Penicillin-allergic Individuals Research Articles

β-Lactam Allergy and Cross-Reactivity: A Clinician's Guide to Selecting an Alternative Antibiotic.

β-Lactams which include penicillins, cephalosporins, carbapenems, and monobactams are the most common antibiotic classes reported to cause allergic reactions to drugs. This review is mainly about published studies assessing the cross-reactivity among β-lactams in penicillin- or cephalosporin-allergic subjects by carrying out diagnostic tests with alternative β-lactams and, if appropriate, graded challenges. Several studies demonstrated that cross-reactivity connected with the β-lactam ring, causing positive responses to allergy tests with all β-lactams, is infrequent in subjects with an IgE-mediated allergy and anecdotal in those with a T-cell-mediated allergy. Identities or similarities of β-lactam side-chain structures are mainly responsible for cross-reactivity among these antibiotics. For example, in aminopenicillin-allergic subjects, cross-reactivity with aminocephalosporins could possibly be over 30%. On the other hand, in a few prospective studies of penicillin-allergic individuals, less than 1% of cases show a cross-reactivity between penicillins and both aztreonam and carbapenems. Particular patterns of allergy-test positivity observed in some studies that assessed cross-reactivity among β-lactams seem to indicate that prior exposures may be responsible for coexisting sensitivities. Therefore, pre-treatment skin tests with the related β-lactams are suggested before administering them via graded challenges to β-lactam-allergic patients who need alternative β-lactams.

De-labeling of β-lactam allergy reduces intraoperative time and optimizes choice in antibiotic prophylaxis

Suspected penicillin allergic individuals receive suboptimal non-β-lactams for intraoperative prophylaxis which may prolong operations and have negative clinical outcomes. We therefore studied if β-lactam de-labeling optimized choice of prophylactic antibiotics and improved intraoperative time efficiency. A multistep approach was used. It included a risk assessment tool by an allergist, β-lactam skin testing and oral provocation. To determine the value of de-labeling, we appraised intraoperative antibiotic choices and correlated them with time to first incision. A total of 194 patients were evaluated preoperatively. Four patients were diagnosed β-lactam allergic on skin testing. Of the remaining 190 skin test negative patients, 146 were β-lactam challenged. Only 5% reacted and were considered β-lactam allergic. Cefazolin became the perioperative antibiotic of choice for 77% of patients requiring antibiotic prophylaxis. Only 5 confirmed β-lactam allergic patients received intraoperative vancomycin. Patients avoiding use of vancomycin saved an average of 22 minutes in operative time. Of the 44 patients not having a β-lactam challenge, 36 received antibiotics and 18 (50%) of these were prescribed intraoperative cefazolin. Using this three step process, almost all of those claiming penicillin allergy were de-labeled. In most patients that were drug challenged, β-lactam antibiotics became the perioperative drug of choice. In cases where oral challenge was not used in the assessment only 50% were given a β-lactam. The reduced use of vancomycin minimized delays in initiation of incision time, thus improving operative efficiency. Ultimately, randomized controlled studies are required to objectively determine the effectiveness of this approach.

ASCIA‐P62: THE ROLE OF BASOPHIL ACTIVATION TEST IN THE DIAGNOSIS OF TYPE 1 HYPERSENSITIVITY REACTION MEDIATED BY BETA‐LACTAM ANTIBIOTICS

The currently available in vitro and in vivo tests for the diagnosis of type 1 hypersensitivity reactions towards beta-lactams lacks sensitivity and specificity and challenges carry carry significant risks. The basophil activation test (BAT) represents a sensitive and safe alternative for the same. All patients with presumed immediate hypersensitivity reactions to betalactams referred for testing to Immunology unit at RAH underwent BAT and other routine tests as per our protocol. Basophils were gated using CD45+/CD123+/HLADR- gate and CD63 upregulation (>15% as compared to baseline) was used as an activation marker. The BAT results were compared with the specific IgE (sIgE) and skin test (ST) along with the evocative clinical history +/− drug provocation test (DPT). A total of 75 BAT with various beta-lactams were performed in 17 patients consisting of 6 cephalosporin and 11 penicillin allergic individuals. In the 6 cephalosporin allergic individual, 4 exhibited significant basophil activation and two gave negative response to the culprit drug. These were in concordance with the ST and history, thus yielding a 100%sensitivity and specificity. In case of the 11 penicillin allergic individuals, one result was uninterpretable due to baseline activation with the negative control. In 6 out of 10 individuals, BAT results were concordant with the other tests whereas three false negative and one false positive were obtained with amoxicillin and benzyl penicillin respectively. In this group 4/5 gave the same result with both BAT and DPT, apart from one for which a false negative BAT result was obtained. Cross reactivity analysis in both of the beta-lactam group by BAT were found to be highly sensitive. The BAT appears to be a sensitive assay to diagnose beta-lactam allergy and assess cross-reactivity. Further data needs to be generated for the validation of the test in a larger cohort.

