Role of fluoroquinolones in the treatment of tuberculosis

INTRODUCTION: The increasing incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis is hampering efforts to control the global tuberculosis (TB) epidemic. Although treatment of drug-susceptible TB is possible in ≥ 95% of disease cases, long (≥ 6 months) duration of supervised combination therapy is challenging. Non-adherence to treatment often results in much lower cure rates. Treatment of MDR-TB and XDR-TB is far less effective. The aim of this review is to summarize the current status of fluoroquinolones in shortening the duration of drug-susceptible pulmonary TB and in improving the outcome of MDR-TB/XDR-TB.METHODS: All the relevant articles were identified through a search of PubMed and Scopus databases by using search terms like tuberculosis (or M. tuberculosis), fluoroquinolones, drug-susceptible TB, MDR-TB, XDR-TB, combination therapy, treatment regimens, treatment duration, drug target and drug resistance. The current literature on the role of fluoroquinolones in the treatment of TB was reviewed.RESULTS: The fluoroquinolones, particularly newer compounds such as levofloxacin, moxifloxacin and gatifloxacin, have bactericidal activity against M. tuberculosis, excellent oral bioavailability, favorable safety profile and no cross-resistance with other first-line anti-TB drugs. Data from phase II trials of fluoroquinolones-containing regimens for shortening the duration of treatment for pulmonary TB are encouraging and phase III trials are currently underway. The fluoroquinolones are also effective as substitute agents for those individuals who are intolerant to first-line drugs. Several studies and clinical trials have also supported the use of fluoroquinolones in patients with MDR-TB/XDR-TB.DISCUSSION: The fluoroquinolones-containing regimens are being tested to shorten the duration of treatment for pulmonary TB to 4 months. They are also regarded as one of the two cornerstone drugs for the treatment of MDR-TB/XDR-TB. However, they are also among the commonly prescribed antibiotics for lower respiratory tract infections and are becoming increasingly associated with delayed treatment and resistance in TB. If these trends are not reversed soon, we may lose fluoroquinolones as effective anti-TB agents very rapidly

Minor contribution of mutations at iniA codon 501 and embC-embA intergenic region in ethambutol-resistant clinical Mycobacterium tuberculosis isolates in Kuwait

<p>Abstract</p> <p>Background</p> <p>Ethambutol (EMB) is a first-line drug for the treatment of tuberculosis (TB). Resistance to EMB in <it>Mycobacterium tuberculosis </it>isolates is mediated by mutations in several genes involved in arabinan synthesis notably three <it>emb </it>(arabinosyl transferase) and <it>iniA </it>(isoniazid-inducible) genes. Most epidemiologically unrelated EMB-resistant <it>M. tuberculosis </it>strains contain mutations at <it>embB </it>codons 306, 406 and 497, <it>embC-embA </it>intergenic region (IGR) and <it>iniA </it>codon 501 (<it>iniA501</it>).</p> <p>Objective</p> <p>To develop a more comprehensive molecular screen for EMB-resistance detectioamong epidemiologically unrelated EMB-resistant <it>M. tuberculosis </it>strains previously analyzed for <it>embB </it>codon 306, 406 and 497 mutations by including analysis of mutations at <it>iniA501 </it>and in <it>embC-embA </it>IGR.</p> <p>Methods</p> <p>Fifty consecutive and phenotypically documented EMB-resistant and 25 pansusceptible <it>M. tuberculosis </it>strains isolated from 75 different TB patients over a four-year period in Kuwait were analyzed. Mutations at <it>iniA501 </it>were detected by PCR amplification followed by restriction fragment length polymorphism (RFLP) patterns generated with <it>Hpy </it>99 I. Direct DNA sequencing was used to confirm RFLP results and for detecting mutations in <it>embC-embA </it>IGR.</p> <p>Results</p> <p>Nearly same number of EMB-resistant <it>M. tuberculosis </it>strains were resistant to EMB alone and EMB together with additional resistance to rifampicin and isoniazid (9 of 50, 18% and 11 of 50, 22%, respectively). All the 25 pansusceptible strains contained wild-type sequences at <it>iniA501 </it>and in <it>embC-embA </it>IGR. The analysis of 50 EMB-resistant <it>M. tuberculosis </it>isolates showed that only one strain contained a mutated <it>iniA501 </it>while no mutation was detected in <it>embC-embA </it>IGR in any of the isolate.</p> <p>Conclusion</p> <p>Analysis of <it>iniA501 </it>and <it>embC-embA </it>IGR in epidemiologically unrelated EMB-resistant <it>M. tuberculosis </it>isolates in Kuwait indicate that mutations at these locations occur very infrequently and their inclusion for the development of a comprehensive molecular screen will make only minor contribution towards rapid EMB resistance detection.</p

