Immediate hypersensitivity reactions to beta-lactam antibiotics

Allergic reactions to the beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are a major factor limiting their use. Immediate hypersensitivity reactions to penicillins depend on the presence of preformed allergic (IgE) antibodies to several penicillin determinants. These materials can be used in in-vivo skin testing to exclude those patients at risk for immediate or accelerated allergic reactions. The cephalosporins have not had their relevant determinants defined as related to allergic reactions. The results of in-vivo challenges of patients with IgE to penicillin suggest the incidence of reactivity of cephalosporins in patients allergic to penicillin is less than generally appreciated. The monocyclic beta-lactam antibiotic, aztreonam (a monobactam), failed to show cross-reactivity with penicillin antibodies, because immune reactivity toward the monobactam was directed against side chain rather than nuclear determinants. On the other hand, the new bicyclic carbapenem beta-lactam drugs, represented by imipenem, showed extensive in-vivo cross-reactivity with penicillins.     

Hypersensitivity reactions to fluoroquinolones

Fluoroquinolone antibiotics cause immediate and delayed hypersensitivity reactions, and may also affect internal organs and circulating blood cells. The underlying pathomechanisms are only partly understood. The extent of cross-reactivity among different quinolones depends on the type of clinical manifestation and its underlying mechanism. Despite recent advances, reliable diagnostic tests are still lacking. Recent studies have shown quinolone-specific IgE in vitro in more than 50% of patients with immediate-type reactions and a considerable cross-reactivity with related compounds. In maculopapular drug exanthems from ciprofloxacin, specific T-cell clones were identified, and cross-reactivity to related compounds was detected in approximately 50% of the clones. From re-exposure studies in patients with exanthems, cross-reactivity appears to be lower. Cellular tests such as lymphocyte transformation tests are currently not very useful. For prick and intradermal skin tests, widely divergent nonirritant test concentrations have been recommended. Desensitization may be possible in selected patients.     

Hypersensitivity reactions to amsacrine

Five cases of hypersensitivity reactions to amsacrine are reported. These five cases are compared to the three cases previously published. Sixty-two reports on the clinical use of amsacrine in a variety of solid tumors and hematological malignancy were reviewed. Nine cases of hypersensitivity were described in the 2095 patients reported in these clinical trials. The approximate incidence of hypersensitivity to amsacrine is 0.4%.     

Hypersensitivity reactions to metronidazole

BackgroundHypersensitivity reactions to metronidazole are infrequently described. However, we believe that such reactions are increasing due to growing use of the drug for the treatment of amebiasis and anaerobe infections combined with other antibiotics. The present study assesses the need for oral provocation in patients with probable hypersensitivity reactions to metronidazole.MethodsWe performed cutaneous prick tests with spiramycin and metronidazole as well as epicutaneous tests with metronidazole at different concentrations in four patients with cutaneous reactions to Rhodogil^® (metronidazole plus spiramicyn). Controlled oral challenges were then carried out with placebo using erythromycin, spiramycin and metronidazole except in the last patient due to a positive prick test.ResultsOnly one patient showed a positive metronidazole prick test. The epicutaneous tests were negative. All patients tolerated erythromycin and spiramycin up to therapeutic doses. Oral provocation with metronidazole proved positive, the first patient presenting a delayed exanthema and the other two early erythema and itching.ConclusionsWe present four cases of cutaneous exanthemas caused by metronidazole (two early and two delayed) and probably mediated by an immune mechanism which we have only been able to demonstrate in one case. Taking into account the low sensitivity of the cutaneous tests (prick tests and epicutaneous tests), oral provocation must be considered the “gold standard” for establishing the diagnosis in many cases of hypersensitivity reactions to metronidazole.     

Hypersensitivity reactions to ethylenediamine in aminophylline

Adverse reactions to aminophylline are usually manifested by the toxic effects of theophylline on the gastrointestinal, cardiac, and central nervous systems. Reactions to its ethylenediamine component are less commonly encountered. We present here a patient who experienced severe exfoliative erythroderma after intravenous administration of aminophylline. Our investigations suggested that the reaction was a cell-mediated hypersensitivity to ethylenediamine.     

