Mycobacterium leprae: aspectos da resistência aos fármacos na poliquimioterapia / Drug resistance in multidrug therapy for Mycobacterium leprae

Introdução: O diagnóstico da hanseníase possui números significativos que causam preocupação à saúde pública. Os casos de resistência medicamentosa nessa doença se iniciaram em meados dos anos 60 e diante do problema, a Organização Mundial da Saúde instituiu em 1981 a poliquimioterapia, associação dos antibióticos rifampicina, dapsona e clofazimina, tratamento atual de escolha. A resistência aos fármacos na hanseníase é reportada pela literatura, desvelando um obstáculo à sua eliminação. Apresentamos nessa revisão os principais aspectos da resistência medicamentosa no tratamento para hanseníase e seus impactos. Metodologia: Revisão sistemática sobre os aspectos da resistência medicamentosa utilizando a pesquisa exploratória como metodologia de abordagem. Foram pesquisados os termos resistência medicamentosa, hanseníase, recidiva, alterações genéticas e os operadores booleanos "and" e "or" na busca. Resultados e discussão: A dificuldade de tomar a medicação corretamente foi um dos principais fatores que acarretaram resistência do bacilo Mycobacterium leprae aos fármacos. Homens de países norte e sul-americanos e asiáticos foram os mais atingidos por episódios de resistência. A resistência medicamentosa é uma das principais causas de recidivas em hanseníase. O principal fármaco causador de resistência medicamentosa descrito nos trabalhos foi a dapsona (46,6%) e a maioria das alterações genéticas encontradas estão no gene rpoB; 23,2% dos registros relatados foram de resistência secundária aos fármacos e, também, sete casos de resistência múltipla a esses medicamentos. Conclusão: Os principais aspectos da resistência medicamentosa na hanseníase são os equívocos ao ingerir os medicamentos e as alterações genéticas na bactéria. Os impactos causados estão na dificuldade de refazer o tratamento, a possibilidade de nova transmissão e o aparecimento de sintomas mais graves.

Introduction: The diagnosis of leprosy has significant numbers causing public health concern. Reports of drug resistance in this disease begun in the mid-1960s and due to this problem, the World Health Organization instituted a multidrug therapy with rifampicin, dapsone, and clofazimine antibiotic association in 1981, which is currently the first-choice treatment for leprosy. Cases of drug resistance have been reported in literature, revealing an obstacle to the eradication of the disease. This paper has the purpose of presenting the key aspects and impacts of drug resistance in the treatment for leprosy. Methods: Systematic review of the drug resistance aspects using exploratory research as an approach methodology. The authors searched the terms drug resistance, leprosy, recurrence, genetic alterations, and the Boolean operators "and" and "or" between them. Results and discussion: The difficulty in taking the medication correctly was one of the key factors that led to drug resistance for Mycobacterium leprae. Men from North and South American, as well as from Asian countries, were the most affected by episodes of resistance. Drug resistance is one of the main causes of leprosy recurrences. Dapsone was the most frequently identified drug resistance in the studies (46.6%), while most of the genetic alterations were found in the rpoB gene; 23.2% of the cases were from secondary resistance episodes, and seven cases of multiple resistance were reported. Conclusion: The misconceptions when taking the treatment and the Mycobacterium leprae genetic alterations have been described as the key aspects of drugs resistance in leprosy and the impacts caused are the difficulty in redoing the treatment, the possibility of new transmission, and the appearance of more severe symptoms.

Disglucemia asociada a fluoroquinolonas: una revisión estructurada / Hypo or hyperglycemia associated with fluoroquinolone use

Fluoroquinolone type antimicrobials can cause hypo or hyperglycemia in certain patients. We performed a structured review about this side effect, searching articles published in English or Spanish with full text access in PubMed/Medline. The following MESH terms were used: Hypoglycemia, Hyperglycemia, Quinolones, Ciprofloxacin, Levofloxacin, Moxifloxacin. Additionally, we evaluated the clinical relevance of potential drug interactions, based on the probability of occurrence and the severity of the interaction effect. We obtained 42 publications about the issue; 22 references were selected, where the severity of the interaction in patients with risk factors was evaluated. Patients receiving antidiabetic medications and with risk factors such as advanced age and renal failure may be more likely to have a severe hypoglycemia. In these patients, this drug interaction should be considered clinically relevant since its risk is high or very high.

