Stimulation of human T cells with sulfonamides and sulfonamide metabolites

Exposure to sulfonamides is associated with a high incidence of hypersensitivity reactions. Antigen-specific T cells are involved in the pathogenesis; however, the nature of the antigen interacting with specific T-cell receptors is not fully defined.

General considerations on rapid desensitization for drug hypersensitivity - a consensus statement

Drug hypersensitivity reactions can occur with most drugs, are unpredictable, may affect any organ or system, and range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. However, for certain patients, the particular drug may be essential for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance of a compound responsible for a hypersensitivity reaction. It is performed by administering increasing doses of the medication concerned over a short period of time (from several hours to a few days) until the total cumulative therapeutic dose is achieved and tolerated. It is a high-risk procedure used only in patients in whom alternatives are less effective or not available after a positive risk/benefit analysis. Desensitization protocols have been developed and are used in patients with allergic reactions to antibiotics (mainly penicillin), insulins, sulfonamides, chemotherapeutic and biologic agents, and many other drugs. Desensitization is mainly performed in IgE-mediated reactions, but also in reactions where drug-specific IgE have not been demonstrated. Desensitization induces a temporary tolerant state, which can only be maintained by continuous administration of the medication. Thus, for treatments like chemotherapy, which have an average interval of 4 weeks between cycles, the procedure must be repeated for every new course. In this paper, some background information on rapid desensitization procedures is provided. We define the drugs and drug reactions indicated for such procedures, describe the possible mechanism of action, and discuss the indications and contraindications. The data should serve as background information for a database (accessible via the EAACI-homepage) with standardized protocols for rapid desensitization for antibiotics, chemotherapeutic agents, monoclonal antibodies/fusion proteins, and other drugs.

Cross-reactivity in drug hypersensitivity reactions to sulfasalazine and sulfamethoxazole

Sulfonamides are generally classified into 2 groups: antibiotics and non-antibiotics. Recent studies showed that patients allergic to sulfonamide antibiotics do not have a specific risk for an allergy to sulfonamide non-antibiotic. However, the anti-inflammatory drug sulfasalazine represents an important exception. Used in rheumatic diseases, it is classified as a non-antibiotic sulfonamide, but is structurally related to antibiotic sulfonamides. Therefore, we aimed to analyze in vitro the cross-reactivity between the antimicrobial sulfamethoxazole and the anti-inflammatory drug sulfasalazine.

Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

Exposure of patients with cystic fibrosis to sulfonamides is associated with a high incidence of hypersensitivity reactions.

Escherichia coli producing CMY-2 β-lactamase in bovine mastitis milk

An Escherichia coli isolate producing the CMY-2 β-lactamase was found in the milk of a cow with recurrent subclinical mastitis. The isolate was resistant to the antibiotics commonly used for intramammary mastitis treatment, such as penicillins, cephalosporins, β-lactam/β-lactamase inhibitor combinations, aminoglycosides, tetracyclines, and sulfonamides. This is the first report of a plasmid-mediated AmpC-producing Enterobacteriaceae in bovine milk.

Maculopapular drug eruptions

Maculopapular (exanthematous) reactions are the most common adverse drug eruptions affecting the skin. Several studies indicate that immunological mechanisms including cytotoxic T cells (CD4+ > CD8+), both type 1 (e.g. IFN- γ ) and type 2 (e.g. IL-5) cytokines and various chemokines are critically involved in the pathogenesis of these eruptions. While maculopapular exanthems can virtually be elicited by any drug, antimicrobials (e.g. Β -lactam antibiotic, sulfonamides), anticonvulsants, allopurinol, and NSAIDs are most frequently involved. Clinical manifestations are variable and range from faint macules to widespread erythematous and maculopapular lesions, which usually begin on the trunk, neck and upper extremities and subsequently spread downwards in a symmetrical fashion. Although the clinical course is often relatively mild, these exanthems may sometimes progress to erythroderma or represent the beginning of even more severe drug reactions like Stevens-Johnson syndrome, toxic epidermal necrolysis or a drug rash with eosinophilia and systemic symptoms. In most cases, management includes early withdrawal of the offending drug and usually supportive treatment with emollients, topical corticosteroids and systemic antihistamines depending on the severity of the eruption. Allergological work-up is recommended to provide the patient with appropriate information about the causative drug and possible alternatives for future use.

