scholarly journals Role of fluoroquinolones in the treatment of tuberculosis

2011 ◽  
Vol 3 (1) ◽  
pp. 17-31
Author(s):  
Suhail Ahmad ◽  
Eiman Mokaddas
Keyword(s):  
Combination Therapy ◽  
Phase Iii ◽  
Cross Resistance ◽  
Phase Ii Trials ◽  
First Line ◽  
Duration Of Treatment ◽  
Pulmonary Tb ◽  
Mdr Tb ◽  
Tract Infections

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.

scholarly journals Role of fluoroquinolones in the treatment of tuberculosis

2011 ◽  
Vol 3 (1) ◽  
pp. 17
Author(s):  
Suhail Ahmad ◽  
Eiman Mokaddas
Keyword(s):  
Combination Therapy ◽  
Phase Iii ◽  
Cross Resistance ◽  
Phase Ii Trials ◽  
First Line ◽  
Duration Of Treatment ◽  
Pulmonary Tb ◽  
Mdr Tb ◽  
Tract Infections

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.

scholarly journals Current Prospects for the Fluoroquinolones as First-Line Tuberculosis Therapy

2011 ◽  
Vol 55 (12) ◽  
pp. 5421-5429 ◽  
Author(s):  
Howard Takiff ◽  
Elba Guerrero
Keyword(s):  
Multidrug Resistant ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
First Line ◽  
Current Standard ◽  
Standard Drug ◽  
First Line Therapy ◽  
Development Of Resistance ◽  
Mdr Tb ◽  
Phase Iii Trials

ABSTRACTWhile fluoroquinolones (FQs) have been successful in helping cure multidrug-resistant tuberculosis (MDR TB), studies in mice have suggested that if used as first-line agents they might reduce the duration of therapy required to cure drug-sensitive TB. The results of phase II trials with FQs as first-line agents have been mixed, but in at least three studies where moxifloxacin substituted for ethambutol, there was an increase in the early percentage of sputa that converted to negative for bacilli. Phase III trials are in progress to test the effectiveness of 4-month FQ-containing regimens, but there is concern that the widespread use of FQs for other infections could engender a high prevalence of FQ-resistant TB. However, several studies suggest that despite wide FQ use, the prevalence of FQ-resistant TB is low, and the majority of the resistance is low-level. The principal risk for resistance may be when FQs are used to treat nonspecific respiratory symptoms that are in fact TB, so curtailing this use of FQs could reduce the development of resistance and also the delays in TB diagnosis and treatment that have been documented when an FQ is given in this setting. While the future of FQs as first-line therapy will likely depend upon the results of the ongoing phase III trials, if they are to be effectively employed in high-TB-burden regions their use for community-acquired pneumonias should be restricted, the prevalence of FQ-resistant TB should be monitored, and the cost of the treatment should be comparable to that of current standard drug regimens.

Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
S. Sukumaran ◽  
N. Pavlakis ◽  
K. B. Pittman ◽  
K. Patterson ◽  
T. J. Price
Keyword(s):  
Phase Ii ◽  
Phase Iii ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
First Line ◽  
Hand Foot Syndrome ◽  
Phase Iii Trials ◽  
Grade 3 ◽  
Phase Ii And Iii ◽  
First Line Treatment

e15100 Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established. No significant financial relationships to disclose.

Phase II study of oxaliplatin and sorafenib in advanced gastric cancer after failure of cisplatin-fluoropyrimidine-based (PF) treatment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4079-4079 ◽  
Author(s):  
Rosa Gallego ◽  
Marta Martin-Richard ◽  
Carles Pericay ◽  
Jesus Garcia-Foncillas ◽  
Bernardo Queralt ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Iii ◽  
Cross Resistance ◽  
First Line ◽  
Stage Design ◽  
First Line Therapy ◽  
Pathway Activation ◽  
Adequate Organ Function ◽  
Previously Treated ◽  
Vegfr Inhibitor

4079 Background: PF-based chemotherapy is the standard first line treatment in advanced GC. Although some drugs as taxanes or oxaliplatin (Ox) have shown efficacy in combination with P or F, no established second line exists. RAF/MEK/ERK pathway activation as well as VEGF expression have been related with more advanced GC. Sorafenib (S) is a potent Raf and VEGFR inhibitor and Ox has demonstrated non-cross resistance with P. Methods: A multicenter phase II to evaluate the efficacy of OX- S combination in gastric or GEJ adenocarcinoma (pts) with progressive disease after CF based first line chemotherapy, was planned. Other inclusion criteria: ECOG 0-2, measurable disease and adequate organ function. Treatment doses were Ox 130mg/m2/3 weeks and S 800 mg/bid/d until progression or toxicity. CT scan evaluation every 3 cycles. The study followed a A-Hern single-stage design (HR = 1.67, median expected PFS of 4.3m if treatment ineffective, sample size: 43). The study was closed with the inclusion of 40 pts, maintaining a power > 87%. Ten pts would have to be alive and free of progression at 12m to consider the study positive. Results: Forty pts were included and evaluable for PFS. Thirty-six pts were evaluable for response. Median age was 63 ( range 39 - 76) years, ECOG 0/1/2 in 36/59/5 % of pts. PFS to 1st line was > 6m in 59% of pts. One CR and, 47.2% of SD were observed. Gr ¾ toxicity (%) was: neutropenia (9.8), thrombocitopenia (7.3), neurotoxicity (4.9) and diarrhea (4.9). Median PFS was 3 (95 %CI: 2.3-4.1 )m and median OS was 6.5 ( 95% CI: 5.2-9.6)m. PFS at 12 m was 0%. Median OS in pts with PFS to 1º line > 6m/ <6m was 9.7m and 5.6m respectively (p0.04). Conclusions: The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF shows a safe profile but these results do not support the implementation of a phase III trial. Our results show that PFS under a CP-based first line therapy determine subgroups of GC patients with different clinical behaviors.

