Sulfonamide desensitization in solid organ transplant recipients: A protocol-driven approach during the index transplant hospitalization.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line agent for Pneumocystis jiroveci pneumonia (PJP) prophylaxis for solid organ transplant (SOT) recipients because of its efficacy for this indication, extended antimicrobial coverage, and favorable cost. Reported sulfonamide allergy is not uncommon and often results in TMP-SMX avoidance. Desensitization offers an efficacious and cost-effective alternative to TMP-SMX avoidance. Herein, we reviewed our experience with desensitization during the index transplant hospitalization among 52 SOT recipients with history of a non-anaphylactic sulfonamide allergy. Of those enrolled in the desensitization protocol, 92% (48/52) completed the protocol, with nearly 80% (41/52) still on TMP-SMX at 3 months without adverse reaction. Eleven patients discontinued TMP-SMX (7 for allergic reactions and 4 for non-allergic reasons) and switched to pentamidine. A cost savings of $575 per desensitization was calculated based on annual wholesale drug prices, for a total savings of $23 575. Additionally, the protocol did not delay discharge in any patient nor was it associated with any severe allergic reactions. These findings suggest TMP-SMX desensitization is safe and effective in SOT recipients with a history of non-anaphylactic, non-life-threatening sulfonamide hypersensitivity.

Antibodies to co-trimoxazole (trimethoprim and/or sulfamethoxazole) related to the presence of the drug in a commercial low-ionic-strength solution.

BACKGROUND: Drug-dependent antibodies have been associated with approximately 10% of acquired immune hemolytic anemia cases. These antibodies are a rare cause of interference in pretransfusion red blood cell (RBC) serologic testing. The aim of this work was to report three cases of subjects developing antibodies against co-trimoxazole, a combination of trimethoprim (TMP) and sulfamethoxazole (SMX). CASE REPORT AND METHODS: Blood samples of donor/patients were referred to our laboratory for the exploration of a positive antibody detection test. There was no recent history of drug taking. Antibody identification was performed by gel test using an indirect antiglobulin test, with reagent RBCs in low-ionic-strength solutions (LISS) containing co-trimoxazole or not. RESULTS: All three sera showed positive reactions when RBCs were resuspended in LISS containing co-trimoxazole, but negative reactions when RBCs were resuspended in LISS without antibiotic. We detected antibodies against co-trimoxazole showing three different antibody patterns: anti-TMP plus anti-SMX, anti-TMP alone, or anti-SMX alone. Anti-TMP showed an apparent anti-Ku specificity in the two cases where it was present. Anti-SMX showed an apparent anti-H specificity in one of the two cases described. The drug-dependent antibodies were not associated with acquired hemolytic anemia or other pathologies. CONCLUSION: Antibodies against co-trimoxazole may only be detected when using a diluent for reagent RBCs containing the drug in question. Antibody pattern (anti-TMP and/or anti-SMX) may vary according to individuals' immune response. Drug-dependent antibodies may react as antibodies against a high-prevalence antigen, supporting the hypothesis of antibodies to drug and membrane components. Drug-dependent antibodies such as anti-co-trimoxazole may be a serologic finding without clinical features.

Hydrochlorothiazide-induced angioedema in a patient allergic to sulfonamide antibiotics: evidence from a case report and a review of the literature.

BACKGROUND: Hypersensitivity reactions in patients receiving sulfonamide antibiotics have been frequently documented in the literature, but cross-reactivity with sulfonamide non-antibiotics rarely has been reported. CASE SUMMARY: An 82-year-old woman with a history of hypersensitivity reactions to sulfamethoxazole-trimethoprim resulting in angioedema and rash presented to the emergency department (ED) with angioedema and severe dysphagia, shortness of breath, and rash after receiving valsartan and hydrochlorothiazide (HCTZ) for 4 months. Valsartan was identified as the most likely cause of the symptoms and was discontinued; however, the patient continued to have weekly episodes of angioedema and eventually returned to the ED. HCTZ was discontinued at the second ED visit, and the angioedema disappeared. However, it reappeared after reinitiation of HCTZ, and the patient returned to the ED again; this time with more severe symptoms. After the third ED visit and second hospitalization, HCTZ was permanently discontinued, and the angioedema has not returned. HCTZ was the definite cause of angioedema in this patient based on a score of 9 on the 10-point Naranjo adverse drug reaction probability scale. CONCLUSIONS: Although the probability of true cross-reactivity is not known, clinicians should be aware that an allergic-like reaction to sulfonamide-containing non-antibiotics may occur in patients with known allergies to sulfonamide-containing antibiotics. These patients should be monitored closely when receiving these drugs. Further evaluation is needed to determine whether angioedema should be added to the list of adverse events associated with HCTZ.