Physician approaches to beta-lactam use in patients with penicillin hypersensitivity

Beta-lactam antibiotics are widely used, but hypersensitivity reactions are common and difficult to manage. This study was designed to identify lack of knowledge regarding the safe use of alternative beta-lactams in penicillin-allergic patients and assess management differences between allergists and nonallergists. An electronic physician survey was sent to 623 providers in allergy, internal medicine, pediatrics, and family medicine, querying beta-lactam use in patients with a history of penicillin allergy. A total of 110 (17.7%) surveys were completed. For patients with a prior maculopapular rash to penicillin, most providers were uncomfortable prescribing penicillins again, although they would use other beta-lactams. In patients with an exfoliative dermatitis to penicillin, 46% of responders would not prescribe any beta-lactam again. For patients with a positive skin test to penicillin, only 45.1% of nonallergists were comfortable prescribing monobactams versus 62.5% of allergists; 30.3% of all responders would give a carbapenem. In patients with urticaria to penicillin, pediatricians were the most comfortable prescribing third- or fourth-generation cephalosporins. Providers (both allergists and nonallergists) were unfamiliar with the safety of prescribing penicillin in patients with history of maculopapular rash, the safety of monobactams, and low cross-reactivity with carbapenems in penicillin-allergic individuals. Nonallergists were also unfamiliar with the usefulness of penicillin skin testing. Improved education is needed to address these areas. Additionally, we found variability in responses regarding exfoliative dermatitis and comfort prescribing cephalosporins in patients with suspected IgE-mediated drug allergy to penicillin, highlighting the need for additional research in these areas.

Erythromycin

Erythromycin

Penicillin Allergy: Value of Including Amoxicillin as a Determinant in Penicillin Skin Testing

Background: Allergy to penicillins remains an important issue. Penicillin skin testing (PST) with major and minor determinants has been shown to be a highly valuable tool for identifying IgE-mediated penicillin allergy. The value of additional testing with side-chain-specific moieties from semisynthetic penicillins such as amoxicillin is not well-established in spite of the widespread use of these medications. Methods: A retrospective review of all consecutive inpatient PST results from 1995 to 2007 comprising 1,068 patients was performed in our institution on individuals with a self-reported history of beta-lactam allergy to assess the importance of including the amoxicillin determinant in a previously validated PST panel. Descriptive statistics were performed. The PST panel included penicilloyl-polylysine, penicillin G, penicilloate, penilloate and amoxicillin. Results: Of 1,068 patients, 243 (23%) had a positive skin test reaction on the PST panel. Testing with amoxicillin was positive in 30.9% of patients, the majority of whom (81%) were also positive to 1 or more standard penicillin reagents. Fourteen of the 243 positive patients (5.8%) had a positive skin test reaction only to amoxicillin. Additionally, the use of penicilloate and penilloate minor determinants in combination with penicillin G identified a greater percentage of penicillin-allergic individuals compared to using only penicillin G (22.6 vs. 6.6%), demonstrating their importance in the PST panel. Conclusions: These data indicate that the inclusion of the amoxicillin determinant appears to identify a small but important group of allergic individuals who may otherwise test negative on a PST panel.

Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis

Primary prevention of acute rheumatic fever is accomplished by proper identification and adequate antibiotic treatment of group A β-hemolytic streptococcal (GAS) tonsillopharyngitis. Diagnosis of GAS pharyngitis is best accomplished by combining clinical judgment with diagnostic test results, the criterion standard of which is the throat culture. Penicillin (either oral penicillin V or injectable benzathine penicillin) is the treatment of choice, because it is cost-effective, has a narrow spectrum of activity, and has long-standing proven efficacy, and GAS resistant to penicillin have not been documented. For penicillin-allergic individuals, acceptable alternatives include a narrow-spectrum oral cephalosporin, oral clindamycin, or various oral macrolides or azalides. The individual who has had an attack of rheumatic fever is at very high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention). The recommended duration of prophylaxis depends on the number of previous attacks, the time elapsed since the last attack, the risk of exposure to GAS infections, the age of the patient, and the presence or absence of cardiac involvement. Penicillin is again the agent of choice for secondary prophylaxis, but sulfadiazine or a macrolide or azalide are acceptable alternatives in penicillin-allergic individuals. This report updates the 1995 statement by the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee. It includes new recommendations for the diagnosis and treatment of GAS pharyngitis, as well as for the secondary prevention of rheumatic fever, and classifies the strength of the recommendations and level of evidence supporting them.