Evaluation of the influence of fluoroquinolone chemical structure on stability: forced degradation and in silico studies

ABSTRACT Fluoroquinolones are a known antibacterial class commonly used around the world. These compounds present relative stability and they may show some adverse effects according their distinct chemical structures. The chemical hydrolysis of five fluoroquinolones was studied using alkaline and photolytic degradation aiming to observe the differences in molecular reactivity. DFT/B3LYP-6.31G* was used to assist with understanding the chemical structure degradation. Gemifloxacin underwent degradation in alkaline medium. Gemifloxacin and danofloxacin showed more degradation perceptual indices in comparison with ciprofloxacin, enrofloxacin and norfloxacin in photolytic conditions. Some structural features were observed which may influence degradation, such as the presence of five member rings attached to the quinolone ring and the electrostatic positive charges, showed in maps of potential electrostatic charges. These measurements may be used in the design of effective and more stable fluoroquinolones as well as the investigation of degradation products from stress stability assays.

Seguridad de las fluoroquinolonas: riesgos habitualmente olvidados para el clínico / Safety of fluoroquinolones: risks usually forgotten for the clinician

Resumen Las quinolonas constituyen una familia de antimicrobianos de amplio uso y si bien son consideradas segura para los pacientes, el conocimiento del perfil de seguridad es necesario para que los profesionales estén alertas a lo que deben vigilar. Sobre el sistema músculo-esquelético, las quinolonas tienen el potencial de dañar cartílagos, provocando incluso muy excepcionalmente rotura de tendón. A nivel endocrino se ha observado hipoglicemia/hiperglicemia, por lo que en pacientes diabéticos se recomienda el control cuidadoso de la glicemia. Las reacciones adversas cardiovasculares son poco frecuentes, pero pueden ir desde alteraciones del ECG como prolongación del QT sin traducción clínica a graves arritmias que pueden ser de riesgo vital. En el sistema nervioso, destaca la aparición de alteraciones del sistema nervioso central y la neuropatía periférica. Durante la evaluación de la seguridad de las quinolonas es importante considerar las potenciales interacciones con otros medicamentos. En niños se prefiere no usar las fluoroquinolonas debido al potencial riesgo de daño a los cartílagos de crecimiento, efectos que no parecen ser tan dramáticos a la luz de la evidencia actual. A pesar del optimismo se debe evaluar la seguridad del tratamiento de estos antimicrobianos en todo paciente pediátrico.

Quinolones are a group of widely used antimicrobials. Although they are considered safe for patients, knowledge of the safety profile is necessary so that professionals become aware of what is necessary to monitor. At the musculoskeletal level, quinolones have the potential to damage cartilage, causing even tendon rupture in infrequent cases. Hypoglycemia / hyperglycemia has been observed at the endocrine level, thus, careful monitoring of glycemia in patients with quinolone is recommended in diabetic patients. At the cardiovascular level, arrhythmias induced by these antimicrobials are rare but severe. At the level of the nervous system, the appearance of alterations of the central nervous system and the peripheral neuropathy are emphasized. When assessing the safety of quinolones, it is important to consider potential interactions with other substances (medical products). In children it is preferred not to use fluoroquinolones because of the potential risk of cartilage damage and growth, effects that do not seem to be so dramatic in the face of new evidence. Despite optimism, the safety of the treatment of these antimicrobials should be evaluated in every pediatric patient.

