Immediate allergic reactions to cephalosporins: cross-reactivity and selective responses

BACKGROUND: After penicillins, cephalosporins are the most important beta-lactams inducing IgE-mediated reactions. Responses may be selective or cross-reactive with common beta-lactam determinants. Unlike determinants derived from benzylpenicillin, cephalosporin allergenic determinants have not been properly identified, even though a wide variety of these beta-lactams is currently used. OBJECTIVE: We sought to evaluate the IgE response in subjects with immediate allergic reactions to injectable cephalosporins and to assess their reactivity to different penicillins and cephalosporins. METHODS: We studied 30 subjects with immediate reactions to one or more of the following cephalosporins: ceftriaxone, cefotaxime, ceftazidime, and cefuroxime. Skin tests and in vitro-specific IgE antibody assays were performed for major and minor determinants of penicillin G, amoxicillin, and ampicillin, as well as for the culprit cephalosporins. Responses to cephalosporins other than the culprit ones were also studied by using skin testing. RESULTS: Twenty-six patients (group A, 86.7%) displayed skin test and RAST negativity to penicillin determinants and skin test positivity to cephalosporins, with RAST confirmation in 9 patients. Four subjects (group B, 13.3%) had a positive response to penicillin determinants. In group A two patterns of reactivity were observed: one characterized by a response only to the culprit cephalosporin (n = 15, 57.7%) and the other by positive responses to different cephalosporins, including the responsible cephalosporins (n = 11, 42. 3%). CONCLUSION: Most patients with a history of immediate reactions to cephalosporins are sensitized to determinants generated only by cephalosporins (group A), although a small percentage react to penicillin determinants (group B). Some patients from group A responded only to the culprit cephalosporin, but others reacted to different cephalosporins. These findings can be explained in terms of either selective response to unique determinants or cross-reactivity.     

Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins

There are some contradicting data about clinical allergic cross-reactivity to cephalosporins among patients who have had a previous allergic reaction to penicillins. The purpose of this study was to assess the safety of administering cephalosporins to penicillin-allergic patients. The diagnosis of penicillin allergy was made by positive skin tests to penicillin reagents and/or provocation tests with the penicillin suspected of causing the allergic reaction. To assess the clinical tolerance to cephalosporins, 41 well-characterized penicillin allergic patients diagnosed by positive skin tests and/or provocation tests were challenged with three cephalosporins that do not share the same side chain to the penicillin that induced the reactions: cephazoline, cefuroxime and ceftriaxone. Skin prick and intradermal tests with all cephalosporins tested were negative. All penicillin-allergic patients tolerated therapeutic doses of the three cephalosporins tested (cephazoline, cefuroxime and ceftriaxone) without any ill effect. These results indicate that the risk of suffering from an allergic reaction on administering cephalosporins to penicillin-allergic patients seems to be very low, provided that cephalosporins with a different side chain to the penicillin responsible for the allergic reaction are used.     

Allergic reactions to penicillins and cephalosporins: diagnosis,assessment of cross-reactivity and management

ABSTRACT

Introduction: Beta-lactams (BL) are the main cause of allergic drug reactions mediated by specific immunological mechanisms. Reactions can be IgE or effector T-cell mediated. The new antigenic determinants are recognized by the immunological system in the context of the common beta-lactam structure or the specific differences in the side chains of the antibiotics of this family plus the protein carrier.

Areas covered: We have reviewed the recent clinical literature concerning new clinical entities, the progress in diagnosis including the difficulties for in in vivo and or in vitro testing as well as the new algorithms proposed for delabelling subjects classified as allergic to beta-lactams, and recommendations for desensitization procedures.

Expert opinion: The knowledge gained over the last years on beta-lactam hypersensitivity has enabled a better understanding and management of cases with allergic reactions to beta-lactams.     