Antimicrobial resistance and resistance gene determinants in clinical Escherichia coli from different animal species in Switzerland

Antimicrobial susceptibility testing was performed on a total of 581 clinical Escherichia coli isolates from diarrhea and edema disease in pigs, from acute mastitis in dairy cattle, from urinary tract infections in dogs and cats, and from septicemia in laying hens collected in Switzerland between 1999 and 2001. Among the 16 antimicrobial agents tested, resistance was most frequent for sulfonamides, tetracycline, and streptomycin. Isolates from swine presented significantly more resistance than those from the other animal species. The distribution of the resistance determinants for sulfonamides, tetracycline, and streptomycin was assessed by hybridization and PCR in resistant isolates. Significant differences in the distribution of resistance determinants for tetracycline (tetA, tetB) and sulfonamides (sulII) were observed between the isolates from swine and those from the other species. Resistance to sulfonamides could not be explained by known resistance mechanisms in more than a quarter of the sulfonamide-resistant and sulfonamide-intermediate isolates from swine, dogs and cats. This finding suggests that one or several new resistance mechanisms for sulfonamides may be widespread among E. coli isolates from these animal species. The integrase gene (intI) from class I integrons was detected in a large proportion of resistant isolates in association with the sulI and aadA genes, thus demonstrating the importance of integrons in the epidemiology of resistance in clinical E. coli isolates from animals.

Genetic characterization of antimicrobial resistance in coagulase-negative staphylococci from bovine mastitis milk

Coagulase-negative staphylococci (CNS; n=417) were isolated from bovine milk and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Nineteen different species were identified, and Staphylococcus xylosus, Staphylococcus chromogenes, Staphylococcus haemolyticus, and Staphylococcus sciuri were the most prevalent species. Resistance to oxacillin (47.0% of the isolates), fusidic acid (33.8%), tiamulin (31.9%), penicillin (23.3%), tetracycline (15.8%), streptomycin (9.6%), erythromycin (7.0%), sulfonamides (5%), trimethoprim (4.3%), clindamycin (3.4%), kanamycin (2.4%), and gentamicin (2.4%) was detected. Resistance to oxacillin was attributed to the mecA gene in 9.7% of the oxacillin-resistant isolates. The remaining oxacillin-resistant CNS did not contain the mecC gene or mecA1 promoter mutations. The mecA gene was detected in Staphylococcus fleurettii, Staphylococcus epidermidis, Staph. haemolyticus, and Staph. xylosus. Resistance to tetracycline was attributed to the presence of tet(K) and tet(L), penicillin resistance to blaZ, streptomycin resistance to str and ant(6)-Ia, and erythromycin resistance to erm(C), erm(B), and msr. Resistance to tiamulin and fusidic acid could not be attributed to an acquired resistance gene. In total, 15.1% of the CNS isolates were multidrug resistant (i.e., resistant to 2 or more antimicrobials). The remaining CNS isolates were susceptible to antimicrobials commonly used in mastitis treatment. Methicillin-resistant CNS isolates were diverse, as determined by mecA gene sequence analysis, staphylococcal cassette chromosome mec typing, and pulsed-field gel electrophoresis. Arginine catabolic mobile element types 1 and 3 were detected in both methicillin-resistant and methicillin-susceptible Staph. epidermidis and were associated with sequence types ST59 and ST111. Because this study revealed the presence of multidrug-resistant CNS in a heterogeneous CNS population, we recommend antibiogram analysis of CNS in persistent infections before treatment with antimicrobials.