Binding of beta-lactam antibiotics to penicillin-binding proteins in methicillin-resistant Staphylococcus aureus

Binding affinity of penicillin-binding proteins (PBP) of Staphylococcus aureus for several beta-lactam antibiotics was examined in a methicillin-susceptible strain and in two methicillin-resistant strains, one heterogeneous and one homogeneous, to determine relationships between PBP binding and expression of resistance. PBPs 1-4 had similar affinities in all three strains. PBP 2a affinities were similar in both resistant strains. For the susceptible strain and for the susceptible subpopulation of cells in the heterogeneous strain, growth inhibition correlated with binding to PBPs 1-3, suggesting that these PBPs mediate susceptibility in both. For resistant cells, growth inhibition correlated only with binding to PBP 2a, suggesting that this is the target in resistant cells. Determination of binding affinity for PBP 2a or the concentration that inhibits growth of the most resistant subpopulation of cells should be included in evaluation of beta-lactam antibiotics for potential activity against methicillin-resistant strains of S. aureus.     

Selection of variants of pseudomonas aeruginosa resistant to beta-lactam antibiotics

Summary In broth cultures ofPseudomonas aeruginosa, containing carbenicillin or azlocillin, regrowth occurred after a period of bactericidal action, to reach visible proportions overnight. Regrowth in the presence of relatively high concentrations of carbenicillin or azlocillin could not be accounted for on the basis of growth of resistant variants nor as a result of drug inactivation. On the other hand, resistant variants could be selected from the regrowth which occurred at concentrations of carbenicillin or azlocillin only slightly in excess of the minimum inhibitory concentration (MIC). Antibiotic resistant variants could also be isolated from individual colonies growing on agar plates containing carbenicillin, ticarcillin, azlocillin or piperacillin at concentrations above the MIC for the majority of the population. Two types of resistant variant were isolated. The first showed a 2–5 fold increase in resistance to carbenicillin, ticarcillin, azlocillin and piperacillin while -lactamase production in these variants appeared to be unchanged. The second type of resistant variant showed unchanged sensitivity to carbenicillin and ticarcillin, or only a slight increase in resistance, whereas resistance to azlocillin and piperacillin was increased as much as 40-fold or more. These variants showed increased constitutive -lactamase production and may be derepressed mutants of the parent culture. Variants of this type were readily selected by culture in the presence of azlocillin or piperacillin but only infrequently as a result of culture in the presence of carbenicillin or ticarcillin. The existence in cultures ofP. aeruginosa of variants showing elevated -lactamase production may account at least in part for the effect of inoculum size on the activity of azlocillin and piperacillin againstP. aeruginosa and the marked discrepancy between MIC and minimum bactericidal concentration (MBC) which is characteristic of the ureido penicillins.

---

Isolierung Beta-Laktam-resistenter Varianten von Pseudomonas aeruginosa

Zusammenfassung In Carbenicillin-und Azlocillin-haltigen Flüssigkulturen wächstPseudomonas aeruginosa nach einer bakteriziden Wirkungsphase des Penicillins erneut an und erreicht ein sichtbares Wachstum in einer Übernachtkultur. Das erneute Wachstum in Gegenwart relativ hoher Carbenicillinoder Azlocillin-Konzentrationen kann weder durch Inaktivierung der Substanzen noch durch das Wachstum resistenter Varianten erklärt werden. Andererseits konnten resistente Varianten aus solchen Kulturen isoliert werden, in denen in Gegenwart geringgradig suprainhibitorischer Carbenicillin- oder Azlocillin-Konzentrationen erneutes Wachstum auftrat. Antibiotikaresistente Varianten konnten auch von individuellen Kolonien isoliert werden, die auf Agarplatten wuchsen, die Carbenicillin, Ticarcillin, Azlocillin oder Piperacillin in geringgradig suprainhibitorischen Konzentrationen enthielten. Zwei Typen resistenter Varianten wurden isoliert; die erste zeigte einen 2- bis 5fachen Resistenzanstieg gegenüber Carbenicillin, Ticarcillin, Azlocillin und Piperacillin. Die Bildung von -Laktamase in diesen Varianten scheint nicht verändert zu sein. Der zweite Typ resistenter Varianten zeigte unveränderte Sensibilität gegenüber Carbenicillin und Ticarcillin bzw. nur einen geringfügigen Resistenzanstieg, wogegen jedoch die Resistenz gegenüber Azlocillin und Piperacillin um das 40fache und mehr anstieg. Diese Varianten bildeten in erhöhtem Maße eine konstitutive -Laktamase und könnten derepremierte Mutanten des ursprünglichen Stammes darstellen. Varianten dieses Typs konnten leicht von Kulturen isoliert werden, die in Gegenwart von Azlocillin und Piperacillin, selten aber nur von Carbenicillin oder Ticarcillin wuchsen. Die Existenz dieser Varianten mit erhöhter -Laktamasebildung inP. aeruginosa-Kulturen kann verantwortlich sein für die Abhängigkeit der minimalen Hemmkonzentration von Azlocillin und Piperacillin vom Inokulum und die ausgeprägte Diskrepanz zwischen der minimalen Hemmkonzentration (MHK) und der minimalen bakteriziden Konzentration (MBK), die für Ureidopenicilline charakteristisch ist.