[Desensitization to cotrimoxazole, rifampicin and penicillin G in nine patients with prior hypersensitivity]. / Original Breve Desensibilización de cotrimoxazol, rifampicina y penicilina G en nueve pacientes con hipersensibilidad previa.

OBJECTIVE: To present a protocol for the administration and development technique of the desensitization regimens for cotrimoxazole, rifampicin and penicillin G hypersensibility. METHOD: A review of the available desensitization protocols for these antibiotics and a retrospective study of desensitization processes undertaken in the center from 1998. A development technique of the antibiotic dosages was designed. RESULTS: Desensitization regimens for cotrimoxazole, rifampicin and penicillin G undertaken in the center in 9 patients came from a protocol by Glucksteins et al., Holland et al. and Wendal et al., respectively. After the literature review and the satisfactory results that allowed subsequent antibiotic administration in the 9 cases, these regimens were established as protocols of the center. CONCLUSIONS: Dosage development and patient administration have a practical application and can help to decrease the potential mistakes related to the complexity of the process.

Efficacy and safety of rechallenge with low-dose trimethoprim-sulphamethoxazole in previously hypersensitive HIV-infected patients.

OBJECTIVE: This study was undertaken to determine whether patients infected with HIV and with prior hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) can be rechallenged successfully with TMP-SMX, what factors predict successful rechallenge, and whether hypersensitivity is due to TMP or to SMX. DESIGN: A prospective, open study. SETTING: A tertiary referral hospital. PATIENT: Thirty-one HIV-infected patients with a history of non-life-threatening hypersensitivity to TMP-SMX. INTERVENTIONS: Patients received TMP (300 mg twice a week) for 2 weeks and, where no major reaction occurred, subsequently with TMP-SMX (160 and 800 mg per tablet, one tablet two times a day, twice a week). Patients who developed significant and persistent hypersensitivity ceased SMX and were subsequently challenged with TMP-dapsone (300 and 100 mg, respectively, twice a week). MAIN OUTCOME MEASURES: That rechallenge is more likely to be successful in those with advanced HIV disease. RESULTS: Five out of 31 (16%) patients developed hypersensitivity to TMP, and two ceased TMP as a result. Fifteen of the 26 (58%) patients who received subsequent TMP-SMX developed hypersensitivity, 12 of whom ceased TMP-SMX because of this reaction. Hypersensitivity to TMP-SMX was significantly less common in those with a CD4+ cell count < 20 x 10(6)/l than in those with a CD4+ cell count > 20 x 10(6)/l (31 versus 85%; P = 0.03). Hypersensitivity to TMP-dapsone occurred in two out of nine patients with hypersensitivity to TMP-SMX on rechallenge. One patient developed transient dyspnoea following a dose of SMX, but no other serious adverse drug reaction occurred. CONCLUSIONS: Rechallenge with TMP-SMX appears safe in HIV-infected patients with a history of non-life-threatening hypersensitivity and is most likely to be successful in patients with a low CD4+ lymphocyte count. The data suggest a low rate cross-hypersensitivity between SMX and dapsone, at least at the doses used.

Acetylation phenotype and cutaneous hypersensitivity to trimethoprim-sulphamethoxazole in HIV-infected patients.