Skin test evaluation in nonimmediate allergic reactions to penicillins

BACKGROUND: Nonimmediate reactions (NIR) to aminopenicillins (AP) are frequent. Although patch testing (PT) and intradermal testing (IT) are used for diagnosis, comparative results have never been adequately performed. We compared PT and IT in subjects with NIR to AP. METHODS: Twenty-one subjects with NIR to AP and positive IT were re-evaluated. Skin tests were performed with amoxicillin (AX) and ampicillin (AM) at different concentrations in petrolatum, 50, 25, and 5% w/w, for PT and in saline, 20, 2, and 0.2 mg/ml for both PT and IT. Skin biopsies from the site of the positive response were studied with haematoxylin-eosin and immunohistochemistry. RESULTS: In the re-evaluation, one case was IT and PT negative and was excluded; 20 were IT positive and 18 PT positive for both AX and AM. Decreasing concentrations of AP induced a reduction in positivity in both methods when diluted in saline, but not when mixed in petrolatum (PT only). With both PT and IT, immunohistochemical studies showed a perivascular mononuclear infiltrate with CD4 and CD8 memory cells expressing perforin and granzyme B. CONCLUSIONS: Both tests appear valuable for the diagnosis of NIR to AP. However, IT diagnosed more patients than PT. The vehicle (saline or petrolatum) had no influence on the response, although in the former the concentration was critical. The immunohistochemical analysis showed skin infiltrates compatible with a T-cell drug reaction.     

Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin

A group of 34 penicillin-allergic patients was studied to determine skin test reactivity to the different penicillins involved in inducing the allergic reaction and the cross-reactivity with side-chain-related and side-chain-unrelated cephalosporins. All the subjects selected for the study had to be skin test positive to at least one of the following determinants: benzyl-penicilloyl-polylysine (BPO-PLL), minor-determinant mixture (MDM), amoxicillin (AX), or ampicillin (AMP), or to possess in vitro IgE to the following conjugates: benzyl-penicilloyl-human-serum albumin (BPO-HSA), ampicilloyl-human-serum albumin (AMP-HSA), and amoxicilloyl-human-serum albumin (AX-HSA). Cephalexin (CE) and ceftazidime (CEF) were used to assess cross-reactivity. If skin tests to any of these compounds were positive, the patient was considered to be allergic; if negative, a challenge test was performed. Sixteen patients (47%) were skin test positive to BPO and/or MDM, and nine (26%) exclusively to AX and/or AMP. In three cases (8%), the RAST was positive although the skin test was negative; one to BPO-HSA and two to AX-HSA and AMP-HSA. Six patients (17%) needed to be challenged with the penicillin involved to establish the diagnosis. In five patients (14%), the skin tests were positive to CE and in none to CEF. In all the others, the skin tests were negative to both cephalosporins, and the patients tolerated the drugs when challenged. These results indicate the relevance of side-chain-specific minor determinants in betalactams allergy and provide support for the role of this chemical structure in the evaluation of cross-reactivity between penicillins and cephalosporins.     

* Immediate allergic reactions to amoxicillin

A large group of patients with suspected allergic reactions to (β-lactam antibiotics was evaluated. A detailed clinical history, together with skin tests, RAST (radioallergosorbent test), and controlled challenge tests, was used to establish whether patients allergic to β-lactam antibiotics had selective immediate allergic responses to amoxicillin (AX) or were cross-reacting with other penicillin derivatives. Skin tests were performed with benzylpenicilloyl-poly-L-lysine (BPO-PLL), benzylpenicilloate, benzylpenicillin (PG), ampicillin (AMP), and AX. RAST for BPO-PLL and AX-PLL was done. When both skin test and RAST for BPO were negative, single-blind, placebo-controlled challenge tests were done to ensure tolerance of PG or sensitivity to AX. A total of 177 patients were diagnosed as allergic to β-lactam antibiotics. We selected the 54 (30.5%) cases of immediate AX allergy with good tolerance of PG. Anaphylaxis was seen in 37 patients (69%), the other 17 (31%) having urticaria and/or angioedema. All the patients were skin test negative to BPO; 49 of 51 (96%) were also negative to MDM, and 44 of 46 (96%) to PG. Skin tests with AX were positive in 34 (63%) patients. RAST was positive for AX in 22 patients (41%) and to BPO in just 5 (9%). None of the sera with negative RAST for AX were positive to BPO. Challenge tests with AX were performed in 23 subjects (43%) to establish the diagnosis of immediate allergic reaction to AX, and in 15 cases (28%) both skin test and RAST for AX were negative. PG was well tolerated by all 54 patients. We describe the largest group of AX-allergic patients who have tolerated PG reported so far. Diagnosis of these patients can be achieved only if specific AX-related reagents are employed. Further studies are necessary to determine the exact extent of this problem and to improve the efficacy of diagnostic methods.     

