ß-Lactam antibiotics form distinct haptenic structures on albumin and activate drug-specific T-lymphocyte responses in multiallergic patients with cystic fibrosis.

ß-Lactam antibiotics provide the cornerstone of treatment for respiratory exacerbations in patients with cystic fibrosis. Unfortunately, approximately 20% of patients develop multiple nonimmediate allergic reactions that restrict therapeutic options. The purpose of this study was to explore the chemical and immunological basis of multiple ß-lactam allergy through the analysis of human serum albumin (HSA) covalent binding profiles and T-cell responses against 3 commonly prescribed drugs; piperacillin, meropenem, and aztreonam. The chemical structures of the drug haptens were defined by mass spectrometry. Peripheral blood mononuclear cells (PBMC) were isolated from 4 patients with multiple allergic reactions and cultured with piperacillin, meropenem, and aztreonam. PBMC responses were characterized using the lymphocyte transformation test and IFN-γ /IL-13 ELIspot. T-cell clones were generated from drug-stimulated T-cell lines and characterized in terms of phenotype, function, and cross-reactivity. Piperacillin, meropenem, and aztreonam formed complex and structurally distinct haptenic structures with lysine residues on HSA. Each drug modified Lys190 and at least 6 additional lysine residues in a time- and concentration-dependent manner. PBMC proliferative responses and cytokine release were detected with cells from the allergic patients, but not tolerant controls, following exposure to the drugs. 122 CD4+, CD8+, or CD4+CD8+ T-cell clones isolated from the allergic patients were found to proliferate and release cytokines following stimulation with piperacillin, meropenem, or aztreonam. Cross-reactivity with the different drugs was not observed. In conclusion, our data show that piperacillin-, meropenem-, and aztreonam-specific T-cell responses are readily detectable in allergic patients with cystic fibrosis, which indicates that multiple ß-lactam allergies are instigated through priming of naïve T-cells against the different drug antigens. Characterization of complex haptenic structures on distinct HSA lysine residues provides a chemical basis for the drug-specific T-cell response.

Successful meropenem desensitization in a patient with cystic fibrosis.

OBJECTIVE: To report a case of successful meropenem desensitization in a patient with cystic fibrosis (CF) with documented hypersensitivity to multiple antibiotics including carbapenems. CASE SUMMARY: A 20-year-old white man with CF was admitted to the hospital for treatment of an acute pulmonary exacerbation caused by multidrug-resistant Burkholderia cepacia complex and methicillin-resistant Staphylococcus aureus (MRSA). Past treatments of his CF exacerbations were complicated by urticarial eruptions following administration of beta-lactams, including meropenem, and ototoxicity from aminoglycosides. Skin testing revealed hypersensitivity reactions to beta-lactam antibiotics including penicillin, piperacillin/tazobactam, ceftazidime, and imipenem. A literature review (MEDLINE, January 3, 2002) and communication with the manufacturer of meropenem revealed no specific information on desensitizing patients to this agent. Because of meropenem's activity against B. cepacia complex alone and in combination with other antimicrobials, a desensitization protocol was adapted and applied to meropenem in an effort to provide the most beneficial treatment available. A 12-dose escalation protocol was successfully employed without incident. DISCUSSION: Antimicrobial therapy is limited in CF patients by susceptibility profiles of common infecting organisms (e.g., Pseudomonas spp., B. cepacia complex, MRSA). Unfortunately, host responses may further reduce the utility of many effective antibiotic classes due to hypersensitivity and/or adverse reactions. Desensitization is a useful alternative that allows the administration of beneficial medications to patients with documented allergy histories. CONCLUSIONS: Meropenem is an important treatment option in the CF population, particularly due to its activity against B. cepacia complex. Successful desensitization using a dose-escalation protocol in patients with a documented carbapenem allergy will allow the most beneficial therapy to continue.