Serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae strains isolated in Japan after introduction of the routine immunization program.

Pneumococcal vaccines have reduced the incidences of Streptococcus pneumoniae infections among children and adults, but a relative increase in the prevalence of non-vaccine serotypes has been reported. To follow the changing epidemiology of pneumococcal diseases, capsular serotyping and antimicrobial susceptibility testing was performed on 534 pneumococcal isolates obtained from a hospital in Japan after routine immunization was launched, between October 2014 and May 2016. Serotype distributions and antimicrobial susceptibilities were evaluated among the total patient population, and were compared by age and sample groups and by serotype group, respectively. Serotypes targeted by the 13-valent pneumococcal conjugate vaccine (PCV13) were identified in 14.6%, 44.5%, and 40.2% of the samples from the <5, 5-64, and ≥65 year age groups, respectively. The 23-valent pneumococcal polysaccharide vaccine serotypes (PPSV23) were identified in 42.4%, 68.2%, and 63.1% of the samples, respectively; whereas non-PCV13 serotypes or non-PPSV serotypes (NVT) comprised 46.8% of all isolates. Among NVT, strain 35B was the most frequently isolated, followed by 15A, particularly in sputum samples collected from children <5 years old. Meanwhile, serotype 3, which is targeted by the PCV13 and PPSV23, was the most prevalent among patients aged ≥65 and 5-64 years. Antimicrobial susceptibility testing revealed that 88.9% and 81.0% of serotype 35B was non-susceptible to penicillin and meropenem, respectively, and 89.4% of 15A was non-susceptible to penicillin. Our data suggest rapid effects of pneumococcal vaccines and progression of serotype replacement. Besides invasive potential, the increased prevalence of non-vaccine serotypes with highly non-susceptible to penicillin was a concern. Continuous monitoring of pneumococcal serotypes and antimicrobial susceptibility is necessary for developing optimal preventive strategies.

Hypersensitivity reactions to penicillins: studies in a group of patients with negative benzylpenicillin G skin test.

BACKGROUND: Although skin tests are usually employed to evaluate current penicillin allergy status, a negative result does not exclude hypersensitivity. There is a need for accurate in vitro tests to exclude hypersensitivity. A radioallergosorbent test (RAST) is a potentially good supplementary approach, but there is little information on the suitability of this method to diagnose penicillin hypersensitivity in subjects with a negative skin test to benzylpenicillin. METHODS: A total of 133 patients with a negative skin test to benzylpenicillin G (PG) and all of whom developed allergic reactions to PG were studied. RAST was used to detect eight kinds of specific IgE antibodies to penicillins in serum, which included four kinds of major and minor antigenic determinants to four penicillin drugs. The combination sites for the specific IgE antibodies were studied by RAST inhibition test. RESULTS: The rate of positive reactions for the specific IgE antibodies was 59.40% (79/133). Of the eight kinds of antigenic determinants, the positive rates for specific IgE against the major and minor determinants were 39.10% (52) and 42.86% (57) respectively. Of the four drugs, positive cases only to PG were 10 (7.5%), were significantly fewer than the cross-reacting positive cases (36) to PG (P < 0.01). In the RAST inhibition studies all drugs exhibited good inhibitory potencies, and in some instances the side-chain of the penicillins could induce specific responses with a variable degree of cross-reactivity among the different penicillins. CONCLUSION: Radioallergosorbent test is a good complementary test in persons who are skin-test negative with PG, and the sensitivity of RAST increases with increasing specificity of IgE antibodies to be detected. 6-APA and the groups, making part of the different side-chains on penicillins, all contributed to the cross-reactivity.

Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy.

BACKGROUND: We developed a clinical pathway to optimize the use of antimicrobials by decreasing vancomycin use in preoperative patients with a history of penicillin allergy. OBJECTIVE: To decrease the use of vancomycin in surgical patients with a self-reported penicillin allergy. METHODS: In June 2002, same-day allergy consultation and penicillin skin testing were made available for preoperative patients with self-reported penicillin allergy at the preoperative evaluation (POE) clinic. We reviewed the penicillin allergy skin test results, recommendations, and beta-lactam antibiotic administration outcomes from July 1, 2002, to September 16, 2003. RESULTS: A total of 1,204 of 11,819 patients were evaluated for beta-lactam allergy at the POE clinic. Of these, 1,120 were approved by the institutional review board for inclusion in the study and 9 were excluded from the study. Of the remaining 1,111 patients, 1,030 (93%) underwent skin testing for penicillin allergy. Forty-three (4%) had a positive skin test result to penicillin. A total of 947 (85%) of the 1,111 patients with a history of beta-lactam allergy were advised to use a beta-lactam antibiotic, and 164 (15%) were advised to avoid beta-lactams. A total of 955 patients (86%) actually received preoperative antibiotics. Of these 955 patients, 716 (75%) received cefazolin, and only 149 (16%) received vancomycin compared with 30% historical controls (P < .01). Among the patients with a negative penicillin skin test result who received a cephalosporin, 5 (0.7%) of 675 experienced an adverse drug reaction to a cephalosporin. CONCLUSIONS: Establishment of a clinical pathway in a preoperative clinic that includes allergy consultation and penicillin skin testing reduced vancomycin use to only 16% in surgical patients with a history of beta-lactam allergy.

