Neo-antigens for the serological diagnosis of IgE-mediated drug allergic reactions to antibiotics cephalosporin, carbapenem and monobactam.

New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for ß-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty ß-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-ß-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-ß-lactam IgE antibodies with high sensitivity (< 0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of ß-lactam antibiotics renders improved molecular recognition events when the 4-member ß-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.

Phenobarbital-induced DiHS and ceftriaxone hypersensitivity reaction: a case of multiple drug allergy.

Patients with DiHS show an increased risk of sensitization to multiple drugs. We report a case of a young woman who developed cutaneous rash, lymphoadenopathy, malaise and fever after the introduction of phenobarbitale. Because of these symptoms, she was treated with ceftriaxone and she experienced a severe flare-up of the cutaneous and general reaction. Allergological work-up, by cutaneous and lymphocyte transformation test, confirmed a double sensitization to phenobarbital and ceftriaxone. In conclusion, the high risk of DiHS during anticonvulsive therapy should suggest caution in using additional drugs, because of an increased risk of multiple reactions.

Cross-reactivity of cefotetan and ceftriaxone antibodies, associated with hemolytic anemia, with other: cephalosporins and penicillin.

Most drug-induced immune hemolytic anemias since the late 1980s have been caused by the second- and third-generation cephalosporins, cefotetan and ceftriaxone, respectively. Cross-reactivity of cefotetan and ceftriaxone antibodies with other cephalosporins or penicillin has been studied only minimally. We tested 7 serum samples previously identified to contain cefotetan antibodies and one serum sample previously identified to contain ceftriaxone antibodies against 9 other cephalosporins, penicillin, and 7-aminocephalosporanic acid in the presence of RBCs and also used hapten inhibition to indicate cross-reactivity. Serum samples containing cefotetan antibodies showed some cross-reactivity with cephalothin and cefoxitin (and to a much lesser extent with penicillin and ceftazidime). The ceftriaxone antibodies showed very weak cross-reactivity with cefotaxime, cefamandole, and cefoperazone. There was very little cross-reactivity between cefotetan antibodies and the drugs tested in the present study. We have no data to determine whether the in vitro data relate to in vivo reactivity.

Boosted IgE response after anaphylaxis reaction to cefuroxime with cross-reactivity with cefotaxime.

BACKGROUND: Cefuroxime is a second-generation lactamase-stable cephalosporin. Its use is on the increase, and in recent years several reactions to this compound have been reported. OBJECTIVE: To describe a case of selective reaction to cefuroxime, showing a boosted immunoglobulin (Ig)E response after administration of this drug. METHODS: Specific serum IgE antibodies to several cephalosporins were monitored in a 52-year-old man after a selective systemic anaphylaxis attributable to cefuroxime, who showed a good tolerance to penicillin V during a single-blind, placebo-controlled challenge. RESULTS: Specific IgE levels to cefuroxime were not detected at the moment of the reaction but became positive 1 day after, increasing to peak at day 51, and still positive after 115 days. Through radioallergosorbent test inhibition, cross-reactivity between cefuroxime and cefotaxime was demonstrated. CONCLUSIONS: IgE-mediated reaction attributable to cefuroxime with cross-reactivity to cefotaxime was reported. A prompt evaluation undertaking skin tests and additional radioallergosorbent test studies with different betalactam derivatives improves the evaluation of subjects with allergic reactions to betalactams.

Cefotaxime desensitization.

We report the successful desensitization to cefotaxime in a patient with severe lumbar osteomyelitis of unknown bacteriology and hypersensitivity to the drug. Desensitization was carried out because of the unknown bacteriology, the favorable response to cefotaxime at that time, and hypersensitivity to other antibiotics. On the first day the patient received 1 mg cefotaxime intravenously. The dose was increased for 13 successive days to 4 g cefotaxime intravenously per day. No allergic reaction occurred during desensitization or within 4 weeks of observation under this therapy. Patients with severe infections of unknown bacteriology might benefit from desensitization if therapy with a second-choice antibiotic is impossible.

Cefodizime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Cefodizime is a third generation cephalosporin with a broad spectrum of antibacterial activity. Administered intravenously or intramuscularly, cefodizime 1 to 4 g daily for an average of 7 to 10 days produced clinical cure in 80 to 100% of patients (adults, elderly or children) with upper or lower respiratory tract infections or urinary tract infections, and in comparative trials cefodizime was as effective as other third generation cephalosporins. A single dose of cefodizime 1 or 2 g is also useful in treating lower urinary tract infections, particularly uncomplicated infections, with a rate of clinical success of 72 to 88%. Urogenital gonorrhoea, whether caused by beta-lactamase producing or non-beta-lactamase producing Neisseria gonorrhoeae, is very effectively treated by single dose therapy with intramuscular cefodizime 0.25 to 1 g (virtually 100% cured). Preliminary data from a small number of patients indicate that cefodizime may also be useful in the treatment of otitis media, sinusitis and gynaecological infections, and for the prophylaxis or treatment of surgical infections. The clinical efficacy of cefodizime in comparison with other third generation cephalosporins is superior to that predicted from in vitro results. This superior activity of cefodizime may be related to the relatively long elimination half-life of the drug or its ability to modify some functions of the immune system--a potentially important finding awaiting further investigation. Cefodizime is well tolerated and has a tolerability profile similar to other members of its class with systemic adverse events being primarily gastrointestinal or dermatological. Thus, limited comparative studies indicate cefodizime has the potential to become a useful alternative to current antimicrobial therapy for the treatment of a variety of infections. Cefodizime may be more convenient to administer than some other agents of its class as it may be given once or twice daily. While there are no trials comparing cefodizime to other third generation cephalosporins in immunosuppressed populations, preliminary information indicates cefodizime may be useful in this group.