Immediate allergic reactions to betalactams: facts and controversies

PURPOSE OF REVIEW: To analyse the available data in the field of immediate allergic reactions to beta-lactams, with particular emphasis on more recent studies, and to comment on the future role of this group of antibiotics. RECENT FINDINGS: The world of beta-lactams has become more complex than initially thought, due to the increased number of chemical structures available, the wide variety of indications for their use in treating different infectious diseases, and possibly also due to the interaction of other as yet undetermined factors. Benzyl penicillin, the original inducer of allergic reactions, has now largely been replaced by amoxicillin and, to a lesser extent, by cephalosporins in inducing IgE-mediated allergic reactions. These structures often share extensive cross-reactivity, eliciting clinical reactions to many compounds, especially amongst penicillins. In other circumstances selective responses are observed which are restricted to one group or one single compound, as occurs in the group of cephalosporins. The application of new determinants for skin testing and the use of adapted in-vitro studies have enabled these findings to be confirmed in detail. SUMMARY: Results indicate that evaluation of immediate reactions to beta-lactams requires the use of several determinants for both in-vitro and in-vivo testing, and which must reflect the relevant drug involved in eliciting the response. This tendency will be strengthened in the future if use of benzyl penicillin continues to decrease as a drug to which populations are exposed.     

Immediate allergic and nonallergic reactions to Christmas and Easter cacti

BACKGROUND: Occupational exposure to Christmas cacti has been reported as a cause of type I allergy. Therefore, the prevalence of immediate-type mucosal and skin reactions related to cactus exposure was studied in 103 employees in a cactus nursery. METHODS: The study was based on a questionnaire followed by clinical examination, skin prick tests (SPT) with standard inhalant allergens and cacti, and a histamine-release test (HRT/Refix) using fresh cactus extracts as elicitor. RESULTS: The questionnaire was answered by 84 (82%) of the nursery employees, and 63 (61%) were interviewed and skin prick tested; 58 of these were tested with HRT/Refix. Furthermore, 22 healthy controls were included and tested in vivo and in vitro. Cactus-related contact urticaria and/or rhinoconjunctivitis were reported by 37% of the cactus workers. Based on a combination of positive history, positive SPT, and positive HRT/ Refix to cactus, 8% of the cactus workers were allergic to cacti. No noncactus workers or controls were allergic to cacti by these criteria. Testing with fresh cactus material elicited positive SPT and negative HRT/Refix in 27 nursery workers and controls, of whom 12 had immediate-type skin and mucosal symptoms. CONCLUSIONS: Christmas and Easter cacti seemed to be able to induce contact urticaria and rhinoconjunctivitis on both an immunologic and a nonimmunologic basis. Personal atopy was associated with positive reactions to cacti.     

Heteroresistance to cephalosporins and penicillins in Acinetobacter baumannii

Heteroresistance to antimicrobial agents may affect susceptibility test results and therapeutic success. In this study, we investigated heteroresistance to cephalosporins and penicillins in Acinetobacter baumannii, a major pathogen causing nosocomial infections. Two A. baumannii isolates exhibited heteroresistance to ampicillin-sulbactam, ticarcillin-clavulanic acid, cefepime, and cefpirome, showing a distinct colony morphology of circular rings within the inhibition halos. Pulsed-field gel electrophoresis (PFGE) and outer membrane protein (OMP) analysis demonstrated that subpopulations around the disks/Etest strips and the original strains all belonged to the same PFGE type and OMP profile. Population analysis profile (PAP) showed the presence of heteroresistant subpopulations with high cefepime resistance levels in two isolates (008 and 328). Interestingly, A. baumannii 008 contained two peaks: one was grown in the presence of up to 1 μg of cefepime/ml, the other apparently occurred when the concentration of cefepime was raised to 256 μg/ml. After serial passages without exposure to cefepime, the PAP curve maintained the same trend observed for the original strain of A. baumannii 008. However, the PAP curve showed a shift to relatively lower cefepime resistance (from 256 to 64 μg/ml) in A. baumannii 328 after 10 passages in antibiotic-free Mueller-Hinton agar plates. Convergence to a monotypic resistance phenotype did not occur. Growth rate analysis revealed that slower growth in resistant subpopulations may provide a strategy against antibiotic challenge. To our knowledge, this is the first report of heteroresistance to cephalosporins and penicillins in A. baumannii.     