OBJECTIVE: Hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) is more common in patients with HIV infection. In non-infected patients, TMP-SMX hypersensitivity is more common in those with a slow acetylator phenotype. This study was conducted to determine whether the slow acetylation phenotype is associated with an increased risk of hypersensitivity to TMP-SMX in patients with HIV infection. METHODS: Acetylation phenotype was determined in 28 HIV-infected subjects, of whom 16 had prior TMP-SMX hypersensitivity and 12 had received long-term TMP-SMX therapy without hypersensitivity, as well as in 29 healthy controls. Acetylation phenotype was determined by measuring the ratio of two urinary caffeine metabolites, 5-acetylamino-6-amino-3-methyl uracil (AAMU) and 1-methylxanthine (1-MX), after ingestion of a single 200 mg dose of caffeine. RESULTS: Of the 28 HIV-infected subjects, 20 (71%) expressed a slow acetylation phenotype and eight (29%) a fast phenotype. By comparison, of the 29 healthy controls, 15 (52%) expressed a slow phenotype (P = 0.11). Of the 16 HIV-infected subjects with prior TMP-SMX hypersensitivity, 15 (94%) had a slow acetylation phenotype, whereas only five out of 12 (42%) non-hypersensitive subjects had a slow acetylation phenotype (P < 0.01). CONCLUSIONS: A slow acetylation phenotype is a risk factor for hypersensitivity to TMP-SMX in HIV-infected subjects.

Effect of clarithromycin on experimental rhinovirus-16 colds: a randomized, double-blind, controlled trial.

PURPOSE: Macrolide antibiotics are frequently prescribed to patients with symptoms of a common cold. Despite their lack of proven antiviral activity, macrolide antibiotics may have anti-inflammatory actions, such as inhibition of mucus secretion and production of interleukins 6 and 8 by epithelial cells. Because the symptoms of rhinovirus colds are attributed to the inflammatory response to infection, we studied the effects of treatment with clarithromycin on the symptomatic and inflammatory response to nasal inoculation with rhinovirus. SUBJECTS AND METHODS: We performed a prospective, double-blind, controlled trial in 24 healthy subjects who were seronegative for antibodies to rhinovirus-16. Subjects were randomly assigned to receive either clarithromycin (500 mg) or trimethoprim-sulfamethoxazole (800/160 mg, as a control antibiotic) twice a day for 8 days, beginning 24 hours before inoculation with rhinovirus-16. RESULTS: All 12 subjects in each group were infected and developed symptomatic colds. The groups did not differ in the intensity of cold symptoms (median [25th to 75th percentile] score in the clarithromycin group of 25 [5 to 33] versus 21 [11 to 26] in the trimethoprim-sulfamethoxazole group, P = 0.86), weight of nasal secretions (25 g [8 to 56 g] versus 12 g [5 to 28 g], P = 0.27), or decline in nasal peak flow during the 8 days following viral inoculation. In both groups, similar and significant increases from baseline were observed in the numbers of total cells and neutrophils, and in the concentrations of interleukins 6 and 8, in nasal lavage fluid during the cold. The changes that we observed did not differ from those in an untreated historical control group. CONCLUSIONS: We conclude that clarithromycin treatment has little or no effect on the severity of cold symptoms or the intensity of neutrophilic nasal inflammation in experimental rhinovirus-16 colds.

Rapid oral desensitization to trimethoprim-sulfamethoxazole in infants and children.

BACKGROUND: Although trimethoprim-sulfamethoxazole is the preferred chemoprophylaxis against Pneumocystis carinii pneumonia, there are frequent IgE-mediated reactions among children infected with the human immunodeficiency virus (HIV). Oral desensitization allows more patients to receive chemoprophylaxis, but it has been studied in only a limited number of children. METHODS: We desensitized five children infected with the HIV using a rapid, 4-h oral protocol. RESULTS: Three children (including two infants) successfully completed desensitization and started maintenance therapy, but the other two experienced reactions that precluded further administration of trimethoprim-sulfamethoxazole. CONCLUSIONS: We conclude that a rapid, oral trimethoprim-sulfamethoxazole desensitization protocol is safe and, in some instances, effective among HIV-infected children and infants with a history of non-life-threatening, IgE-mediated reactions to trimethoprim-sulfamethoxazole.

Antimicrobial resistance of enteropathogenic Escherichia coli strains from a nosocomial outbreak in Kenya.