     

Hypersensitivity reactions to oxaliplatin and other antineoplastic agents

Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States.     

Antibacterial activity of beta-lactam antibiotics in experimental meningitis due to Streptococcus pneumoniae

In order to define the characteristics of the antibacterial activity of beta-lactam antibiotics in the treatment of bacterial meningitis, the relationship between cerebrospinal fluid (CSF) drug concentrations and the rate of bacterial killing was investigated for penicillin G and four new cephalosporins in an animal model of meningitis due to Streptococcus pneumoniae. All five drugs showed a significant correlation between increasing drug concentrations in CSF and increasing bactericidal rates. Minimal activity was observed in CSF at drug concentrations of approximately the broth minimal bactericidal concentration (MBC). Maximal activity occurred with CSF concentrations 10-30 times higher. In vitro tests did not reproduce the unique correlation of increasing drug concentrations and killing activity found in vivo. When evaluating new beta-lactam antibiotics for the treatment of bacterial meningitis, it is reasonable to establish a minimum standard of CSF drug concentrations of greater than or equal to 30 times the MBC against the infecting organism.     

Comparative nephrotoxicity among aminoglycosides and beta-lactam antibiotics

Summary Five hundred thirty-seven elderly male patients with complicated urinary tract infections who received treatment with aminoglycosides (gentamicin, tobramycin, sisomicin, or netilmicin) or -lactam antibiotics (ticarcillin, amoxicillin, or cefamandole) were reviewed with respect to nephrotoxic reactions. Nephrotoxicity was defined as a 31% increase in serum creatinine during treatment for patients with pretreatment creatinine clearances 30 ml/min, or an 18% increase in those patients with a pretreatment creatinine clearance < 30 ml/min. Renal toxicity correlated with advanced age and reduced renal function in the aminoglycoside groups. For patients with pretreatment creatinine clearances 30 ml/min, treatment groups were comparable for all relevant clinical and therapeutical features. Among these treatment groups, tobramycin was the least nephrotoxic of the aminoglycosides. Nephrotoxicity, as defined above, was lower for the -lactam antibiotics than for the aminoglycoside groups combined; however, the decrease was not significant. The mean serum creatinine, however, increased significantly in all patients following aminoglycoside treatment and this increase was significantly higher than in the -lactam group.

---

Vergleich der Nephrotoxizität von Aminoglycosiden und -Lactam Antibiotika

Zusammenfassung 537 ältere männliche Patienten mit komplizierten Harnwegsinfektionen, die mit Aminoglycosiden (Gentamicin, Tobramycin, Sisomicin oder Netilmicin) oder -Lactam Antibiotika (Ticarcillin, Amoxicillin oder Cefamandol) behandelt wurden, wurden im Hinblick auf nephrotoxische Reaktionen überprüft. Nephrotoxizität wurde definiert als Anstieg des Serum-Kreatinin um 31% unter der Behandlung bei prätherapeutischer Kreatinin-Clearance von 30 ml/min oder um 18% bei Patienten, die vor der Behandlung eine Kreatinin-Clearance von < 30 ml/min aufwiesen. In den Aminoglycosid-Gruppen korrelierte die renale Toxizität mit fortgeschrittenem Alter und verminderter Nierenfunktion. Bei Patienten mit einer Kreatinin-Clearance von 30 ml/min waren alle Behandlungsgruppen in sämtlichen wichtigen klinischen und therapeutischen Elgenschaften vergleichbar. Tobramycin wies in diesen Gruppen unter den Aminoglycosiden die geringste Nephrotoxizität auf. Die Nephrotoxizität war entsprechend der oben genannten Definition in den -Lactam-Antibiotikagruppen geringer als in den Aminoglycosidgruppen; jedoch war dieser Unterschied nicht signifikant. Hingegen kam es bei allen Patienten nach Aminoglycosid-Behandlung zu einem signifikanten Anstieg mittleren Serum-Kreatinin-Spiegels, und dieser Anstieg war signifikant höher als in der -Lactam-Gruppe.