Reacciones tardías en las pruebas cutáneas con penicilina: correlación con la anamnesis / Late reactions to penicillin skin tests: correlation with history

Antecedentes y objetivos: La utilidad de las pruebas cutáneas en el diagnóstico de la alergia a las penicilinas está bien demostrada; sin embargo, no siempre existe una buena relación entre la anamnesis y el resultado de estas pruebas. Casos clínicos: Se presentan tres pacientes en los que la anamnesis, ya por el tiempo de aparición de la reacción, ya por el tipo de lesión, sugiere una hipersensibilidad inmediata o acelerada con posible participación de la IgE; las pruebas cutáneas fueron positivas de forma muy tardía, entre 2 y 3 semanas después de su aplicación. Conclusión: No siempre existe un patrón clínico que permita predecir el resultado de las pruebas cutáneas por lo que aconsejamos realizar el estudio alergológico aún cuando la sospecha de hipersensibilidad sea baja

Background and objectives: The useful of skin tests in diagnosis of penicillin allergy is well known; however, there is not always a good correlation between history and results from these tests. Cases: Three cases are presented in which the history, due to the time of appearance or the type of lesions, suggests an potentially IgE-mediated immediate or accelerated hypersensitivity; skin tests were positive very late, between 2 and 3 weeks after their application. Conclusion: There is not always a clinic pattern which permits to predict results of skin tests, so we recommend to perform the allergy study even with a low index of suspicion

[Hypersensitivity to penicillin therapy in the course of treatment: a case report]. / Nadwrazliwosci na penicyline powstajaca w czasie leczenia--opis przypadków.

Adverse reactions to benzylpenicillin are well known. Full allergy testing is time-consuming, expensive and doesn't exclude anaphylaxis to penicillin. It is accepted that penicillin allergy is overdiagnosed. Therefore clinical observations are not useful for pathogenesis research without follow up examination. 100 patients with negative skin test before and with symptoms of penicillin hypersensitivity during treatment was diagnosed. We report only 4 cases of patients, whose allergy to penicillin was confirmed by the same skin test. They had received penicillin during serious bacterial infections and had experienced allergic symptoms. Skin rush, asthma or hypotension have been observed during treatment with penicillin. Immediate hypersensitivity was confirmed by positive skin test after treatment. This study reinforce findings of our experimental study, when intraperitoneal injections of penicillin and Freunds adjuvant or bacterial lysate lead to anaphylactic shock and death of guinea pigs. Eastaway et all published similar case report of gas gangrene complicated by penicillin allergy. These observations indicate that pathogenesis of penicillin allergy may be associated with bacterial infection and nonspecific inflammation.

Allergy to antibiotics: T-cell recognition of amoxicillin is HLA-DR restricted and does not require antigen processing.

Allergic immune responses are initiated and maintained by T cells that recognize peptidic fragments of allergens in the context of major histocompatibility complex (MHC) class II molecules. An anomaly of this model exists in the T-cell response to haptens. Haptens are nonpeptide antigens that alone are too small to provoke an immune response. Nevertheless, T-cell responses to haptenic allergens clearly occur and are critically involved in allergic immune responses to drugs such as penicillin. Although the mechanisms that generate T-cell epitopes from protein antigens are well understood, haptens create T-cell epitopes by alternative mechanisms. These may include binding of haptens directly to preformed MHC-peptide complexes on the cell surface, or indirect association with MHC molecules after conjugation with self cell surface or serum proteins that are then processed and presented as haptenated peptide antigens. Which of these unorthodox mechanisms of epitope generation is dominant in allergy to penicillin is unknown. This study aims to determine the nature of the epitopes recognized by amoxicillin-specific T cells from allergic donors, and to clarify whether T-cell responses to penicillin antibiotics are MHC-restricted and require haptenated self proteins to be processed before recognition. Human T-cell lines specific for amoxicillin were raised and used in assays with processing-disabled and MHC-class II-typed antigen-presenting cells to determine the MHC restriction and processing requirements of T cells recognizing amoxicillin. Fixation of antigen-presenting cells with paraformaldehyde, before or after pulsing with amoxicillin, established that T cells can recognize amoxicillin-containing epitopes with a similar efficiency irrespective of whether the antigenic conjugate has been internalized and processed. These results suggest that amoxicillin can bind directly to performed MHC-peptide complexes and need not necessarily involve the processing of haptenated self carrier proteins before recognition of the conjugate by amoxicillin-specific T cells.

beta-Lactam drug allergens: fine structural recognition patterns of cephalosporin-reactive IgE antibodies.

