Incidence, Clinical Manifestation, Treatment Outcome, and Drug Susceptibility Pattern of Nontuberculous Mycobacteria in HIV Patients in Tehran, Iran.

BACKGROUND: Nontuberculous mycobacterial (NTM) infections have radically increased worldwide due to the increase in HIV infections. The disease activity increases with progressive immunodeficiency. METHODS: A total of 216 HIV seropositive patients suspected of having mycobacterial infection were recruited for this study. Clinical samples were collected from each patient and cultured on Lowenstein-Jensen media. Detection and species identification were simultaneously done using Reverse Blot Hybridization Assay System. Also, the minimum inhibitory concentrations (MIC) for each isolate were determined in 7H9 broth media for 10 antibiotics. RESULTS: In this study, 4 rapid and 4 slow-growing NTM species were isolated and identified. Mycobacterium fortuitum was the most common NTM species, 3/8 (37.5%), followed by Mycobacterium kansasii, 2/8 (25%). The cases were identified as pulmonary disease, 5/8 (62.5 %), disseminated infection, 2/8 (25%), and skin abscess, 1/8 (12.5%). M. chelonae and Mycobacterium avium were isolated from patients diagnosed with disseminated infection with treatment failure. The skin abscess was caused by infection with M. simiae. The results of the MIC testing were as follows: M. kansasii and M. fortuitum were susceptible to amikacin (AMK); M. avium to clarithromycin (CLA); M. fortuitum 2/3 (67%) to ciprofloxacin (CIP); 1/2 (50%) of M. kansasii isolates to CLA, and M. chelonae to rifampin (RIF), linezolid (LIN), AMK, and CIP at medium and high concentrations. CONCLUSION: AMK showed incredible in vitro activity against M. kansasii and M. fortuitum. Also, M. avium was susceptible to CLA, whereas M. simiae and M. chelonae were resistant to the tested drugs in this study.

Efficacy and tolerability of desensitization in the treatment of delayed drug hypersensitivities to anti-tuberculosis medications.

BACKGROUND: Delayed drug hypersensitivity to first-line anti-tuberculosis medication is a major challenge in tuberculosis treatment. OBJECTIVE: This study was performed to investigate the efficacy/tolerability of desensitization therapy in treatment of first-line anti-tuberculosis medication hypersensitivity and the usefulness of immunologic evaluation therein. METHODS: This study was conducted as a prospective, observational cohort study. Subjects who experienced hypersensitivity reactions, including maculopapular exanthema (MPE) and drug reaction with eosinophilia and systemic symptoms (DRESS), to first-line anti-tuberculosis medications (isoniazid [INH], ethambutol [EMB], rifampin [RFP], and pyrazinamide [PZA]) were enrolled. Patch, intradermal, lymphocyte transformation, and oral provocation tests were performed to determine culprit drugs, which were desensitized with rapid and graded challenge protocols. Breakthrough reactions (BTRs) during or after desensitization were assessed. RESULTS: In total, 31 desensitization treatments (INH, 8; EMB, 8; RFP, 11; PZA, 4) to 12 patients (8 with MPE and 4 with DRESS) were performed. The overall success rate of desensitization was 80.7%. All the study subjects except one completed the full course of anti-tuberculosis treatment. The overall BTR free rate was 64.5%. Sixteen (80%) treatments for MPE and four (36.4%) for DRESS were BTR free (P = 0.023). Drugs that were positive on any two of three immunologic studies showed significantly high BTR rates (P = 0.014), although this was not correlated with desensitization failure rate. CONCLUSION: Rapid desensitization therapy to multiple anti-tuberculosis medications for delayed drug hypersensitivity was safe and successful. Combination of multiple immunologic evaluations may predict BTR although it needs validation in larger studies.

Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome.

BACKGROUND: A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. OBJECTIVES: To investigate drug-specific T-cell responses in patients with antituberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. METHODS: We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-γ/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen-restricted T-cell responses. RESULTS: Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. CONCLUSIONS: This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.

Desensitization to antibiotics in children.

Drug hypersensitivity reactions can occur to almost all drugs and antibiotics are among the most common cause for this kind of reactions. Drug hypersensitivity may affect any organ or system, and manifestations range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. In case of infection, there is usually a safe antibiotic alternative. Nonetheless, in some cases, no alternative treatment exists for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance to a drug which can only be maintained by continuous administration of the medication responsible for the hypersensitivity reaction. Desensitization is mainly performed in IgE-mediated reactions. Increasing doses of the implicated drug are administered over a short period of time, until the therapeutic dose is achieved and tolerated. Very few studies confined to children are found in literature. Most of them are case reports. In general, the proposed desensitization schemes are similar to those used in adults differing only in the final dose administered. The purpose of this study is to review desensitization to antibiotics in children presenting and discussing three clinical practical cases of desensitization in this age group.