Diagnostic Performance of 1→3-β-d-Glucan in Neonatal and Pediatric Patients with Candidemia

Fungal sepsis is one of the major problems in neonatal and pediatric care unit settings. The availability of new diagnostic techniques could allow medical practitioners to rapidly identify septic patients and to improve their outcome. The aim of this study was to evaluate the performance of the 1→3-β-d-glucan (BDG), individually and in comparison with the Candida mannan (CM) antigen, in ten preterm infants and five onco-haematological pediatric patients with Candida bloodstream infections already proven by positive culture. The serum levels of BDG were >80 pg/mL on the same day as a positive blood culture in all examined patients, while CM antigen was negative in the patients with C. parapsilosis fungemia and in one further case due to C. albicans. These results suggest that a regular monitoring of serum circulating antigens (i.e., 1→3-β-d-glucan) combined with other microbiological and clinical information, may allow earlier and accurate diagnosis. However, further studies are necessary to confirm its usefulness in routine clinical practice

Extensive transmission of isoniazid resistant M. tuberculosis and its association with increased multidrug-resistant TB in two rural counties of eastern China: A molecular epidemiological study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the molecular characteristics of isoniazid resistant <it>Mycobacterium tuberculosis </it>(MTB), as well as its contribution to the dissemination of multi-drug resistant TB (MDR-TB) in rural areas of eastern China.</p> <p>Methods</p> <p>A population-based epidemiological study was conducted in two rural counties of eastern China from 2004 to 2005. In total, 131 isoniazid resistant MTB isolates were molecularly characterized by DNA sequencing and genotyped by IS<it>6110 </it>restriction fragment length polymorphism (RFLP) and spoligotyping.</p> <p>Results</p> <p>The <it>katG</it>315Thr mutation was observed in 74 of 131 isoniazid resistant isolates and more likely to be MDR-TB (48.6%) and have mutations in <it>rpoB </it>gene (47.3%). Spoligotyping identified 80.2% of isoniazid resistant MTB isolates as belonging to the Beijing family. Cluster analysis by genotyping based on IS<it>6110 </it>RFLP, showed that 48.1% isoniazid resistant isolates were grouped into 26 clusters and <it>katG</it>315Thr mutants had a significantly higher clustering proportion compared to those with <it>katG </it>wild type (73%.vs.18%; OR, 12.70; 95%CI, 6.357-14.80). Thirty-one of the 53 MDR-TB isolates were observed in 19 clusters. Of these clusters, isoniazid resistance in MDR-TB isolates was all due to the <it>katG</it>315Thr mutation; 18 clusters also contained mono-isoniazid resistant and other isoniazid resistant isolates.</p> <p>Conclusions</p> <p>These results highlighted that isoniazid resistant MTB especially with <it>katG</it>315Thr is likely to be clustered in a community, develop extra resistance to rifampicin and become MDR-TB in Chinese rural settings.</p

Serotype Distribution and Drug Resistance in Streptococcus pneumoniae, Palestinian Territories

