patient refused challenge)
Study Author Conclusions	These data indicate the tolerability of both aztreonam and carbapenems in penicillin-allergic subjects. In those who especially require these alternative beta-lactams, however, we recommend pretreatment skin tests, both because rare cases of cross-reactivity have been reported and because negative results indicate tolerability.
InpharmD Researcher Critique	A key limitation of the study is the lack of complete therapeutic courses following challenges, as the research focused on patients for study purposes rather than clinical indications for aztreonam or carbapenem treatments, which may not reflect real-world scenarios. Additionally, while skin testing is noted for its high negative predictive value, the study does not address potential false positives or variability in individual responses. The limited sample size and absence of long-term follow-up data further restrict the generalizability of the results, particularly to diverse patient populations with varying comorbidities.

References:

Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2015;135(4):972-6.

Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins
Design	Prospective study N= 204
Objective	To evaluate the use of carbapenems in patients with a documented T-cell-mediated penicillin allergy
Study Groups	All patients (N= 204)
Inclusion Criteria	Patients aged ≥15 years with confirmed T-cell-mediated hypersensitivity to penicillins
Exclusion Criteria	Not disclosed
Methods	Patients with positive patch and/or delayed-reading skin tests to any of the penicillin agents (ampicillin, amoxicillin, amoxicillin, piperacillin) underwent skin testing with imipenem cilastatin (0.5 mg/mL in 0.9% normal saline [NS]), meropenem (1 mg/mL in 0.9% NS), and ertapenem (1 mg/mL in 0.9% NS); ertapenem was not included in study until 2002. Carbapenem challenges were initiated in patients with negative carbapenem skin test results, with intravenous (IV) doses given once weekly at one-hundreth of therapeutic dose (500 mg of imipenem plus 500 mg of cilstatin, 1 g of meropenem and ertapenem); doses of each carbapenem were given on different days. Subsequent doses were given weekly if patient continued to have negative results, with one-tenth of the doses administered, followed by a full dose; after 30 challenges, a shorter frequency of dose escalation with carbapenems were administered. All patients were monitored during allergy testing and 6 hours following carbapenem challenges.
Duration	1997 to 2012
Outcome Measures	Incidence of cross-reactivity between carbapenem use and confirmed penicillin allergy
Baseline Characteristics		All patients (N= 204)
	Age, years	42.7 ± 16.7
	Female	137 (67.1%)
	Personal history of allergic disease	44 (21.6%)
	Time since last drug reaction, months (range)	12 (1-540)
	Total number of documented beta-lactam reactions Amoxicillin Ampicillin Bacampicillin Piperacillin Benzylpenicillin Benzathine penicillin Cephalexin Pivampicillin Unspecified	298 165 (55.3%) 87 (29.2%) 28 (9.4%) 7 (2.3%) 3 (1%) 1 (0.3%) 1 (0.3%) 1 (0.3%) 5 (1.7%)
Results	All patients, with positive patch tests and/or delayed reading skin tests to at least one penicillin reagent, were negative for all carbapenem skin tests. All patients included in the study (N= 204) with negative skin tests to imipenem/cilastatin and meropenem accepted carbapenem challenges and tolerated them (100%; 95% confidence interval 98.2% to 100%).
Adverse Events	Common clinical manifestations with beta-lactam reactions included maculopapular exanthema (48.3%), maculopapular exanthema plus edema (38.9%), and erythema (4%).
Study Author Conclusions	These data demonstrate the absence of clinically significant T-cell-mediated cross-reactivity between penicillins and carbapenems. Negative delayed-reading skin testing with carbapenems in individuals with documented T-cell-mediated hypersensitivity to penicillins correlates well with subsequent clinical tolerance of therapeutic doses of carbapenems.
InpharmD Researcher Critique	Study results are limited by its small sample size. Study findings show limited evidence for potential cross-reactivity between carbapenem use and T-cell-mediated penicillin allergies, as no patients with a penicillin allergy (including ampicillin) exhibited meropenem allergic reactions upon skin testing and drug challenge.