A Review of Evidence Supporting the American Academy of Pediatrics Recommendation for Prescribing Cephalosporin Antibiotics for Penicillin-Allergic Patients

Purpose of the Study. The American Academy of Pediatrics, in their evidence-based guidelines for treatment of otitis media and sinusitis, endorse the use of cephalosporin antibiotics for patients with reported allergies to penicillin. Many physicians, however, remain reluctant to prescribe such agents. This article reviews evidence in support of the American Academy of Pediatrics recommendations for administration of cephalosporins to penicillin-allergic children. Study Population and Methods. The author reviewed data from published studies related to penicillin and cephalosporin allergies in children and adults and in animal models. Results. Included in this review is an examination of the types and incidence of reactions to penicillins and cephalosporins, the frequency of cross-reactivity between these 2 groups of agents, and a thorough discussion of the clinical guidelines related to penicillin and cephalosporin allergy. Experimental and clinical studies that suggest that side chain–specific antibodies predominate in the immune response to cephalosporins, thereby explaining the lack of cross-sensitivity between most cephalosporins and penicillins. Specific recommendations for the treatment of patients on the basis of their responses to previously prescribed agents are summarized. Conclusions. The author concludes that there is a low but measurable (0.5%) attributable risk associated with administration of a first-generation or selected second-generation cephalosporin to a patient with penicillin allergy. This increased risk is not present for third- or fourth-generation cephalosporins or for second-generation molecules with non–cross-reactive side chains. Reviewer Comments. This is a very careful, comprehensive, and clinically useful review article. I recommend this article to physicians who would like to understand the evidence base and immunologic concepts underlying the use of cephalosporins in penicillin-allergic individuals.

Re-prescription of penicillin in patients who have had allergic-like reactions: Investigation using a large electronic medical record

Rationale To determine the frequency of re-prescription of penicillin to penicillin-allergic individuals and the risk of a second reaction in those who had a previous reaction. Methods A retrospective cohort study was conducted within the UK General Practice Research Database, an electronic medical record. All patients who had received a prescription for penicillin, 1987 through 9/2001, and those who had received a second prescription for a penicillin at least 60 days later, were selected. Patients with events consistent with a hypersensitivity (allergic-like) reaction within 30 days after the first prescription were compared to those without such events. Results 3,375,162 patients received at least one prescription for penicillin. Of 6212(0.18%) who experienced an allergic-like reaction to the initial penicillin prescription, 48.5% were given a second prescription for penicillin, compared with 59.8% of those without an initial allergic reaction (OR 0.6, 95% CI 0.6, 0.7). 2,017,957 patients were given two or more prescriptions for penicillin. 3014 (0.15%) experienced an allergic-like reaction with the first prescription and 57 (1.89%) of those had another reaction after the second prescription. The unadjusted OR of an allergic-like reaction with the second prescription for those who experienced an allergic-like reaction following the first prescription, compared with those who had no initial reaction, was 11.2 (95% CI 8.6, 14.6). Adjusting for confounding had no substantive effect on this result. Conclusions The risk of an allergic-like reaction to penicillin is markedly increased in those who have had a prior event. Re-prescription of penicillin to such patients is more frequent than anticipated.

Is Listeria monocytogenes an Important Pathogen for Prosthetic Joints?