Assessment on the adverse effects of Aminoglycosides and Flouroquinolone on sperm parameters and male reproductive tissue: a systematic review

Antibiotic therapies used in treatment of many diseases have adverse effects on fertility. This review analyzes previous comparative studies that surveyed the effects of two common groups of antibiotics on male fertility. To evaluate histo-pathological effects of fluoroquinolones and aminoglycosides on sperm parameters and male reproductive tissue. Articles about the effects of aminoglycosides and fluoroquinolones on male infertility, sperm parameters, male reproductive tissue, and spermatogenesis in English and Persian languages published on Google Scholar and PubMed databases from January 2000 to December 2013 were assessed. Randomized controlled trials [RCTs] assessing the effects of aminoglycosides or fluoroquinolones on sperm parameters, artificial insemination, and male reproductive tract or RCTs comparing aminoglycosides vs. fluoroquinolones were eligible for inclusion. For ascertaining the reliability of study, data were extracted independently and in duplicate by two investigators. Sperm viability was decreased significantly with streptomycin, gentamicin, and neomycin [p<0.001]. Sperm motility was decreased significantly with gentamicin and neomycin [p<0.05]. Total sperm count was significantly decreased with ofloxacin, gentamicin, streptomycin, and neomycin [p<0.022]. There was significant decrease in post-thawing motility with low dose and high dose of ciprofloxacin. Testis weight was decreased with gentamicin and ofloxacin significantly [p<0.011]. There was significant decrease in seminal vesicle weight with gentamicin, neomycin, and ofloxacin [p<0.022]. Furthermore, changes in epididymis weight, percentage of total apoptotic cells, and diameter of seminiferous tubule were significant with all drugs including streptomycin, gentamicin, neomycin, and ofloxacin [p<0.05]. Streptomycin has less negative effects on cell's apoptosis and sperm parameters as compared to other drugs. Gentamicin has more detrimental effects so lesser dosage and duration is recommended. Fluoroquinolones showed negative effects on testis tissue and sperm parameters. Ciprofloxacin has less adverse effects than gentamicin in artificial insemination

Preparation and evaluation of enrofloxacin microspheres and tissue distribution in rats

New enrofloxacin microspheres were formulated, and their physical properties, lung-targeting ability, and tissue distribution in rats were examined. The microspheres had a regular and round shape. The mean diameter was 10.06 microm, and the diameter of 89.93% of all microspheres ranged from 7.0 microm to 30.0 microm. Tissue distribution of the microspheres was evaluated along with a conventional enrofloxacin preparation after a single intravenous injection (7.5 mg of enrofloxacin/kg bw). The results showed that the elimination half-life (t(1/2beta)) of enrofloxacin from lung was prolonged from 7.94 h for the conventional enrofloxacin to 13.28 h for the microspheres. Area under the lung concentration versus time curve from 0 h to infinity (AUC(0-infinity)) was increased from 11.66 h.microg/g to 508.00 h.microg/g. The peak concentration (Cmax) in lung was increased from 5.95 microg/g to 93.36 microg/g. Three lung-targeting parameters were further assessed and showed that the microspheres had remarkable lung-targeting capabilities.

The efficacy of moxifloxacin-based triple therapy in treatment of Helicobacter pylori infection: a systematic review and meta-analysis of randomized clinical trials

Recent evidence shows that moxifloxacin could exert an antimicrobial effect against Helicobacter pylori in both in vitro and in vivo models. To systematically evaluate whether moxifloxacin-containing triple therapy could improve eradication rates and reduce side effects in first-line or second-line anti-H. pylori treatment, eligible articles were identified by searches of electronic databases. We included all randomized trials comparing moxifloxacin-based triple therapy with standard triple or quadruple therapy during H. pylori eradication treatment. Statistical analysis was performed with Review Manager 5.0.10. Subanalysis/sensitivity analysis was also performed. We identified seven randomized trials (n=1263). Pooled H. pylori eradication rates were 79.03% (95%CI: 75.73-82.07) and 68.33% (95%CI: 64.44-72.04) for patients with moxifloxacin-based triple therapy or with standard triple or quadruple therapy, respectively (intention-to-treat analysis). The odds ratio (OR) was 1.82 (95%CI: 1.17-2.81), the occurrence of total side effects was 15.23% (95%CI: 12.58-18.20) and 27.17% (95%CI: 23.64-30.92) for groups with or without moxifloxacin, and the summary OR was 0.45 (95%CI: 0.26-0.77). In subgroup analyses, we noted that the second-line eradication rate in the moxifloxacin group was significantly higher than that in the quadruple therapy group (73.33 vs 60.17%, OR: 1.78, 95%CI: 1.16-2.73, P<0.001). However, there was no difference in first-line eradication treatment. Findings from this meta-analysis suggest that moxifloxacin-based triple therapy is more effective and better tolerated than standard triple or quadruple therapy. Therefore, a moxifloxacin-based triple regimen should be used in the second-line treatment of H. pylori infection.