References:

Romano A, Gaeta F, Valluzzi RL, et al. Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins. Allergy. 2013;68(12):1618-1621. doi:10.1111/all.12299

Brief Communication: Tolerability of Meropenem in Patients with IgE-Mediated Hypersensitivity to Penicillins
Design	Prospective skin testing and antibiotic challenge N= 104 participants
Objective	To assess the tolerability of meropenem in patients with documented penicillin allergy
Study Groups	All study subjects (N = 104)
Inclusion Criteria	Participants older than 13 years with histories of immediate reactions to penicillins and positive skin test results to at least 1 penicillin reagent
Exclusion Criteria	Pregnancy, use of β-blockers, severe cardiovascular, renal, or respiratory conditions
Methods	Skin testing with classic penicillin reagents (penicilloyl polylysine, minor determinant mixture, benzylpenicillin) and semisynthetic penicillins (ampicillin, amoxicillin, piperacillin) was conducted over two days. On the third day, meropenem was tested at a concentration of 1 mg/mL in normal saline. Skin tests included prick tests, followed by intradermal tests if results were negative, with positive and negative controls established using histamine and normal saline, respectively. Prick and intradermal tests with meropenem were performed on 20 healthy participants who tolerated penicillins. Challenges with intravenous meropenem were conducted for those with negative skin test results, starting with one-hundredth of the therapeutic dose, followed by one-tenth after one hour if negative, and a full dose an hour later if still negative. Patients were monitored during testing and for two hours post-challenge, and those with positive skin test results to meropenem were not challenged.
Duration	January 2002 to June 2006
Outcome Measures	Tolerability of meropenem in patients with penicillin allergy, rate of cross-reactivity between penicillins and meropenem
Baseline Characteristics	Variable	Study subjects (N = 104)
	Age, years	47.83
	Women	66 (63%)
	Median time since last penicillin reaction, mo	6 (1–360)
	Family history of allergic diseases	34 (32%)
	Personal history of allergic diseases	24 (23%)
	Reactions	138
	Culprit penicillins Amoxicillin Ampicillin Bacampicillin Piperacillin Benzathine-penicillin Benzyl-penicillin	73 (52%) 25 (18%) 18 (13%) 16 (11%) 3 (2%) 3 (2%)
	Manifestations Anaphylactic shock Urticaria Urticaria and angioedema	85 (61%) 29 (21%) 24 (17%)
	Positive skin test results to penicillins Penicilloyl polylysine Minor determinant mixture Benzylpenicillin Ampicillin Amoxicillin Piperacillin	27 (25%) 35 (33%) 44 (42%) 63 (60%) 63 (60%) 44 (42%)
Results	Variable	Study subjects (N = 104)
	Participants with positive skin test results to meropenem	1 (0.9%)
	Participants with negative skin test results to meropenem	103 (99.1%)
	Participants with negative skin test results who tolerated meropenem challenges	103 (100%)
	Positive skin test results to imipenem–cilastatin	1/69 (1%)
	Positive skin test results to cephalosporins	3/22 (13%)
	Positive specific IgE assay results Penicilloyl G Penicilloyl V Ampicilloyl Amoxicilloyl	23 (22%) 27 (25%) 28 (26%) 19 (18%)
Adverse Events	No adverse events reported during the study
Study Author Conclusions	The data indicate a low rate of cross-reactivity between penicillins and meropenem. The practice of avoiding meropenem therapy in penicillin-allergic patients should be reconsidered. Pretreatment skin tests are recommended as negative results indicate tolerability.
Critique	The study has several limitations that impact its conclusions, primarily the lack of full therapeutic courses following challenges, as it focused on research rather than clinical indications for meropenem treatment. While skin testing with meropenem demonstrates a high negative predictive value, its reliability in acute illness may vary, and the findings may not fully reflect individual patient complexities, particularly in penicillin-allergic individuals requiring meropenem. Consequently, the study suggests graded challenges for patients with negative results, underscoring the need for further research to validate the negative predictive value of skin testing in diverse clinical scenarios.

References:

Romano A, Viola M, Guéant-Rodriguez RM, Gaeta F, Valluzzi R, Guéant JL. Brief communication: tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillins. Ann Intern Med. 2007;146(4):266-269. doi:10.7326/0003-4819-146-4-200702200-00005