Studies on cross reactivity to penicillins in patients with immediate allergic reactions caused by amoxicillin

In this study we have explored the presence of cross reactivity to penicillin and ampicillin in patients with immediate allergic reactions caused by amoxicillin. Skin test results with amoxicillin were positive in 66.66% and in the remaining 33.34% were negative. In 81.48% patients we observed positive results of skin tests with penicillin and/or ampicillin. Only in 14.48% of the patients we observed selective response to amoxicillin. On the basis of obtained results we conclude that sensitivity of skin tests with amoxicillin is rather moderate and confirmation of amoxicillin hypersensitivity can be obtained using skin tests with other penicillins. In our material selective amoxicillin hypersensitivity can be defined as a relatively rare phenomenon. These data should have the important implications in antibiotics' selection in patients with amoxicillin allergy.     

Immediate allergic reactions to Myrmecia ant stings: immunochemical analysis of Myrmecia venoms

Abstract. IgE antibody reactivities to the venoms of Myrmecia pilosula, Myrmecia nigrocincta, Myrmecia tarsata, Myrmecia pyriformis, Myrmecia simillima and Myrmecia gulosa have been identified in sera from subjects allergic to ant venom. Sera with IgE reactivity to only a single Myrmecia venom most often recognize M. pilosula venom although all six venoms appear capable of inducing IgE antibodies. The six different Myrmecia venoms were electrophoretically separated by sodium dodecyl sulfate polyacrylamide gel etectrophoresis (SDS-PAGE), Western blotted to nitrocellulose and probed with sera from ant venom-allergic subjects. Four to six IgE-binding components ranging in size from 2 to 25 kDa were identified in each of the venoms. Similarities in molecular weights of the IgE-binding components exist and close taxonomic relationships between the species suggest that common or similar peptides may be present in the different venoms.     

Sensitivity of Citrobacter freundii and Citrobacter koseri to cephalosporins and penicillins

An examination of 99 field and reference strains of Citrobacter freundii showed 79% of them to be resistant to cephaloridine and sensitive to carbenicillin, while 96% of 45 field and reference strains of Citrobacter koseri examined were sensitive to cephaloridine and resistant to carbenicillin. Susceptibility tests with these two antibiotics are therefore useful in separating the two species of Citrobacter.     

IgE-mediated allergic reactions to fruit gums and investigation of cross-reactivity between gelatine and modified gelatine-containing products

A 32-year-old female reacted with a contact urticaria syndrome after eating 'gummy bears' (fruit gums). The reaction began in the oral mucosa and led to treatment on an inpatient basis. RAST measurements with allergen discs produced with gelatine and gelatine-containing products (among them 'gummy bears') demonstrated the presence of IgE antibodies in the serum of this patient. Proteins with molecular weights in the range of 40-120 kD were identified as the allergens in gelatine by using Western blot analysis. RAST inhibition showed cross-reactivity between gelatine, gelatine-containing products and the modified gelatine used in some plasma substitutes. Allergic reactions towards coloured fruit candies and 'gummy bears' may result from an IgE-mediated hypersensitivity towards gelatine. The long-known anaphylactoid reactions towards gelatine-containing plasma substitutes may, at least in part, be of an allergic nature.     

The role of beta-lactamase in staphylococcal resistance to penicillinase-resistant penicillins and cephalosporins.