A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous drug reactions. No large scale epidemiological data are available for this disorder in India. Aims: To carry out a systematic review of the published evidence of the drug-induced SJS and TEN in Indian population. Methods: Publications from 1995 to 2011 describing SJS and TEN in Indian population were searched in PubMed, MEDLINE, EMBASE and UK PUBMED Central electronic databases. Data were collected for the causative drugs and other clinical characteristics of SJS and TEN from the selected studies.Results: From 225 references, 10 references were included as per selection criteria. The major causative drugs were antimicrobials (37.27%), anti-epileptics (35.73%) and non-steroidal anti-inflammatory drugs (15.93%). Carbamazepine (18.25%), phenytoin (13.37%), fluoroquinolones (8.48%) and paracetamol (6.17%) were most commonly implicated drugs. Regional differences were observed for fluoroquinolones, sulfa drugs and carbamazepine. Total 62.96% of patients showed systemic complications. Most common complications were ocular (40.29%) and septicemia (17.65%). Higher mortality was observed for TEN as compared to SJS (odd ratio-7.19; 95% confidence interval (CI) 1.62-31.92; p = 0.0023). Observed mortality is higher than expected as per SCORTEN score 3. Duration of hospital stay was significantly higher in TEN (20.6 days; 95% CI 14.4-26.8) as compared to SJS (9.7 days; 95% CI 5.8-13.6; p = 0.020). Cost of management was significantly higher in TEN (Rs. 7910; 95% CI 5672-10147; p < 0.0001) as compared to SJS (Rs 2460; 95% CI 1762-3158). No statistical data were described for steroid use in the studies included. Conclusion: Carbamazepine, phenytoin, fluoroquinolones and paracetamol were the major causative drugs. TEN is showing higher mortality, morbidity and economic burden than SJS.

Hypersensitivity Reaction to Ofloxacin.

The quinolones are generally well tolerated. The adverse reactions of quinolones include gastrointestinal symptoms, which are the most frequent, neuropsychiatric symptoms, hematologic abnormalities and less frequently, hypersensitivity skin reactions. Herein we report a case of 13 years old boy, who was suffering from upper respiratory tract infection and was treated with ofloxacin by a private practitioner and developed hypersensitivity reaction, one hour after taking ofloxacin tablet. Hospitalization and treatment of patient was carried out. Since hypersensitivity reaction to ofloxacin is rare, proper history of drug reactions should be taken while prescribing ofloxacin. Attention must be paid to potential side-effects of the drug while prescribing any medication, and close follow-up with patients is a medical necessity to evaluate for these adverse reactions, especially with quinolones.

A probable association of acute dystonia with gemifloxacin administration.

Gemifloxacin is a recently introduced fluoroquinolone antibiotic frequently used for its broad spectrum and once-daily dosing. Fluoroquinolones are associated with various neuropsychiatric side effects, such as seizures, insomnia, confusion, lightheadedness, psychosis, paranoia and hallucinations. We report a case of a 36-year-old woman given gemifloxacin for an upper respiratory tract infection who developed acute dystonia on the third day following therapy initiation. The clinical implications are discussed.

Faecal carriage of extended-spectrum beta-lactamase-producing bacteria in the community

We determined the faecal carriage of extended-spectrum beta-lactamase-[ESBL]-producing bacteria in the community in Saudi Arabia. A total of 716 faecal specimens [from 505 healthy individuals and 211 community outpatients] were screened for ESBL using the double-disk synergy test and confirmed by the Clinical Laboratory Standards Institute combined disk method. We found 91 [12.7%] isolates were ESBL-producers. Of these, 87 [95.6%] were Escherichia coli and 4 [4.4%] Klebsiella pneumoniae. A similar rate of faecal carriage of ESBL-producers was demonstrated in community outpatients and healthy individuals: 62 [12.3%] healthy persons and 29 [13.7%] outpatients. We conclude that the community could be a reservoir of these ESBL-producing bacteria and enzymes

Advancing age and renal impairment as important predisposing factors of gatifloxacin-induced hyperglycemia in non-diabetes patients.