To determine antimicrobial drug resistance of Streptococcus pneumoniae serotypes, we analyzed isolates from blood cultures of sick children residing in the West Bank before initiation of pneumococcal vaccination. Of 120 serotypes isolated, 50.8%, 73.3%, and 80.8% of the bacteremia cases could have been prevented by pneumococcal conjugate vaccines. Serotype 14 was the most drug-resistant serotype isolated

Molecular analysis of Mycobacterium isolates from extrapulmonary specimens obtained from patients in Mexico

<p>Abstract</p> <p>Background</p> <p>Little information is available on the molecular epidemiology in Mexico of <it>Mycobacterium </it>species infecting extrapulmonary sites in humans. This study used molecular methods to determine the <it>Mycobacterium </it>species present in tissues and body fluids in specimens obtained from patients in Mexico with extrapulmonary disease.</p> <p>Methods</p> <p>Bacterial or tissue specimens from patients with clinical or histological diagnosis of extrapulmonary tuberculosis were studied. DNA extracts from 30 bacterial cultures grown in Löwenstein Jensen medium and 42 paraffin-embedded tissues were prepared. Bacteria were cultured from urine, cerebrospinal fluid, pericardial fluid, gastric aspirate, or synovial fluid samples. Tissues samples were from lymph nodes, skin, brain, vagina, and peritoneum. The DNA extracts were analyzed by PCR and by line probe assay (INNO-LiPA MYCOBACTERIA v2. Innogenetics NV, Gent, Belgium) in order to identify the <it>Mycobacterium </it>species present. DNA samples positive for <it>M. tuberculosis </it>complex were further analyzed by PCR and line probe assay (INNO-LiPA Rif.TB, Innogenetics NV, Gent, Belgium) to detect mutations in the <it>rpo</it>B gene associated with rifampicin resistance.</p> <p>Results</p> <p>Of the 72 DNA extracts, 26 (36.1%) and 23 (31.9%) tested positive for <it>Mycobacterium species </it>by PCR or line probe assay, respectively. In tissues, <it>M. tuberculosis </it>complex and <it>M. genus </it>were found in lymph nodes, and <it>M. genus </it>was found in brain and vagina specimens. In body fluids, <it>M. tuberculosis </it>complex was found in synovial fluid. <it>M. gordonae</it>, <it>M. smegmatis</it>, <it>M. kansasii</it>, <it>M. genus</it>, <it>M. fortuitum/M. peregrinum </it>complex and <it>M. tuberculosis </it>complex were found in urine. <it>M. chelonae/M. abscessus </it>was found in pericardial fluid and <it>M. kansasii </it>was found in gastric aspirate. Two of <it>M. tuberculosis </it>complex isolates were also PCR and LiPA positive for the <it>rpo</it>B gene. These two isolates were from lymph nodes and were sensitive to rifampicin.</p> <p>Conclusion</p> <p>1) We describe the <it>Mycobacterium </it>species diversity in specimens derived from extrapulmonary sites in symptomatic patients in Mexico; 2) Nontuberculous mycobacteria were found in a considerable number of patients; 3) Genotypic rifampicin resistance in <it>M. tuberculosis </it>complex infections in lymph nodes was not found.</p

Species Distribution and Susceptibility to Azole Antifungals of Candida Bloodstream Isolates from Eight University Hospitals in Korea

