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

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

Antibacterial resistance and their genetic location in MRSA isolated in Kuwait hospitals, 1994-2004

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of serious infections in hospitals and in the community worldwide. In this study, MRSA isolated from patients in Kuwait hospitals were analyzed for resistance trends and the genetic location of their resistance determinants. METHODS: Between April 1994 and December 2004, 5644 MRSA isolates obtained from different clinical samples were studied for resistance to antibacterial agents according to guidelines from the National Committee for Clinical Laboratory Standards and the British Society for Antimicrobial Chemotherapy. The genetic location of their resistance determinants was determined by curing and transfer experiments. RESULTS: They were resistant to aminoglycosides, erythromycin, tetracycline, trimethoprim, fusidic acid, ciprofloxacin, chloramphenicol, rifampicin, mupirocin, cadmium acetate, mercuric chloride, propamidine isethionate and ethidium bromide but susceptible to vancomycin, teicoplanin and linezolid. The proportion of the isolates resistant to erythromycin, ciprofloxacin and fusidic acid increased during the study period. In contrast, the proportion of isolates resistant to gentamicin, tetracycline, chloramphenicol and trimethoprim declined. High-level mupirocin resistance increased rapidly from 1996 to 1999 and then declined. They contained plasmids of 1.9, 2.8, 3.0, 4.4, 27 and 38 kilobases. Genetic studies revealed that they carried plasmid-borne resistance to high-level mupirocin resistance (38 kb), chloramphenicol (2.8 – 4.4 kb), erythromycin (2.8–3.0 kb) and cadmium acetate, mercuric chloride, propamidine isethionate and ethidium bromide (27 kb) and chromosomal location for methicillin, the aminoglycosides, tetracycline, fusidic acid, ciprofloxacin and trimethoprim resistance. Thus, the 27 kb plasmids had resistance phenotypes similar to plasmids reported in MRSA isolates in South East Asia. CONCLUSION: The prevalence of resistance to erythromycin, ciprofloxacin, high-level mupirocin and fusidic acid increased whereas the proportion of isolates resistant to gentamicin, tetracycline, chloramphenicol and trimethoprim declined during the study period. They contained 27-kb plasmids encoding resistance to cadmium acetate, mercuric chloride, propamidine isethionate and ethidium bromide similar to plasmids isolated in MRSA from South East Asia. Molecular typing of these isolates will clarify their relationship to MRSA from South East Asia

The 13-valent pneumococcal conjugate vaccine (PCV13) does not appear to provide much protection on combined invasive disease due to the six PCV13 non-PCV7 serotypes 1, 3, 5, 6A, 7F, and 19A in Kuwait during 2010–2019

Kuwait started immunizing children 65 y and all ages, compared to the pre-vaccination period, August 2003–July 2006 (period I). In the current study, we allowed additional time, August 2013–July 2019 (period III) for better vaccine effect and repeated the analysis. We did not find any significant decrease of invasive disease due to the non-PCV7 serotypes of PCV13 in period III and combined II and III periods compared to period I. However, these comparisons showed significant reductions for four of the six and total serotypes of PCV7, and total serotypes of PCV13. Reduction for total PCV13 serotypes was contributed by serotypes of PCV7. It appears that the six non-PCV7 serotypes in PCV13 do not offer much protection. Some contributory factors for the poor effect of the non-PCV7 serotypes may be related to few cases with underpowered statistical analysis, lack of vaccine coverage data, method of vaccine efficacy analysis based on vaccine serotypes relative to all serotypes and unusual rise in non-typeable isolates post vaccination that would have masked true serotypes

Comparison of performance of two DNA line probe assays for rapid detection of multidrug-resistant isolates of <i style="">Mycobacterium tuberculosis</i>

454-462 Infections with multidrug-resistant (resistant at least to rifampicin, RIF and isoniazid, INH) strains of Mycobacterium tuberculosis (MDR-TB) are associated with high case fatality rates. Rapid identification of MDR-TB strains is important for early institution of appropriate therapy. Two DNA line probe assays, GenoType MTBDR (GT-MTBDR) and INNO-LiPA Rif. TB (INNO-LiPA) were compared for their abilities to detect resistance to INH and RIF in 80 M. tuberculosis isolates. The test results were compared to those obtained by conventional drug susceptibility testing (DST), DNA sequencing and/or PCR-restriction fragment length polymorphism (RFLP) analysis of regions of interest of M. tuberculosis genome. Compared to the DST and katG codon 315 PCR-RFLP results, GT-MTBDR test results were concordant for INH resistance for 63 of 80 (78.7%) isolates. For RIF resistance, GT-MTBDR and INNO-LiPA test results were concordant with DST for 74 of 80 (92.5%) and 76 of 80 (95%) strains, respectively. The GT-MTBDR test results correlated with sequencing results for 77 of 80 (96.2%) while INNO-LiPA results for 79 of 80 (98.7%) isolates. Both the tests are useful for rapid detection of MDR-TB strains, however, GT-MTBDR assay offers the advantage of detecting the resistance to both INH and RIF simultaneously when MDR-TB is suspected. </smarttagtype

Tobacco Agar, a New Medium for Differentiating Candida dubliniensis from Candida albicans

Isolates of Candida dubliniensis may be misidentified as Candida albicans in microbiological laboratories if only the germ tube and/or the chlamydospore test is used for identification to the species level. In this study, we have evaluated the efficacy of tobacco agar for the differentiation of C. dubliniensis from C. albicans. On this medium at 28°C, all 30 C. dubliniensis isolates produced yellowish-brown colonies with hyphal fringes and abundant chlamydospores, whereas 54 C. albicans isolates formed smooth, white-to-cream-colored colonies with no chlamydospore production. This medium provides a simple tool for presumptive differentiation of C. dubliniensis from C. albicans