Rare immediate hypersensitivity to rifampicin in a patient with tuberculosis requiring drug discontinuation.

A 47-year-old Turkish female patient was diagnosed with tuberculosis of the sacro-iliac joints and terminal ileum. She developed a severe adverse drug reaction while taking first-line tuberculosis therapy consisting of isoniazid, pyrazinamide and rifampicin as Rifater and ethambutol. Within 5 min of ingestion she developed pruritic rash, angioedema and breathing difficulties, resulting in an A&E admission. The tuberculosis therapy was discontinued. Intradermal and oral challenge tests for rifampicin were conducted but abandoned early on due to reactions which included audible wheeze, vomiting, throat pain and violent rigours. Clinical manifestations were swiftly treated with appropriate medications. This resulted in a change to the tuberculosis treatment regime, where streptomycin, isoniazid, ethambutol and pyrazinamide were given for 2 months and isoniazid and ethambutol for 12 months. Allergic reactions to rifampicin are rare and should be distinguished from flushing due to pyrazinamide. Prompt diagnosis and treatment by clinicians can be life saving.

Nonirritant intradermal skin test concentrations of ciprofloxacin, clarithromycin, and rifampicin.

BACKGROUND: Intradermal skin testing of the clinically important antibiotics ciprofloxacin, clarithromycin, and rifampicin in the case of suspected allergies to antibiotics is poorly standardized. For clinical practice, standardized procedures and protocols are desired. METHODS: Fifteen healthy volunteers were tested with different concentrations of the antibiotics as well as with appropriate controls. Test readings included wheal area measured by digital image analysis and blood flow increase measured by laser Doppler flowmetry (LDF). To reduce interpersonal variability, test results were normalized with the individual controls using a novel protocol. RESULTS: Nonirritating concentrations of the three antibiotics (ciprofloxacin ~0.0067 mg/ml, clarithromycin ~0.05 mg/ml, rifampicin ~0.002 mg/ml) could be defined for healthy volunteers. Laser Doppler flowmetry generates comparable results to wheal area measurement. Normalization of the test results is necessary and can be applied in a practical algorithm. CONCLUSIONS: Standardized skin testing to detect sensitization to broadly used nonbetalactam antibiotics was presented and should be applied in truly sensitized patients. This approach should help to minimize the inter- and intraindividual differences in reactivity.

Flow cytometry in the diagnosis of drug-induced thrombocytopenia: two illustrative cases.

Drug-induced thrombocytopenia is a challenging diagnosis in the clinical practice because of the many drugs or alternative causes that may be implicated. Exact identification of such drug(s) is required to guide future management and avoid re-exposure. We describe two cases of isolated thrombocytopenia in which cytometric analysis, a readily available technique, allowed the identification of the causative drug in the context of complex therapies (rifampicin and abciximab causing late onset thrombocytopenia).

[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.

Immediate hypersensitivity to rifampicin in 3 patients: diagnostic procedures and induction of clinical tolerance.

BACKGROUND: Desensitization with drugs may be indicated in some clinical situations. Apart from large experiences with beta-lactam antibiotics and cotrimoxazole in HIV infection, experience with other drugs is limited. Rifampicin may elicit exanthema and urticaria, and their pathomechanisms are not known in detail. Since therapy with rifampicin may be indispensable in mycobacterial infections or against multiresistant Staphylococcus aureus, desensitization may be indicated in some patients. OBJECTIVE: Report of immediate hypersensitivity to rifampicin and description of diagnostic and desensitization procedures. METHODS: We report 3 patients with immediate urticarial reactions to rifampicin. Diagnostic procedures included skin and in vitro tests (specific IgE, lymphocyte transformation test, LTT, and CAST). The non-irritant cutoff concentration was evaluated in 24 volunteers. A 7-day desensitization procedure was used. RESULTS: Only intradermal tests at a dilution of at least 1:10,000 (concentration of rifampicin approximately 0.006 mg/ml) were true positive, whereas in vitro tests (IgE, LTT and CAST) did not correctly identify hypersensitive patients. Two patients had positive accidental reexposure. All patients were successfully desensitized with rifampicin according to a slow 7-day protocol. CONCLUSIONS: Rifampicin rarely elicits immediate hypersensitivity symptoms which may be diagnosed by intradermal skin tests. In vitro tests did not contribute to the diagnosis. Therefore, an IgE-mediated mechanism remains to be proven. Desensitization with rifampicin using different protocols has been reported. In our 3 cases, clinical tolerance to rifampicin was achieved using a 7-day protocol.