[Antigenicity test of cefodizime sodium].

The antigenicity studies of a beta-lactam antibiotic, cefodizime sodium (THR-221), were examined in mice and guinea pigs and the following results were obtained. 1) In passive cutaneous anaphylaxis (PCA) with sera from BALB/c or C3H/He mice, a slight PCA reaction was observed only in BALB/c mice by using THR-221-ovalbumin (OVA) plus Freund's complete adjuvant (FCA) as the immunogen and THR-221 itself as the eliciting antigen. 2) Immunological cross-reactivity between THR-221 and CTX was present at the rat PCA reaction. 3) Antibodies against THR-221 were detected by PCA in guinea pigs. The anti-THR-221 antibodies gave PCA responses smaller than those of CMZ by using antibiotic plus FCA as the immunogen and the antibiotic-bovine serum albumin (BSA) as the eliciting antigen. 4) In the observation of active systemic anaphylaxis (ASA), no symptoms were observed in guinea pigs sensitized with THR-221 and provoked with THR-221-BSA. On the other hand, guinea pigs sensitized with THR-221 plus FCA by injecting THR-221-BSA showed fetal anaphylactic reactions. 5) The results of passive hemagglutination (PHA) also indicated that the PHA titer of THR-221 was lower than that of CMZ. 6) Protein binding property of THR-221 with human serum albumin was lower than other beta-lactam antibiotics. 7) Antibodies against THR-221-OVA by using THR-221-BSA as the eliciting antigen were detected in any tests above mentioned. It is concluded from these results that immunological activity of THR-221 was equivalent to the other beta-lactam antibiotics.

Influence of ceftizoxime on the immune system.

In the last few years the interest about the influence on host/parasite relations exerted by antibiotics has increased. In this study we have studied the effect of ceftizoxime, a third generation cephalosporin, on some functional parameters of human macrophages and granulocytes. Ceftizoxime does not seem to exert any stimulatory effect on phagocytosis and chemotaxis, but at the same time it allows these cells to explicate their functions during an infective process. A separate series of experiments was designed in order to investigate the immunogenicity of ceftizoxime and its immunological cross-reactivity versus other beta-lactam antibiotics. The low ELISA title of ceftizoxime indicates its weak immunogenic power. Cross-reactivity was also very low (title 1:25) when ceftizoxime was tested against the other antibiotics.

The influence of some cephalosporins on immunological response.

The effect of cefotaxime and cephradine on the activity of some immune mechanisms was investigated in mice. It was found that cefotaxime in therapeutic doses did not affect the humoral and cellular immune response against sheep erythrocytes, whereas cephradine suppressed the humoral response in doses corresponding to those used for the treatment of patients. The response in vitro of mouse spleen lymphocytes to PHA was suppressed by both cephalosporins; however this occurred at therapeutic concentrations only in the case of cephradine. Neither cephalosporin affected the phagocytic and chemotactic activity of mouse peritoneal macrophages and rabbit microphages.

Pharmacokinetic assessment of immunosuppressive activity of antibiotics in human plasma by a modification of the mixed lymphocyte reaction.

Antibiotics may impair the development and expression of specific or nonspecific immune responses. Prophylactic administration of antibacterial antibiotics is widely used in ICUs. We studied the immunosuppressive activities of cefotaxime, chloramphenicol, gentamicin, metronidazole, and rifamycin as a function of time after the administration of these drugs to ICU patients, finding that the last 4 drugs had an immunosuppressive activity detectable up to 8 h by a mixed lymphocyte reaction. When these antimicrobial agents were added to normal pooled plasma in concentrations similar to those obtained in vivo, a similar degree of inhibition was observed.

[Studies on the skin test of cefotiam and anti-cefotiam antibody].

Patients having previously not received cefotiam (CTM), a recently introduced cephem antibiotic, were subjected to skin tests with a 300 micrograms/ml solution of CTM in physiological saline before and after CTM therapy to detect sensitization with the drug. Anti-CTM antibody titration was carried out on sera from patients who showed a positive skin test and those who developed signs of hypersensitivity during CTM therapy. The results were as follows: Of 1,927 patients examined by skin test with CTM prior to initiation of CTM therapy, 31 patients (1.61%) showed positive reactions with formation of a wheal and erythema. There were 7 patients (0.36%) who proved negative in the skin test but developed mild symptoms of hypersensitivity in association with the skin test. The 847 patients negative on the CTM skin test were retested after a completion of CTM therapy, of whom 6 (0.71%) were found to have become positive showing formation of a wheal and erythema and 3 others (0.35%) showing a negative skin test developed mild adverse reactions associated with the skin test. Sixty-eight serum samples collected from the patients positive on the CTM skin test and those who developed manifestations of hypersensitivity following CTM therapy were examined for anti-CTM antibody by the Prausnitz-K ustner reaction, passive cutaneous anaphylaxis test and hemagglutination test. All proved negative in these tests. Of various background factors assessed, none was found to have causal relation to the skin reaction in any of the patients showing positive skin reactions to CTM.