c7 Cefaclor

Summary

Cefaclor is a broad-spectrum, second-generation, beta-lactam antibiotic belonging to the class of cephalosporins. The beta-lactam ring and the side chains (R1 and R2) are the sites of immunological recognition. Cross-reactivity is frequently attributed to the aminobenzene side chain (R1), which is shared between aminopenicillins (amoxicillin and ampicillin) and aminocephalosporins (cefaclor and cephalexin). Hypersensitivity to cefaclor can present as immediate or delayed reactions. Frequent clinical manifestations include urticaria and angioedema, but severe systemic reactions (anaphylaxis) are also reported. Clinical history alone is not reliable for the diagnosis of cefaclor allergy, hence one or more among skin and blood tests for cefaclor sensitization and cefaclor provocation tests are required. Cefaclor skin testing and cefaclor-specific IgE determination are highly specific but lack diagnostic sensitivity for immediate allergic reactions. Risk factors of immediate cefaclor allergy are hypertension, liver disease, asthma, atopic dermatitis, urticaria, allergic conjunctivitis, and intake of non-steroidal anti-inflammatory drugs. Similar to other beta-lactams, alleged allergy to cefaclor is confirmed only in a small proportion of patients.

Allergen         

Nature

Cefaclor is a broad-spectrum, second-generation, beta-lactam antibiotic belonging to the class of cephalosporins (Baldo et al. 2013). Similar to all beta-lactams, cefaclor possesses a 4-membered beta-lactam ring fused with a thiazolidine ring, collectively denoted as a penam ring. In addition to the side chain R1 also found in penicillins, cephalosporins also feature a second side chain,containg a chlore atom in cefaclor (Caruso et al. 2021, NIH-Pubchem 2024). Cefaclor is a semi-synthetic derivative of the first-generation cephalosporin cephalexin, itself a derivative of the natural cephalosporin C extracted from the opportunistic fungus Sarocladium strictum, previously known as Cephalosporium acremonium  (NIH-Pubchem 2024, Perez-Cantero et al. 2020).

Cefaclor is available for oral intake in capsule,  tablet, and suspension form (NIH-Pubchem 2024).

Like other small molecules, cephalosporins are not immunogenic by themselves, instead requiring binding to a carrier protein, such as serum albumin, through a process called haptenization.

Several mechanisms, namely IgE (immediate reactions) and T cells (nonimmediate reactions), can trigger allergic reactions to cephalosporins. The R1 side chains are considered as the main cause of allergic reactions to cephalosporins, but the R2 side chain and the beta-lactam ring can also induce sensitization (Baldo et al. 2013, Khan et al. 2022, Stone et al. 2021). The R1 side chain of cefaclor is identical to those of its precursor (cephalexine) and of aminopenicillins (mainly amoxicillin and ampicillin) (Macy et al. 2022).

Epidemiology

Worldwide distribution

Alleged allergy to cephalosporin has a prevalence of 1-2% in general population (Stone et al. 2021). Among patients with a history of beta-lactam allergy, cefaclor was suspected in 4% of US-based patients, in 2% of Australia-based patients, and in 6% of pregnant Canadian patients (Genis et al. 2023, Stone et al. 2021). However, it is estimated that allergological work-up could delabel around 90% of patients labeled as beta-lactam allergic (Brockow et al. 2025). This is possibly due to two reasons: inaccurate diagnosis and the gradual loss of sensitization with time (Siew et al. 2019). Hence, delabelling through allergological investigation is advised, considering the harms of false allergy labels.

The reported prevalence of adverse drug reactions for cephalosporins was 1.7% in the U.S. (Zhou et al. 2016) with an incidence of 0.8% for oral administrations (Macy et al. 2015). A survey on 3,999,290 individuals in San Diego during 2010–2012 involved 5269 individuals receiving 6459 courses of cefaclor; about 0.54% (35/6459) of new cefaclor reactions were reported in these individuals (Macy et al. 2015).

A retrospective study conducted in Korea found 6883 cases of adverse drug reactions attributed to cefaclor with an incidence rate of 1.92/10,000 individuals, including 1.17/10,000 individuals for hypersensitivity reactions, and 0.38/10,000 individuals for anaphylactic reactions (Rhyou, Nam et al. 2021).

A prospective study was conducted in Italy with 236 patients, of whom 216 had a history of immediate cephalosporin reaction. Cefaclor allergy was found in 19/236 subjects, of whom 5/19 showed positive skin tests, 2/19 had elevated serum specific IgE (sIgE) to cefaclor, and 7/19 were positive for both tests (Romano et al. 2021).