Listeria monocytogenes usually causes meningitis or bacteremia, often in immunocompromised adults, pregnant women, or infants. We report a case of septic arthritis caused by L. monocytogenes in a patient with seronegative rheumatoid arthritis (RA) whose hip replacement was infected. She subsequently died, probably secondary to an adult respiratory distress syndrome, a rare complication of listerial infection. We also reviewed all 18 previously reported cases of septic arthritis caused by L. monocytogenes. The frequency of underlying RA, diabetes, neoplastic disease, and immunosuppressive therapy is prominent, as is the concurrent presence of a previous knee or hip replacement. Thus, the simultaneous presence of immune suppression and certain medical disorders or their treatment and a prosthetic joint should alert the clinician to the possibility that L. monocytogenes is the offending microbial agent. In contrast, in immunocompetent persons the usual Gram-positive cocci such as staphylococci, streptococci, or even pneumococci predominate. Although the outcome of appropriate treatment with penicillin or ampicillin alone (or with an aminoglycoside or trimethoprim/sulfamethoxazole in penicillin-allergic individuals) is usually favorable, complicating medical disorders can lead to death. Cephalosporins are rarely effective antimicrobial agents in patients with listeriosis.

Optimisation of the prevention and treatment of bacterial endocarditis.

This paper reviews currently established guidelines for the prevention and treatment of bacterial endocarditis. Endocarditis remains a life-threatening disease with substantial morbidity and mortality. Primary prevention of endocarditis, whenever possible, is therefore very important. In an individual with endocarditis, rapid diagnosis and effective treatment are essential to good patient outcome. The guidelines discussed here are largely based on those issued by the American Heart Association. While most cases of endocarditis are not attributable to an invasive procedure, certain procedures are associated with bacteraemia by organisms commonly associated with endocarditis, and antibacterial prophylaxis is recommended before such procedures. Patient cardiac conditions are stratified into high, moderate and negligible risk categories based on potential outcome if endocarditis develops. For oral, dental, respiratory tract, and oesophageal procedures (most often associated with viridans streptococci) the standard antibacterial regimen is oral amoxicillin. For gastrointestinal and genitourinary procedures (most often associated with enterococci), parenteral antibacterials are most often recommended. For high-risk patients, intramuscular or intravenous ampicillin and gentamicin (or vancomycin and gentamicin in penicillin-allergic individuals) is recommended. For moderate risk patients, an option of oral amoxicillin or parenteral ampicillin is offered. Treatment of bacterial endocarditis is guided by identification of the causative micro-organism. Approximately 80% of cases of endocarditis are due to the gram-positive cocci: streptococci and staphylococci. Other gram-positive organisms include enterococci (predominantly Enterococcusfaecalis and E. faecium) and the HACEK group of organisms (Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus [Haemophilus] actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). In general, for uncomplicated cases of endocarditis due to penicillin-susceptible viridans streptococci or Streptococcus bovis 4 weeks of benzylpenicillin (or ceftriaxone) is the preferred regimen for most patients aged >65 years. A 2-week course of treatment can be used when gentamicin is added, in patients at low risk for adverse events caused by gentamicin therapy. When endocarditis is caused by strains of viridans streptococci or S. bovis relatively resistant to penicillin, or by enterococci, both benzylpenicillin and gentamicin are recommended. For staphylococcal endocarditis on native heart valves, nafcillin or oxacillin with or without gentamicin is the preferred regimen. In prosthetic valve staphylococcal endocarditis, nafcillin (or oxacillin) with rifampicin and gentamicin is recommended. For all of the above situations, vancomycin is recommended for the patient allergic to penicillin (or methicillin). Finally, consideration of out-of-hospital therapy in selected patients is discussed.

Treatment of Acute Streptococcal Pharyngitis and Prevention of Rheumatic Fever: A Statement for Health Professionals

Primary prevention of acute rheumatic fever is accomplished by proper identification and adequate antibiotic treatment of group A β-hemolytic streptococcal (GAS) tonsillopharyngitis. Diagnosis of GAS pharyngitis is best accomplished by a throat culture. Penicillin (either oral penicillin V or injectable benzathine penicillin) remains the treatment of choice, because it is cost effective, has a narrow spectrum of activity, has long-standing proven efficacy, and GAS resistant to penicillin have not been documented. Various macrolides, oral cephalosporins, and other β-lactam agents are acceptable alternatives, particularly in penicillin-allergic individuals. The individual who has had an attack of rheumatic fever is at very high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention). The duration of prophylaxis depends on the number of previous attacks, the time lapsed since the last attack, the risk of exposure to streptococcal infections, the age of the patient, and the presence or absence of cardiac involvement. Penicillin is again the agent of choice for secondary prophylaxis, but sulfadiazine or erythromycin are acceptable alternatives in penicillin-allergic individuals. This report is an update of a 1988 statement by this committee. It expands on the previous statement, includes more recent therapeutic modalities, and makes more specific recommendations for the duration of secondary prophylaxis.