REGARD: A phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. LBA5-LBA5 ◽  
Author(s):  
Charles S. Fuchs ◽  
Jiri Tomasek ◽  
Jae Yong Cho ◽  
Filip Dumitru ◽  
Rodolfo Passalacqua ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Disease Progression ◽  
Gastroesophageal Junction ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Vegf Receptor ◽  
First Line ◽  
Double Blind ◽  
Cancer Pathogenesis ◽  
Line Therapy

LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.

Irinotecan/Fluorouracil Combination in First-Line Therapy of Older and Younger Patients With Metastatic Colorectal Cancer: Combined Analysis of 2,691 Patients in Randomized Controlled Trials

2008 ◽  
Vol 26 (9) ◽  
pp. 1443-1451 ◽  
Author(s):  
Gunnar Folprecht ◽  
Matthew T. Seymour ◽  
Leonard Saltz ◽  
Jean-Yves Douillard ◽  
Hartmut Hecker ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Elderly Patients ◽  
Metastatic Colorectal Cancer ◽  
Significant Interaction ◽  
Phase Iii ◽  
First Line ◽  
Younger Patients ◽  
Combined Analysis ◽  
Phase Iii Trials

PurposeUncertainty exists about whether elderly patients benefit to the same extent as younger patients from combination therapy with irinotecan in the first-line treatment of metastatic colorectal cancer (CRC).Patients and MethodsCombined analysis was carried out with source data from the fluorouracil (FU)/folinic acid (FA) and the irinotecan/FU/FA arms of four first-line, phase III trials of CRC to investigate the efficacy and safety of combination and monotherapy in elderly (age ≥ 70 years; n = 599) compared with younger (age < 70 years; n = 2,092) patients.ResultsResponse rates were improved with irinotecan-based combination therapy compared with FU/FA in patients both younger than 70 years and ≥ 70 years (46.6% v 29.0% P < .0001; and 50.5% v 30.3%, P < .0001, respectively). With irinotecan/FU/FA, progression-free survival was better for both younger (hazard ratio [HR], 0.77; 95% CI, 0.70 to 0.85; P < .0001) and elderly patients (HR, 0.75; 95% CI, 0.61 to 0.90; P = .0026). In younger patients, overall survival was improved with combination therapy (HR, 0.83; 95% CI, 0.75 to 0.92; P = .0003). The same trend was observed in elderly patients (HR, 0.87; 95% CI, 0.72 to 1.05; P = .15). There was no significant interaction between treatment arm and age in the regression analysis. The expected differences in toxicity between combination and monotherapy in elderly and younger patients were observed. A significant interaction between treatment and age (cutoff, 70 years) for vomiting and hepatotoxicity was not confirmed by analysis that used age as a continuous variable.ConclusionPatients older than 70 years of age who were selected for inclusion in phase III trials derived similar benefits as younger patients from irinotecan-containing chemotherapy, and the risk of toxicity was similar.

scholarly journals Spontaneous Intracerebral and Intraventricular Hemorrhage

Neurosurgery ◽  
2014 ◽  
Vol 74 (suppl_1) ◽  
pp. S142-S150 ◽  
Author(s):  
Mahua Dey ◽  
Agnieszka Stadnik ◽  
Issam A. Awad
Keyword(s):  
Randomized Trials ◽  
Lessons Learned ◽  
National Institutes Of Health ◽  
Phase Iii ◽  
Recent Experience ◽  
Preliminary Treatment ◽  
Phase Ii Trials ◽  
Invasive Techniques ◽  
The Impact

Abstract Optimal management of spontaneous intracerebral hemorrhage (ICH) remains one of the highly debated areas in the field of neurosurgery. Earlier studies comparing open surgical intervention with best medical management failed to show a clear benefit. More recent experience with minimally invasive techniques has shown greater promise. Well-designed phase II trials have confirmed the safety and preliminary treatment effect of thrombolytic aspiration and clearance of spontaneous ICH and associated intraventricular obstructive hemorrhage. Those trials are reviewed, including respective protocols and technical nuances, and lessons learned regarding patient selection, the concept of hemorrhage stabilization, optimization of the surgical procedure, and thrombolytic dosing decisions. These concepts have been incorporated in the design of ongoing definite phase III randomized trials (MISTIE and CLEAR) funded by the National Institutes of Health. These are presented including the role of surgical leadership in the training and monitoring of the surgical task and quality assurance. The impact of these techniques on neurosurgical practice is discussed.