Lack of experimental findings on the spectrum of cephalosporin allergenic determinants has hindered diagnosis of adverse reactions to these drugs and retarded understanding of allergenic cross-reactions between cephalosporins and between cephalosporins and penicillins. Subjects allergic to the widely used cephalosporin antibiotic cefaclor have serum immuno globulin (Ig) E antibodies that react with the drug. Quantitative hapten inhibition studies employing sera from subjects allergic to cefaclor revealed fine structural recognition differences between the combining site specificities of cefaclor-reactive IgE antibodies in the sera of different subjects. Unlike penicillins, where discrete side chain or thiazolidine ring determinants alone may be recognized, IgE binding determinants on cefaclor encompassed the entire molecule. Fine structural recognition specificity differences at positions R1 (side-chain) and R2 (substituent attached to dihydrothiazine ring) were detected between IgE antibodies in different sera. Some antibodies showed clear preferential recognition of the aminobenzyl group at position R1 and Cl at R2 while with others, a greater degree of recognition tolerance was seen at R1 where, for example, the aminohydroxybenzyl or aminodihydrobenzyl groups were recognized, and at R2 where a methyl or even an ester group was tolerated. As with the penicillins, cephalosporins as allergens cannot simply be considered as a group of compounds with a common allergenic determinant structure. IgE antibodies that bind to cefaclor show great heterogeneity indicated by clear, fine structural differences in recognition of the R1 and R2 groups on the drug.

Basic aspects related to penicillin-allergy skin testing: on the variability of the hapten-paratope interaction.

Ampicillin and benzylpenicillin conjugated to human serum albumin were used as immunogens in order to obtain antihaptenic IgG responses in outbred guinea pigs according to different schedules, all involving complete Freund's adjuvant. The individual responses were characterized by ELISA and by ELISA inhibition using ampicillin, benzylpenicillin, and carbenicillin peptidic conjugates for coating and for inhibition. In several instances, drastically reduced cross-reactivity and even its absence were observed, although the penicillin antigens differ only in the side-chain. The notion that the invariantly present thiazolidine ring will always provide significant binding to antibodies against all penicillins differing only in the side-chain has to be dropped. The experiments were performed in relation to newer findings of clinical penicillin-allergy skin testing which suggest that benzylpenicillin-based reagents alone are not able to detect or predict all reactions against semisynthetic penicillins. The experimental evidence here obtained corroborates this conclusion.

Demonstration of human, rye grass pollen extract-specific, helper and suppressor stimulating activity of modified allergens by effects on in vitro hapten-specific antibody production.

An in vivo system is described in which penicilloyl antibody was produced from peripheral leucocytes of a grass pollen-sensitive patient who had received penicillin therapy, by challenge of the cells with penicilloyl-grass pollen extract conjugate. Incubation of these leucocytes with a number of modified preparations of grass pollen extract with various T-cell-stimulating properties was shown to affect penicilloyl antibody production. Both chymotryptically fragmented rye grass pollen extract and a conjugate of f met-leu-phe and rye grass pollen extract enhanced penicilloyl-specific antibody similarly to the enhancement induced by unmodified extract, though at high concentration some suppression was seen. A conjugate of polysarcosine and rye grass pollen extract, previously shown to cause antibody suppression in mice, was similarly suppressive for penicilloyl-specific antibody. The system therefore shows potential for the evaluation of the effects of modified allergen treatment on antibody levels via T-cell mechanisms.

Contact sensitivity in guinea pigs to different penicillins.

The ability of penicillins of varying lipophilicity to induce and elicit cellular allergic responses were analysed in guinea pigs. Epicutaneous application of the penicillins benzylpenicillin (Bp), cloxacillin (Clox) and Bacampicillin (Bamp) did not cause any unspecific skin irritation. Intracutaneously injected, however, Bamp, Clox and to a lesser extent Bp caused irritation at concentrations of 1.25%. Solutions of 0.12% of penicillins were inactive in this respect. Cellular allergic responses were induced with Bp, Bamp and Clox after repeated epicutaneous application. The magnitude of responses was related to the lipophilic properties of the penicillins, Bamp being superior. In the guinea pig maximization (GPM) test of Magnusson and Kligman employing intradermal injections of the penicillins with Freund's complete adjuvant, similar sensitizing abilities of the three penicillins were observed. The cellular allergic responses were elicited with Bp, Bamp, Clox and in addition ampicillin and the 1'-ethoxycarbonyloxyethyl ester of Bp. An extensive cross-reactivity between the penicillins was seen in Bp- and Bamp-sensitized animals, whereas the Clox-sensitized animals showed a specificity limited to Clox. Bamp was shown to possess a superior activity to elicit reactions, possibly due to its lipophilic properties together with an irritating effect exerted by the NH2 group.