PURPOSE: The incidence of Candida bloodstream infections (BSI) has increased over the past two decades. The rank order of occurrence and the susceptibility to antifungals of the various Candida species causing BSI are important factors driving the establishment of empirical treatment protocols; however, very limited multi-institutional data are available on Candida bloodstream isolates in Korea. MATERIALS AND METHODS: We investigated the susceptibility to azole antifungals and species distribution of 143 Candida bloodstream isolates recovered from eight university hospitals over a six-month period. Minimal inhibitory concentrations (MICs) of fluconazole, itraconazole, and voriconazole for each isolate were determined by the broth microdilution method of the Clinical and Laboratory Standards Institute (CLSI). RESULTS: The Candida species recovered most frequently from the blood cultures was C. albicans (49%), followed by C. parapsilosis (22%), C. tropicalis (14%), and C. glabrata (11%). The MIC ranges for the Candida isolates were 0.125 to 64 microg/mL for fluconazole, 0.03 to 2 microg/mL for itraconazole, and 0.03 to 1 microg/mL for voriconazole. Overall, resistance to fluconazole was found in only 2% of the Candida isolates (3/143), while the dose-dependent susceptibility was found in 6% (8/143). The resistance and dose-dependent susceptibility of itraconazole were found in 4% (6/143) and 14% (20/143) of the isolates, respectively. All bloodstream isolates were susceptible to voriconazole (MIC, < or = 1 microg/mL). CONCLUSION: Our findings show that C. albicans is the most common cause of Candida-related BSI, followed by C. parapsilosis, and that the rates of resistance to azole antifungals are still low among bloodstream isolates in Korea.ope

Levels of (1→3)-β-D-glucan, Candida mannan and Candida DNA in serum samples of pediatric cancer patients colonized with Candida species

<p>Abstract</p> <p>Background</p> <p>Surveillance cultures may be helpful in identifying patients at increased risk of developing invasive candidiasis. However, only scant information exists on the effect of <it>Candida </it>colonization on serum levels of diagnostic biomarkers. This prospective surveillance study determined the extent of <it>Candida </it>colonization among pediatric cancer patients and its possible impact on serum levels of (1-3)-β-D-glucan (BDG), <it>Candida </it>mannan and <it>Candida </it>DNA.</p> <p>Methods</p> <p>A total of 1075 swabs originating from oropharynx (n = 294), nostrils (n = 600), rectum (n = 28), groin (n = 50), ear (n = 54), and axilla (n = 49) of 63 pediatric cancer patients were cultured for the isolation of <it>Candida </it>spp. Patients yielding <it>Candida </it>spp. from any sites were considered as colonized. Serum samples were collected from patients at the time of first surveillance culture for detection of BDG by Fungitell kit and <it>Candida </it>mannan by Platelia <it>Candida </it>Ag. <it>Candida </it>DNA was detected by using panfungal primers and identification was carried out by using species-specific primers and DNA sequencing.</p> <p>Results</p> <p>Seventy-five (7.6%) swab cultures from 35 (55.5%) patients yielded <it>Candida </it>spp. These isolates included <it>C. albicans </it>(n = 62), <it>C. dubliniensis </it>(n = 8), <it>C. glabrata </it>and <it>C. tropicalis </it>(n = 2 each) and <it>C. krusei </it>(n = 1). Eleven patients were colonized at three or more sites. Eight of 36 serum samples from 6 colonized patients yielded BDG values higher than the currently recommended cut-off value of ≥80 pg/ml. However, none of the serum samples yielded <it>Candida </it>mannan levels ≥0.5 ng/ml and PCR test for <it>Candida </it>DNA was also negative in all the serum samples of colonized patients. During the study period, only two colonized patients subsequently developed candidemia due to <it>C. tropicalis</it>. Besides positive blood cultures, <it>C. tropicalis </it>DNA, BDG and <it>Candida </it>mannan were also detected in serum samples of both the patients.</p> <p>Conclusions</p> <p>The present study demonstrates that while mucosal colonization with <it>Candida </it>species in pediatric cancer patients is common, it does not give rise to diagnostically significant levels of <it>Candida </it>mannan or <it>Candida </it>DNA in serum specimens. However, BDG values may be higher than the cut-off value in some pediatric patients without clinical evidence of invasive <it>Candida </it>infection. The study suggests the utility of <it>Candida </it>mannan or <it>Candida </it>DNA in the diagnosis of invasive candidiasis, however, the BDG levels in pediatric cancer subjects should be interpreted with caution.</p