Another study conducted retrospectively on 476 French patients with alleged cephalosporin allergy found 22.3% (106/476) patients having confirmed cephalosporin allergy, of which 33% (35/106) concerned cefaclor, cefalexin, cefadroxil, and cefatrizine (Touati et al. 2021).

A retrospective study conducted in Korea on 47 patients with a history of cefaclor allergy reported elevated cefaclor sIgE in 89.4 % (42/47) patients, while skin tests were positive in 61.5% (8/13) of patients and oral provocation tests for cefaclor were positive in 100% (11/11) (Yoo et al. 2014).

An Australia-based study conducted on 564 subjects with a history of beta-lactam allergy found 90 patients with primary cephalosporin allergy. Of these 90 patients, 55 had a history of IgE-mediated reaction. Cephalosporin allergy was confirmed in 24/55 patients through sIgE or skin testing. Cefaclor sIgE was found in 4 patients (Yuson et al. 2019).

Risk factors

Risk and predictive factors contribute to the stratification of patients’ risk of having genuine beta-lactam allergy, and thus to the choice of the diagnostic strategy (Brockow et al. 2025).

Females and patients with penicillin allergy are at higher risk of cephalosporin allergy (Macy et al. 2015, Romano et al. 2018). A study found hypertension, liver disease, asthma, atopic dermatitis, urticaria, allergic conjunctivitis, and intake of non-steroidal anti-inflammatory drugs to be associated with immediate cefaclor allergy (Rhyou, Doo et al. 2021).  

Pediatric issues

Beta-lactam antibiotics are the most prevalent medications that trigger allergic reactions in children. A retrospective cohort study on 83 pediatric patients (11 months to 12 years) with serum sickness-like reactions reported cephalosporin as the cause in 8.5% of cases. Cutaneous manifestations included erythema multiforme (38%), urticaria type (35%) and maculo-papular rashes (26%). Labial or palpebral edema was seen in 31%, fever was reported in 44.5% and edema with pain in hands and feet was found in 60% of all cases (Del Pozzo-Magana et al. 2021).

Route of Exposure     

Main

Cefaclor is only available for oral administration.  

Clinical Relevance    

Beat-lactam allergies are divided into two categories: immediate and delayed, each stemming from different immune responses. Immediate reactions happen within 1 to 6 hours of taking the drug, with symptom onset taking place during the first 15 minutes in 85% of patients and can range from urticaria to life-threatening anaphylaxis. Delayed reactions occur at least 6 hours after dosing, with a majority taking place 1 to 2 weeks after intake, and may present as benign maculopapular exanthema but severe, life-threatening  presentations are also reported, such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (Castells et al. 2019, Khan et al. 2022).

A study identified 55 subjects with a history of cephalosporin-induced IgE-mediated hypersensitivity out of 564 subjects with a history of beta-lactam allergy. Clinical features of their reactions were erythema (36.3%), urticaria (30.9%), angioedema (21.8%), hypotension (16.3%), and  bronchospasm (5.4%). Symptoms of nausea, vomiting and diarrhoea ocuured in 9% subjects (Yuson et al. 2019).

A survey-based study reported 6883 cases of cefaclor and 15,024 cases of other cephalosporin-induced adverse drug reactions, of which cefaclor-induced manifestations were anaphylaxis (32.7%), urticaria (27%), and angioedema (7.7%). Severe adverse drug reactions such as disability, life-threatening conditions, prolonged hospitalization, death and others were found in 20.4% of cases of cefaclor hypersensitivity (Rhyou, Nam et al. 2021). Furthermore, another study with 459 cases of immediate cefaclor allergy found cutaneous manifestations in 73% of cases, followed by 61.2% cases of anaphylaxis, dyspnea/hypoxemia in 45.3%, angioedema in 31.8%, hypotension in 15.9 % cases, and 6.3% showing alternation in mental state (Rhyou, Doo et al. 2021). Similarly, a Korean study conducted on 47 patients with a history of immediate cefaclor hypersensitivity reported anaphylaxis as the most frequent (78.7%) manifestation of immediate reactions. Urticaria, along with/without angioedema, was found in 21.3% of cases (Yoo et al. 2014). Moreover, anaphylaxis was also reported to be the most common (65.3%) clinical manifestation in a study of 1247 subjects with 193 patients having cefaclor allergy. Among the patients showing anaphylactic reactions, 9.5% patients had mild, 60.3% had moderate, and 30.2% had severe anaphylactic reactions (Nam et al. 2018).