A comparative study of the immunogenicity of some penicillins and of their cross reactions.

The immunogenicity of four penicillin preparations was comparatively investigated by titration of penicilloyl (PO) specific hemagglutinating antibodies found in sera of rabbits inoculated with equimolecular amounts of these penicillins incorporated in Freund incomplete adjuvant. Benzylpenicillin (BP) was shown to be endowed with the highest immunogenicity, while oxacillin (OX), ampicillin (AM) and Amoxil (AX) were found significantly less immunogenic. By examining comparatively the titers of hemagglutination reactions given by the sera of each animal with erythrocytes coated with the penicillin used for its immunization as well as with the other penicillins investigated, important cross immunological reactions were found in all of the cases. Interestingly, the cross reactions produced by AM- and AX-specific antisera with heterologous penicillins were apparently higher than the reactions obtained with the homologous penicillin. No significant differences were found concerning the ability of the four penicillins to form PO conjugates with BGG. Thus, the differences in immunogenicity exhibited by the four penicillin preparations may not be explained in this way.

Antigens in penicillin allergy. V. On the relative allergenic potency of antigens carrying penicilloyl determinants derived from azidocillin, ampicillin and benzylpenicillin.

The effects of the different acyl side chains of azidocillin, ampicillin and benzylpenicillin on the immunogenic potency of penicilloylated antigens as well as on the specificity of the developed antibodies were investigated in CBA mice. The antigens used were penicilloylated bovine gammaglobulin (BGG), bovine serum albumin (BSA) and human serum albumin (HSA). Immunization was performed with injection of high doses of antigens together with adjuvant or by injection of minute amounts of antigen over periods of 10 days. IgE antibodies were recorded with PCA in rats and IgG antibodies were measured with a double antibody assay. The nature of the carrier as well as the number of epitopes was found to influence the development of antibodies irrespective of the immunization schedule used. The immunogenic activity of the PO-BSA antigens was related to the epitope density. The PO-BSA antigens were, in contrast to the PO-BGG antigens, weak immunogens in the CBA mice. The acyl side chains of the different penicillins influenced the induction and specificity of the IgE antibody responses obtained after daily treatment.

Induction if immunological tolerance to the major antigenic determinant of penicillin: a therapeutic approach to penicillin allergy.

High titered IgE, IgG, and IgM antibody responses to the major antigenic determinant of penicillin, the benzylpenicilloyl hapten, were elicited by the intraperitoneal injection of the hapten coupled to keyhole limpet hemocyanin mixed with the appropriate adjuvant. However, treatment of such mice with the benzylpenicilloyl derivatized synthetic copolymer of D-glutamic acid and D-lysine, either before or after primary immunization, resulted in significant suppression of the subsequent anti-benzylpenicilloyl antibody responses of the IgE and IgG classes, as measured at the humoral and cellular levels. The state of tolerance induced by benzylpenicili-poly(DGlu, Lys) was highly specific, of long duration, and could be induced in a manner that would be appropriate for clinical use. These results provide a direct demonstration of the potential application of the poly(DGlu, Lys) immunotherapeutic approach to penicillin allergy in humans.

[Evaluation of exanthemas following high-dosage intravenous penicillin combinations in intensive care]. / Zur Wertung von Exanthemen nach hochdosierten intravenösen Penicillinkombinationen in der Intensivpflege

118 patients of a non specialized intensive care unit have been studied, all of them under high dose bactericidal cover (10 MIU of Na-Penicillin G and 2,0 Ciclacillin q 12 hrs.) for a period of days to 4 weeks. In 17 (14,4%) a skin rash was observed. 10 of these could be studied using special techniques (radial immunodiffusion, passive hemagglutination, RIST and RAST), however in none of these cases there was a hint of the existence of penicillin specific antibodies. In 6 patients also skin tests were performed. There was no immediate type reaction, only twice delayed type reactions occured to Na Pencillin G.6 patients had continuing treatment on spite of the rash and without further steps the effluorescences vanished within 3-6 days. Therefore continuation of the antibiotic therapy in spite of rash along with strict clinical and laboratory monitoring seems to be preferable to a hastened change of antibiotic regime