Belated diagnosis in three patients with rifampicin-induced immune haemolytic anaemia.

We report three patients who developed haemolysis following rifampicin treatment. Initially, autoimmune haemolytic anaemia (AIHA) of the warm type and/or an acute haemolytic transfusion reaction (AHTR) was suggested. The direct antiglobulin tests (DAT) were strongly positive for IgG and C3d, and tests for rifampicin-dependent antibodies were positive in all three cases, featuring C-specificity in one case. The outcome was fatal in two out of the three cases, presumably due to belated diagnosis. This shows that rifampicin may stimulate the production of autoantibodies (aab) and/or drug-dependent antibodies (ddab), and that the resulting haemolytic syndrome bears similarities with AIHA and AHTR.

Considerações acerca dos estados reacionais do portador de Hanseníase no Município de Itajaí / Considerations on reactional states of Itajaí's hansen's carriers

A pesquisa teve por objetivo, compreender e avaliar os estados reacionais de pacientes portadores de hanseníase e o tratamento das reações. O método de abordagem do estudo foi indutivo, tendo como base o referencial bibliográfico, tomou-se como fonte de dados os prontuários dos portadores de hanseníase, disponíveis no Programa de Controle de Hanseníase da Secretaria Municipal de Saúde de Itajaí. Através do trabalho com os 78 pacientes inscritos no programa, observou-se que: 60,3 por cento tem de 15-49 anos; 65,4 por cento são do sexo masculino; 70,5 por cento manifestam a forma Virchowiana da doença; 60,3 por cento apresentaram estados reacionais durante tratamento; metade destes aproximadamente apresentaram quadro clínico de neurite, tendo sido tratados com prednisona. Também foram observados outros sintomas clínicos como o eritema nodoso hansênico, e o tratamento de escolha, sempre que possível foi a talidomida. A avaliação dos estados reacionais indica que, mais da metade dos portadores em tratamento, apresentam esta manifestação imunológica. É julgada pela literatura como consequência da doença e possível reação ao esquema poliquimioterápico

[Immuno-allergic accidents with rifamipcin]. / Accidents immuno-allergiques à la rifampicine.

We report 2 new cases of immuno-allergic side-effects of rifampicin (RMP), occurred in leprosy patients treated by multidrug therapy. These cases illustrate the various features of this type of complication. In one case, the patient exhibited few days after restarting of RMP (600 mg daily), a typical flu syndrome associated to a thrombopenia. Previously, the patient had received discontinued RMP (300 mg, 3/5 days) that had to be stopped after 11 months for "general malaise" that in fact corresponded to a flu syndrome. The second patient developed a flu syndrome associated with a diffuse eczematous eruption one year after the onset of daily RMP (600 mg). Anti-RMP antibodies were detected only in the first case. The pathogenic mechanisms and the clinico-biologic features are discussed.

Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX-specific quinine-dependent antibodies.

The drug-dependent antibody of a patient with rifampicin-induced thrombocytopenia was characterized using the antigen-capture enzyme-linked immunosorbent assay (MAIPA assay), flow cytometry, and immunoprecipitation. The antibody was found to bind glycoprotein (GP) Ib-IX but not GPIIb-IIIa because (1) it immunoprecipitated drug-dependently the former but not the latter glycoprotein complex and (2) the MAIPA assay showed strong rifampicin-dependent antibody binding when anti-GPIb-IX monoclonal antibodies (mAbs) (AK2 and FMC25) but not anti-GPIIb-IIIa mAbs (AP2, SZ21, and SZ22) were used to capture the antigen. The antibody binding site was further localized to the GPIX subunit of the GPIb-IX complex because flow cytometric analysis revealed drug-dependent antibody binding to L cells transfected with human GPIbbeta and GPIX complementary DNA (L betaIX cells) but not with human GPIbalpha and GPIbbeta complementary DNA (L alphabeta cells). Finally, in the MAIPA assay, the rifampicin-dependent antibody almost completely cross-blocked the binding of the anti-GPIX mAb (SZ1) to platelets. Similar cross-blocking of SZ1binding to platelets by the quinine-dependent antibodies was also observed. This finding not only confirms that the epitope of the rifampicin-dependent antibody is on GPIX but it is also identical to or located in close proximity to that of the quinine-dependent antibody and SZ1. Further characterization of the epitopes of these antibodies may have important implications for a general understanding of the mechanism of drug-induced thrombocytopenia. (Blood. 2000;95:1988-1992)