There have been case reports about adverse effects to glucose homeostasis related to gatifloxacin use. The authors report an elderly, non-diabetic patient who developed severe hyperglycemia after receiving oral gatifloxacin 400mg/d. He was a 73-year-old male, patient with a history of hypertension, cured vesical pheochromocytoma, idiopathic dilated cardiomyopathy, chronic renal insufficiency (baseline serum creatinine of 1.7 mg/dL), and gouty arthritis admitted to the hospital with a diagnosis of acute bronchitis. Seven days after initiating gatifloxacin, his symptoms were improved. Subsequently he developed polyuria, polydipsia, and fatigue with an increase in serum creatinine to 2.8 mg/dL, and random plasma glucose levels elevated to 903 mg/dL. Gatifloxacin was stopped. Intravenous regular insulin infusion was administered. Euglycemia was achieved within 8 hours after fluid rehydration and only low dose insulin was required He maintained normal glucose levels without any antidiabetic drugs afterward. Old age and renal impairment were considered significant contributing factors for this hyperglycemic adverse event from gatifloxacin.

Gatifloxacin induced abnormalities in glucose homeostasis in a patient on glimepiride.

Gatifloxacin, a commonly prescribed antimicrobial can produce profound hypoglycemia and disturbances in glucose homeostasis especially in diabetes patients on sulphonylureas. Also new onset disturbances in glucose homeostasis can occur in patients who were unaffected by the previous use of gatifloxacin. Therefore it is suggested that gatifloxacin is better avoided in patients with diabetes and in the elderly.

Gatifloxacin-induced severe hypoglycemia in a patient with type 2 diabetes mellitus.

A case of Gatifloxacin-induced severe and recurrent hypoglycemia in 62-year-old type 2 diabetic patient is presented. Possible mechanisms responsible for hypoglycemia are discussed and the literature on the subject is reviewed.

An open multicenter study of the use of gatifloxacin for the treatment of non-complicated acute bacterial rhinosinusitis in adults

The bacteriological and clinical efficacy and the safety of gatifloxacin for the treatment of non-complicated acute rhinosinusitis was evaluated in 49 adult patients in an open-label multicenter study in Brazil. Patients under age 18, or with associated systemic diseases, were excluded. Diagnosis was based on symptoms, otorhinolaryngological examination, and X-rays of the sinus. At the first visit, all patients were treated with a single daily dose of 400 mg gatifloxacin for 10 days. Middle nasal meatus secretion was collected and sent for culture before and after treatment. Patients were all reevaluated at days 3 to 5; days + 1 to + 5 and 18 to 25 days + 7 to + 14 . Ninety three percent of the patients were considered clinically cured at the end of the treatment. The most frequent bacteria isolated were Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, and at the end of the treatment, presumed bacteriological eradication was observed in almost all patients. Adverse effects were observed in 19 of the cases, mostly mild and self limiting, including diarrhea, abdominal pain, nausea and vomiting. Treatment had to be interrupted in two cases. Gatifloxacin was found to be efficacious and safe for the treatment of acute rhinosinusitis in adults.

[Drug tendon disorders]

Tendinitis is a rare adverse reaction described after drugs use. It's described with drug belonging to the same class. Physiopathology is still unknown. Fluoroquinolones especially pefloxacine, were the most incriminated. This drug induced tendinitis in older people aged more than 60 years. Approximatively one case out of five leads to tendon breaking off. The others lead to a favourable outcome after drug withdrawal. In three cases, tendinitis was described with statines, and concerned 2 men and I woman, aged more than 50 years. Simvastatine was suspected in two cases and the outcome was favourable in all cases after drug withdrawal. Other drugs, like corticosteroids, can exceptionally induce this side effect that can be serious. Consequences of drug tendinitis can then be dangerous and prescription of this class, and especially fluoroquinolones, must be cautious