We showed that most Staphylococcus aureus strains that have borderline or intermediate susceptibility to the penicillinase-resistant penicillins (PRPs) react this way because of the activity of their beta-lactamase on these antimicrobial agents. These strains produced large amounts of staphylococcal beta-lactamase that rapidly hydrolyzed penicillin and partially hydrolyzed the PRPs. Susceptibility to hydrolysis was penicillin greater than oxacillin greater than cephalothin greater than methicillin. The borderline results and the hydrolysis could be prevented by the beta-lactamase inhibitors clavulanic acid and sulbactam. For intrinsically methicillin-resistant (heteroresistant) S. aureus, the inhibitors reduced the penicillin MICs, but the strains remained resistant to all the beta-lactam antimicrobial agents, including penicillin. We conclude that the borderline in vitro susceptibility or resistance to PRPs in most of these S. aureus strains is mediated by beta-lactamase and they are not heteroresistant or intrinsically resistant. We do not know whether this in vitro resistance is expressed clinically.     

Occupational allergic rhinoconjunctivitis and asthma to goat and cross-reactivity with cow epithelium.

BACKGROUND: The development of sensitization and symptoms after the inhalation of epithelial allergens is common. OBJECTIVES: To investigate the allergic response (in vivo and in vitro) of 3 individuals clinically sensitive and occupationally exposed to cow and goat and to evaluate the allergenic cross-reactivity between cow and goat epithelium extracts. METHODS: Three patients--a butcher and 2 doctors in veterinary medicine--were evaluated. These patients reported allergic respiratory symptoms after occupational exposure to goats and cows. Extracts were prepared from epithelia of both animals. All the patients underwent organ-specific allergen challenges with cow and goat extracts. Four nasal and 2 bronchial challenges were conducted following standardized procedures. RESULTS: All 3 patients had positive challenge results with the offending allergen extract. Specific IgE to goat allergens was detected in all patients. Several IgE-binding bands were detected. Inhibition assays (enzyme allergosorbent test and immunoblots) confirmed moderate-to-high cross-reactivity between goat and cow extracts. CONCLUSIONS: We confirm clinical sensitivity and specific IgE binding to goat and cow allergens in occupationally exposed individuals. There was good correlation among the clinical history, exposure, and the laboratory findings.     

Treatment difficulties of a listerial rhombencephalitis in an adult patient allergic to penicillins

Rhombencephalitis is not a rare presentation of listerial central nervous system infections in healthy adults. This report describes a case with several management difficulties linked to antibiotic related adverse events, pointing to alternative solutions to aminopenicillins. In addition, the role of dexamethasone in the management of inflammation and neurological symptoms is discussed.     

*Nonimmediate reactions to betalactams: prevalence and role of the different penicillins

In patients treated with penicillins, adverse cutaneous reactions can occur within minutes or may take several days to develop. IgE antibody-mediated reactions are well documented, but other mechanisms may also be involved. In particular, nonimmediate reactions have not been studied extensively, and the purpose of the present work was to establish the incidence of such reactions among a large group of patients and to study the penicillins involved. A total of 380 subjects with a history of a cutaneous reaction following administration of a penicillin antibiotic was included in the study. Skin tests and specific IgE measurements (RAST) were carried out using various penicillins and penicillin-related reagents, and patients were also challenged with various penicillins. In some patients with delayed skin test responses, skin biopsies were carried out. The tests confirmed that 74 subjects (19.4% of total investigated) had suffered a cutaneous reaction to a penicillin derivative, and 29 of these subjects (7.6%, of total or 39% of confirmed) showed evidence of having suffered a nonimmediate reaction. The latter group were identified by giving a positive delayed direct challenge, and in 65% of the cases a delayed skin test response was detected. In most cases, these responses were to amino penicillins. Skin biopsies showed a lymphomonocytic cell infiltrate. Nonimmediate reactions to penicillins are a reproducible phenomenon, suggesting that a specific mechanism is responsible. By direct challenge, 93 Q of responders were positive to amino penicillins (10.3% ampicillin, 82.7% amoxicillin), indicating a major role for these penicillins in nonimmediate reactions. The high percentage (65%) of subjects in this group who showed delayed skin test responses, taken together with the biopsy results, suggests that a lymphocyte-mediated reaction occurred. However, the possibility that other mechanisms may also have been involved cannot be ruled out