The majority of the 78 enteropathogenic (EPEC) and the 151 non-EPEC Escherichia coli strains isolated from preterm neonates during an outbreak of gastroenteritis in a hospital in Nairobi, Kenya, were resistant to trimethoprim-sulfamethoxaxole, chloramphenicol, oxytetracycline and ampicillin, but only a few strains were resistant to cefazolin, cefamandole, cefotaxime, amikacin and nalidixic acid. Fourteen different antimicrobial resistance patterns were observed in the 229 strains of E. coli analysed. Eighty-two percent of the EPEC strains belonged to two resistance pattern compared with 79% of non-EPEC strains which exhibited three resistance patterns. There was no consistent relationship between plasmid profile group and antimicrobial resistance pattern, although one resistance pattern was more frequently observed in EAF-positive strains belonging to the dominant plasmid profile group. Nine percent of the EPEC strains were resistant to gentamicin compared to 37% in the non-EPEC group. No correlation was observed between administration of gentamicin and percentage of resistant strains isolated. None of the nine neonates receiving gentamicin died during the outbreak. Gentamicin resistance was observed in E. coli strains from six out of these nine neonates. Five out of fourteen neonates who received other antimicrobials, or no antibiotic treatment at all, died.

Desensitization to co-trimoxazole (trimethoprim-sulphamethoxazole) in HIV-infected patients: is patch testing a useful predictor of reaction?

OBJECTIVE: To establish the safety and efficacy of desensitization to co-trimoxazole in hypersensitive HIV-infected subjects. To assess if delayed hypersensitivity (type IV) to co-trimoxazole predicts those unable to be desensitized. METHOD: desensitization to co-trimoxazole, comprising trimethoprim (T) 0.4 mg and sulphamethoxazole (S) 2 mg initially with doubling dose daily, full strength co-trimoxazole (T/S 160 mg/800 mg) at 10 days. Patch testing with 4.5% and 9% co-trimoxazole in yellow soft paraffin, CMI Multitest. RESULTS: nineteen patients, 18 male and one female, were recruited and completed the desensitization regime. Of these 80%(15) achieved successful desensitization. Three of those who reacted did so within 18 days. All patients were successfully managed in an outpatient setting. There were no major adverse reactions. Of those reacting none gave a positive patch test to co-trimoxazole and all showed absent delayed type hypersensitivity reactions to recall antigens. CONCLUSIONS: co-trimoxazole desensitization is a safe and efficacious procedure, with a success rate of 80% using the above regime. Patch testing with co-trimoxazole gives no useful information about those that reacted.

Evaluation of drug-related hypersensitivity reactions in children.

Patients with drug reactions are often referred to allergists for "allergy". Skin testing and clinical history seem to have a good negative predictive value, however, although drug challenge could be dangerous, it is the only way to confirm the diagnosis. We aimed to demonstrate that most children with a history of non-life-threatening drug reactions do not have a true drug allergy and examined the use of drug challenge in childhood. Patients with reactions were referred to our clinic by pediatricians. In 1 year, 354 reactions were studied in 239 children. Patients were classified according to their positive or negative history of drug allergy. Skin prick testing was done in all cases. Exclusion criteria for challenge included drug anaphylaxis, Stevens-Johnson syndrome, systemic reactions with severe concomitant illness, beta-inhibitor drug therapy or positive skin test to the implicated drug with a positive history. It was found that the beta-lactam antibiotics were involved in 50% of suspected reactions, aspirin in 10% and sulfonamides in 9%. Histories were considered positive only in 25%. Drug challenges confirmed only 4% of all reactions. It was concluded that drug challenge may be the gold standard for most childhood reactions that are considered to be allergic, non-life-threatening and drug-related. Only 4% of these suspected reactions were exclusively caused by drug allergy.

[The determination of specific IgE in allergy diagnosis. The clinical significance of specific IgE in drug allergies]. / Il dosaggio delle IgE-specifiche nella diagnostica allergica. Significato clinico delle IgE-specifiche nelle allergie a farmaci.