Occurrence and Genetic Characteristics of Third-Generation Cephalosporin-Resistant Escherichia coli in Swiss Retail Meat

Prevalence and genetic relatedness were determined for third-generation cephalosporin-resistant Escherichia coli (3GC-R-Ec) detected in Swiss beef, veal, pork, and poultry retail meat. Samples from meat-packing plants (MPPs) processing 70% of the slaughtered animals in Switzerland were purchased at different intervals between April and June 2013 and analyzed. Sixty-nine 3GC-R-Ec isolates were obtained and characterized by microarray, PCR/DNA sequencing, Multi Locus Sequence Typing (MLST), and plasmid replicon typing. Plasmids of selected strains were transformed by electroporation into E. coli TOP10 cells and analyzed by plasmid MLST. The prevalence of 3GC-R-Ec was 73.3% in chicken and 2% in beef meat. No 3GC-R-Ec were found in pork and veal. Overall, the blaCTX-M-1 (79.4%), blaCMY-2 (17.6%), blaCMY-4 (1.5%), and blaSHV-12 (1.5%) β-lactamase genes were detected, as well as other genes conferring resistance to chloramphenicol (cmlA1-like), sulfonamides (sul), tetracycline (tet), and trimethoprim (dfrA). The 3GC-R-Ec from chicken meat often harbored virulence genes associated with avian pathogens. Plasmid incompatibility (Inc) groups IncI1, IncFIB, IncFII, and IncB/O were the most frequent. A high rate of clonality (e.g., ST1304, ST38, and ST93) among isolates from the same MPPs suggests that strains persist at the plant and spread to meat at the carcass-processing stage. Additionally, the presence of the blaCTX-M-1 gene on an IncI1 plasmid sequence type 3 (IncI1/pST3) in genetically diverse strains indicates interstrain spread of an epidemic plasmid. The blaCMY-2 and blaCMY-4 genes were located on IncB/O plasmids. This study represents the first comprehensive assessment of 3GC-R-Ec in meat in Switzerland. It demonstrates the need for monitoring contaminants and for the adaptation of the Hazard Analysis and Critical Control Point concept to avoid the spread of multidrug-resistant bacteria through the food chain.

[Drug-induced Stevens-Johnson syndrome in a patient with AIDS]

The Stevens-Johnson syndrome is a severe potentially life-threatening form of the erythema multiforme, affecting both skin and mucous membranes. We present a case of a 49-year-old male patient with AIDS who developed a Stevens-Johnson syndrome while being treated with pyrimethamine, sulfadiazine and phenytoin for cerebral toxoplasmosis. Further diagnostic evaluation of this dangerous cutaneous affection may prove difficult for several reasons. In particular, in patients with AIDS who are more susceptible for adverse drug reactions and who are simultaneously receiving a variety of drugs with a considerable potential of cutaneous side effects, therapy cannot be withhold for lack of therapeutic alternatives. Moreover, the low lymphocyte count in this case may have made reliable testing with lymphocyte transformation studies impossible. The evaluation and the differential diagnosis of the drug-induced Stevens-Johnson syndrome are discussed. Especially long- and moderately long-acting sulfonamides belong to the most important agents that can cause a drug-induced Stevens-Johnson syndrome. The pathogenesis and the risk factors for cutaneous hypersensitivity reactions in HIV-infected patients are only poorly understood. These kind of reactions, however, seem to occur more often in patients with a more advanced immunodeficiency.

Emergence of Klebsiella pneumoniae co-producing NDM-1, OXA-48, CTX-M-15, CMY-16, QnrA and ArmA in Switzerland

Extensively drug-resistant (XDR) Klebsiella pneumoniae isolates usually carry a single carbapenemase (e.g. KPC, NDM, OXA-48-like). Here we describe an XDR K. pneumoniae of sequence type 101 that was detected in the screening rectal swab of a patient transferred from the intensive care unit of a hospital located in Belgrade (Serbia) to Bern University Hospital (Switzerland). The isolate was resistant to all antibiotics with the exception of colistin [minimum inhibitory concentration] (MIC≤0.125μg/mL), tigecycline (MIC=0.5μg/mL) and fosfomycin (MIC=2μg/mL). The isolate co-possessed class B (NDM-1) and class D (OXA-48) carbapenemases, class A extended-spectrum β-lactamase (CTX-M-15), class C cephalosporinase (CMY-16), ArmA 16S rRNA methyltransferase, substitutions in GyrA and ParC, loss of OmpK35 porin, as well as other genes conferring resistance to quinolones (qnrA), tetracyclines [tet(A)], sulfonamides (sul1, sul2), trimethoprim (dfrA12, dfrA14), rifampicin (arr-1), chloramphenicol (cmlA1, floR) and streptomycin (aadA1). The patient was placed under contact isolation precautions preventing the spread of this nearly untreatable pathogen.