Heterogeneous T cell responses to beta-lactam-modified self-structures are observed in penicillin-allergic individuals.

To investigate the role of T cells in drug allergy, we stimulated PBMC from penicillin-allergic patients with reactive penicillin G itself or penicillin G coupled with human serum albumin (BPO-HSA). T cell clones specific for penicillin G or BPO-HSA were established and their phenotype and reactivity to both forms of the beta-lactam were analyzed. T cell clones stimulated by penicillin G were CD4 and CD8 positive, whereas BPO-HSA stimulated the growth of CD4+ T cells. The penicillin G-specific clones were HLA class I or class II restricted and processing was not required as fixed APC could still present penicillin G. In contrast, BPO-HSA has to undergo processing to stimulate BPO-HSA-specific T cell clones. In addition to classical APC, activated MHC class II expressing T cells could also restimulate the penicillin G-specific clones, indicating that various cell types might serve as APC. Penicillin G and BPO-HSA-specific T cell clones produced a heterogeneous cytokine pattern as most clones produced high amounts of IL-2, IFN-gamma, TFN-alpha, and rather variable levels of IL-4 and IL-5. Since no Ag processing was required, penicillin G may stimulate T cells by binding directly to MHC molecules on the cell surface or to their embedded peptide. Alternatively, it may bind to soluble proteins like HSA, which are processed and subsequently presented in an immunogenic form. These different modes of presentation, which elicit a variety of immunological reactivities, may explain the great heterogeneity of the clinical pictures seen in penicillin allergy.

Cross-Allergenicity and Immunogenicity of Aztreonam

The immunochemistry of aztreonam, the prototype of the new monobactam class of beta-lactam antibiotics, was studied in a series of experimental and clinical investigations. Rabbit antibodies to aztreonam and naturally occurring human antibodies that recognize aztreonam were found to have negligible cross-reactivity with benzylpenicillin, cephalothin, and cefotaxime. Aztreonam likewise displayed negligible cross-reactivity (less than or equal to 0.001%) with antibodies to penicillin (including human IgE antibodies to major and minor penicillin determinants) and to cephalothin. These studies suggest that aztreonam may be well tolerated by penicillin-allergic individuals, and this possibly is now being evaluated in clinical trials. Seven (6.25%) of 112 healthy persons tested had preexisting IgG antibodies to aztreonam in low titer, presumably as a result of exposure to naturally occurring cross-reacting moieties. Only two of seven patients with preexisting IgG antibodies to aztreonam had a rise in titer following aztreonam treatment. No IgE antibody to aztreonam was detected in serum specimens obtained on day 10 during any of the 112 courses of therapy. These clinical observations suggest but do not prove that aztreonam has only weak potential to elicit a drug-specific immunologic response.

Cephaloridine in Meningitis

To the Editor. —I read with interest the report of Newlands1 concerning meningitis after stapedectomy. It is essential that the otologic surgeon be prepared to handle this complication at an early stage to preserve the life of his patient. The use of cephaloridine may not be effective in treating or preventing meningitis, however. An article in a recent issue of the Medical Letter 2 based on a consensus of its infectious disease consultants recommends chloramphenicol as the first-choice antibiotic in penicillinallergic individuals with pneumococcal meningitis and states that cephalosporins are not generally recommended for the treatment of this disease. Likewise, a recent review by Moellering and Swartz ' emphasizes the poor penetration of cephalosporins into cerebrospinal fluid, representing one of the greatest drawbacks of this class of antibiotics. Fisher et al 4 found that only 76% of 72 patients with meningitis responded favorably to cephaloridine, despite intrathecal administration in many cases.

Nurse Practitioners and the Treatment of Sore Throats

The facts of the prevention of acute rheumatic fever are disarmingly simple. For a patient with an acute sore throat, we need to know simply, "Is the culture positive for hemolytic streptococci?" If not, the trouble and expense of antibiotics can be spared. If so, several effective options are open to the practitioner. A single injection of 1.2 million units of benzathine penicillin G (or 0.6 million in young children) is optimal treatment. The alternative of ten days of oral penicillin G therapy, or, for penicillin-allergic individuals, of erythromycin therapy, is also effective, but dependent on unpredictable patient fidelity. Unfortunately, the implementation of these principles is more complex than the simple facts of prevention suggest. The best programs for rapid and routine diagnosis of sore throats often have been mounted in communities in which rheumatic fever does not seem to be a problem at all. The streptococcal strains in such