Is it Safe to Use Carbapenems in Patients with a History of Allergy to Penicillin?
Design	Retrospective, case-control chart review N= 266
Objective	To ascertain the clinical safety of administering carbapenems, imipenem/cilastatin and meropenem, in patients with a history of penicillin allergy compared to patients without penicillin allergy
Study Groups	Patients with penicillin allergy (n= 163) Patients without penicillin allergy (n= 103)
Inclusion Criteria	Patients admitted to Cleveland Clinic Health System-Eastern Region Hospitals with ≥1 day of carbapenem treatment; for patients with penicillin allergy, previously documented penicillin allergy
Exclusion Criteria	Incomplete or unavailable charts for review
Methods	A retrospective chart review identified patients who received ≥1 day of carbapenem therapy with a documented penicillin allergy and patients without a penicillin allergy matched based on the time of admission (±3 days of case patient) and age (±5 years of case patient). Identification of imipenem/cilastatin and meropenem allergies were based upon evidence of hypersensitivity reactions that resolved following carbapenem discontinuation; hypersensitivity reactions were defined as developing a rash, hives, fever, angioedema, bronchospasm, or pruritus.
Duration	2001 to 2002
Outcome Measures	Incidence of imipenem/cilstatin or meropenem allergic reactions in patients with and without penicillin allergies
Baseline Characteristics		Patients with penicillin allergy (n= 163)	Patients without penicillin allergy (n= 103)	p-Value
	Age, years (range)	70.6 (32-91)	74 (39-91)	0.045
	Male	69 (42%)	65 (63.1%)	0.001
	Reported reaction to penicillin Rash Facial swelling and/or anaphylaxis Unknown Other	57 (34.9%) 10 (6.1%) 88 (54%) 8 (4.9%)	- - - -	<0.001 0.026 <0.001 0.056
	Other antibiotic allergies Cephalosporins Sulfa drugs Fluoroquinolones Macrolides	7 (4.3%) 36 (22%) 17 (10.4%) 9 (5.5%)	5 (4.9%) 11 (10.7%) 2 (1.9%) 2 (1.9%)	0.941 0.028 0.017 0.261
Results	Endpoint	Patients with penicillin allergy (n= 163)	Patients without penicillin allergy (n= 103)	p-value
	Allergic reaction to carbapenem	15 (9.2%)	4 (3.9%)	0.164
	Allergic reactions to carbapenem use developed on an average of 3.6 days for patients with penicillin allergy, with patients without penicillin allergies developing a reaction 5.5 days on average. Of the 7 patients with both penicillin and cephalosporin allergies, 4 (57%) developed an allergic reaction with carbapenem use. Only 1 patient out of 10 who reported anaphylaxis with penicillin administration developed a reaction to carbapenem use.
Adverse Events	Common Adverse Events: Maculopapular rash (6.7% of patients with penicillin allergy vs. 2.9% of patients without penicillin allergy), pruritus (0.6% vs. 0)
	Serious Adverse Events: Drug fever and rash (0.6% vs. 1%), facial edema (0.6% vs. 0)
	Percentage Discontinued due to Adverse Events: N/A
Study Author 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.
InpharmD Researcher Critique	Study limitations are primarily due to retrospective nature, with a majority of patients having an undocumented or unknown penicillin allergic reaction and potential overestimation of true hypersensitivity reactions. Despite study findings purporting a lack of evidence for cross-reactivity between patients with penicillin allergies and carbapenem use, specific agents were not identified and analyzed for hypersensitivity incidence. Study results should be interpreted with caution, as direct evidence of ampicillin and meropenem cross-reactivity were not reported.

References:

Sodhi M, Axtell SS, Callahan J, Shekar R. Is it safe to use carbapenems in patients with a history of allergy to penicillin?. J Antimicrob Chemother. 2004;54(6):1155-1157. doi:10.1093/jac/dkh454

Meropenem-induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in a Patient with Known Type IV Penicillin Hypersensitivity
Design	Case study report
Case presentation	A 67-year-old female patient with a past medical history of diabetes, hypertension, and cerebrovascular accident, presented to the hospital with fever, diffuse abdominal pain, and dark-colored urine for 3 days. She had a history of type IV hypersensitivity reaction (SJS) to amoxicillin, known to the providers. She was diagnosed with pyelonephritis and started on empiric treatment with meropenem and vancomycin; urine cultures confirmed Klebsiella pneumoniae susceptible to meropenem and vancomycin was discontinued. On day 3 of therapy, the patient manifested with an erythematous rash beginning on the torso and spreading diffusely with mucosal involvement, severe itching, nausea, and vomiting. Dermatologic symptoms progressed to vesicles and bullae formation, characteristic of toxic epidermal necrolysis (TEN), with a SCORTEN score of 3, indicating an estimated 35.5% mortality risk. Histopathological findings from a skin biopsy revealed full-thickness epidermal necrosis, confirming the diagnosis of SJS, which was thought to be triggered by meropenem. The reaction was managed by discontinuing meropenem, administering systemic corticosteroids and diphenhydramine, and providing supportive care including fluid balance and wound care. Notably, despite the patient’s known history of beta-lactam hypersensitivity, the case highlighted the potential for cross-reactivity between penicillins and carbapenems in inducing type IV hypersensitivity reactions.
Study Author Conclusions	This case report highlights the need to avoid all beta-lactam ring containing antibiotics in a patient with documented history of a severe T-cell-mediated hypersensitivity reaction like SJS/TEN to any beta-lactam containing antibiotic and in order to prevent similarly severe outcomes.

References:

Sameed M, Nwaiser C, Bhandari P, Schmalzle SA. Meropenem-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in a patient with known type IV penicillin hypersensitivity. BMJ Case Rep. 2019;12(8):e230144. Published 2019 Aug 20. doi:10.1136/bcr-2019-230144