IgE-mediated allergic reactions to drugs may be diagnosed on the basis of anamnestic criteria, clinico-pathological manifestations as well as by the measurement of allergen-specific IgE. The concordance of these diagnostic procedures was investigated in 50 patients with a history of sensitivity to penicillin (12), sulphamethoxazole (9) or both (14), aspirin (2) and pyrazolones (13). All subjects displayed chronic urticaria/angioedema syndrome. Optimal concordance values were observed for penicillin and sulphamethoxazole, while no specific IgE were detected in the ASA-sensitive group. False positive results were noted in pyrazolone-sensitive patients with high total IgE levels. Based on these results, serological methods that detect drug-specific IgE may be carefully used as complementary diagnostic procedure only in those patients in whom an adverse reaction to antibiotics is suspected.

Successful outpatient graded administration of trimethoprim-sulfamethoxazole in patients without HIV and with a history of sulfonamide adverse drug reaction.

BACKGROUND: The outcomes of trimethoprim-sulfamethoxazole (TMP-SMX) desensitization have been widely reported in the HIV literature but less so in the non-HIV literature. OBJECTIVE: To evaluate the safety and efficacy of graded administration of TMP-SMX in patients without HIV and with a history of TMP-SMX adverse drug reaction (ADR). METHODS: A retrospective chart review, 2004-2012, of all the patients without HIV seen in the Division of Allergic Diseases and with a history of TMP-SMX ADR who underwent outpatient graded administration of TMP-SMX was conducted. The medical record was reviewed for age, sex, details of the initial ADR to TMP-SMX, an indication for TMP-SMX administration, and outcome. Patients also were contacted by telephone, and medical records were reviewed to determine long-term outcomes. RESULTS: Seventy-two patients (46 women [64%]; mean [SD] age, 57.7 ± 13.89 years]) were included. The most common patient-reported reactions to TMP-SMX were rash 39 (54%), and hives 9 (13%). TMP-SMX administration was needed for the following indications: prophylaxis (62 [86%]) and treatment of infection (10 [14%]). Forty-three of the patients (60%) underwent a 1-day TMP-SMX administration protocol. Thirty-five of the 43 (81%) underwent a 6-step (90 minutes to 6 hours) protocol and 7 of the 43 (16%) underwent a novel 14-step TMP-SMX protocol. Twenty-nine (40%) underwent a >1-day TMP-SMX administration protocol. Our overall success rate was 90% (mean duration of 11 months). Ninety-eight percent of the patients successfully completed a 1-day graded administration protocol, and 76% successfully completed a >1-day protocol. TMP-SMX was stopped in 8 patients because of the ADR. CONCLUSION: We report the largest case series of successful outpatient graded administration of TMP-SMX with both 1-day and >1-day protocols, which have shown to be safe and well tolerated in patients without HIV and with a history of sulfonamide ADR.

Trimethoprim-sulfamethoxazole-induced hepatotoxicity in a pediatric patient.

Due to the escalating rates of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection, trimethoprim-sulfamethoxazole (TMP-SMX) is being used increasingly in the pediatric population for skin and soft tissue infections. Although this combination agent has been associated with a hypersensitivity syndrome involving cutaneous skin eruptions, pediatric cases of TMP-SMX-induced hepatotoxicity are rare. We describe a relatively healthy, 9-year-old boy who developed a CA-MRSA skin and soft tissue infection and was treated with TMP-SMX. After 14 days of therapy, he was taken to the emergency department with a 3-day history of fever, headache, and neck pain. He was diagnosed with a viral syndrome, acetaminophen was prescribed, and he was sent home. Three days later, the patient returned to the emergency department with fever, vomiting, decreased energy and appetitie, and suprapubic abdominal pain, and he was hospitalized. Laboratory test results revealed elevated liver function test values. After other potential causes of liver toxicity were excluded, TMP-SMX was determined to be the cause of his acute liver toxicity. The drug was discontinued, his symptoms resolved, and his liver function tests returned to normal. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's development of hepatotoxicity and the TMP-SMX therapy. This rare adverse reaction to TMP-SMX has been reported in adults; however, to our knowledge, it has been reported in only five other children. Due to the increasing use of TMP-SMX in children, clinicians should be aware of this potentially life-threatening, immunemediated hypersensitivity reaction. Fortunately, however, the hepatotoxicity appears to resolve after discontinuation of the TMP-SMX therapy in most reported cases. This case report illustrates the importance of early detection of drug-induced hepatotoxicity and timely drug discontinuation to prevent the need for liver transplantation.