A diagnosis of anaphylaxis to cefaclor was confirmed in two cases of adult female patients having a prior history of drug allergies. In both cases, a history of immediate reaction to cefaclor, skin prick tests positive for multiple allergens and a positive oral challenge with cefaclor were reported. Oral challenge with cefaclor resulted in vomiting, hypertension, itching and more severe symptoms at higher concentrations in the first case, while skin rash, breathing difficulty, chest tightness, edema and angioedema were reported in the second case (Noh et al. 2018).

A case series of immediate hypersensitive reactions to cefaclor in 7 females and 1 male was presented. Immediate reactions were manifested as angioedema, urticaria, generalized erythema and anaphylaxis (Springer 2021).  

Diagnostics Relevance

Clinical predictors for true beta-lactam allergies are lacking, hence suspected allergy cases need to be confirmed by specific IgE testing and if necessary, by an in vivo drug challenge test (Siew et al. 2019). Skin testing to cefaclor is not included in standard testing panels, but amoxicillin, which shares a similar R1 side chain with cefaclor, allows to identify R1-linked cross-reactivity. Serum specific IgE testing is safe, is not influenced by ongoing antihistamine medication and can be performed in primary care settings (Lendal et al. 2025).

Serum-specific IgE (sIgE) tests or immunological assays that measure sIgE of beta-lactams have shown diagnostic performance comparable to skin tests. A study with 193 patients diagnosed with cefaclor allergy reported that a value of 0.11 kU/l of sIgE cefaclor was optimum for discriminating immediate cefaclor allergic reactions. The specificity and sensitivity for immediate cefaclor allergy at this cut-off were 81.6% and 80.2% (Nam et al. 2018).

Early investigation can be performed with specific IgE determination in acute samples obtained at the time of an immediate reaction (Garvey et al. 2019). Specific IgE testing is recommended as the first-line investigation in high-risk patients, e.g. having experienced severe immediate reactions to beta-lactams (Demoly et al. 2014, Dona et al. 2025). A clearly positive IgE test can be considered sufficient for the diagnosis of beta-lactam allergy in patients with an evocative clinical history, especially anaphylaxis (Garvey et al. 2019, Romano et al. 2020)

If specific IgE tests are negative, additional examinations with skin and drug provocation test become necessary (Dona et al. 2025, Lendal et al. 2025).

Conversely, USA practice parameter recommends skin testing over blood IgE testing due to lower diagnostic sensitivity of the latter (Khan et al. 2022).

Prevention and Therapy

Avoidance

The reaction to cefaclor could be transient immunologically but clinically it could be persistent. Therefore, it is usually recommended to avoid the culprit cephalosporin along with similar beta-lactams (Brockow et al. 2025, Romano et al. 2021). However, the rate of real-world cross-reactivity might be lower than inferred from chemical structures (Liang et al. 2020, Macy et al. 2022, Ramsey 2022).

Molecular Aspects

Cross-reactivity

Cross-reactivity to cephalosporin allergy is attributed to the R1 side chain, which is the major antigenic component (Yuson et al. 2019, Zagursky et al. 2018). The most common side chain, aminobenzene, is found among the aminopenicillin group (amoxicillin and ampicillin) and aminocephalosporins (cefaclor and cephalexin). Cross-reactivity can also involve only a part of R1 side chain or a combination of R1 (aminobenzyl) and R2 (chloro, methy or ester) groups (Baldo et al. 2013, Yuson et al. 2019). However, cephalosporin allergy in patients with penicillin allergy showed variation depending on the side chain similarity (Caruso et al. 2021). On the other hand, allergic cross-reactivity between cephalosporins and carbapenems or aztreonam was found to be low (Romano et al. 2010).

Explained results

Allergen information

Cefaclor is a semi-synthetic, broad-spectrum, second-generation cephalosporin

Clinical information

Cefaclor hypersensitivity reactions with a demonstrated adaptive immune mechanism are termed cefaclor allergy. Immediate ampicillin allergy (1-6 hours after administration) is IgE-dependent, while delayed ampicillin allergy (>6 hours after administration) is T cell-dependent. Like other beta-lactams, confirmed cefaclor allergy represents around 10% of patients with a label of cefaclor allergy, prompting recommendations for proactive allergy delabeling after risk stratification.

Cross-reactivity

Cefaclor carries a risk of cross reactivity with potential clinical relevance with aminopenicillins (amoxicillin and ampicillin) and aminocephalosporins (cephalexin).

Compiled by Turacoz

Reviewed by Dr. Joana Vitte, September 2025