scholarly journals First Line Anti-Tubercular Drug Resistance Pattern of Mycobacterium Tuberculosis Isolated From Specialized Hospitals of Dhaka City

2016 ◽  
Vol 8 (2) ◽  
pp. 41-46 ◽  
Author(s):  
Md Mohiuddin ◽  
J Ashraful Haq
Keyword(s):  
Drug Resistance ◽  
Extrapulmonary Tuberculosis ◽  
Surrogate Marker ◽  
Cross Resistance ◽  
Resistance Pattern ◽  
First Line ◽  
Drug Resistance Pattern ◽  
Mdr Tb ◽  
Lowenstein Jensen ◽  
High Level

The present study was undertaken to determine the drug resistance pattern of M. tuberculosis isolated from 225 pulmonary and 45 extrapulmonary tuberculosis cases. The samples were cultured on Lowenstein Jensen (L-J) media for isolation of M. tuberculosis. Drug resistance to first line anti tubercular drugsnamely isoniazid (INH), rifampicin (RIF), Ethambutol (ETH) and streptomycin (SM) were determined by indirect proportion method. The overall drug resistance of M. tuberculosis was 53.6% to any of the first line anti tubercular drugs. Rate of multi drug resistant tuberculosis (MDR-TB) among the untreated cases was 4.2%, while it was 36.0% in previously treated cases. It was found that 83.3% rifampicin resistant M. tuberculosis was cross resistant to one or more of other first line anti-tubercular drugs, while cross resistance of INH, ETH and SM resistant isolates was much low. The present study revealed that high level of drug resistance exists to individual anti tubercular drugs and MDR-TB is an emerging problem, particularly in treated cases. Rifampicin resistance could be used as a surrogate marker for drug resistance to other first line anti tubercular drugs.Ibrahim Med. Coll. J. 2014; 8(2): 41-46

Sunitinib versus interferon-alfa (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC): Updated results and analysis of prognostic factors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5024-5024 ◽  
Author(s):  
R. J. Motzer ◽  
R. A. Figlin ◽  
T. E. Hutson ◽  
P. Tomczak ◽  
R. M. Bukowski ◽  
...  
Keyword(s):  
Risk Factors ◽  
Prognostic Factors ◽  
Median Duration ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Duration Of Treatment ◽  
First Line Treatment

5024 Background: In a randomized phase III trial of patients (pts) with mRCC, sunitinib demonstrated a significant improvement in progression-free survival (PFS) and objective response rate (ORR) compared to IFN-a as first-line therapy (Proc ASCO 2006;24:2s [Abstract LBA3]). We present the most recent data from this trial and an analysis of prognostic factors. Methods: Untreated pts with clear-cell mRCC were randomized 1:1 to receive either sunitinib (repeated 6-week cycles of 50 mg/day orally for 4 weeks, followed by 2 weeks off treatment) or IFN-a (9 MU given subcutaneously three times weekly). The primary endpoint was PFS. Results: A total of 750 pts were randomized: 375 to sunitinib, 375 to IFN-a. The median duration of treatment is 11 months (range: <1–25) for sunitinib vs. 4 months (range: <1–22) for IFN-a. The updated ORR by investigator assessment is 44% (95% CI: 39, 49) for sunitinib vs. 11% (95% CI: 8, 15) for IFN-a (p <0.000001), including 4 complete responses for sunitinib and 2 for IFN-a. The median duration of response in the sunitinib group (n=165) is 12 months (95% CI: 10, 14) vs. 10 months (95% CI: 8, 17) in the IFN-a group (n=43). The median PFS is 11 months (95% CI: 10, 11) for sunitinib vs. 4 months (95% CI: 4, 5) for IFN-a. The median PFS for pts with 0 risk factors is 14 months (95% CI: 11, 16) for sunitinib vs. 8 months (95% CI: 7, 10) for IFN-a; 9 months (95% CI: 8, 11) vs. 4 months (95% CI: 4, 4), respectively, for pts with 1- 2 risk factors; 4 months (95% CI: 2, 10) vs. 1 month (95% CI: 1, 2), respectively, for pts with =3 risk factors. The sunitinib benefit in PFS extends across all MSKCC prognostic risk factor groups (HR=0.488; 95% CI: 0.406, 0.586). The baseline features that predict longer PFS (by investigator assessment) for the sunitinib group are hemoglobin =LLN (p=0.0043), corrected calcium =10 mg/dL (p=0.001), ECOG score of 0 (p=0.0005), number of metastatic sites 0 or 1 (p=0.0064), and time from diagnosis to treatment =1 yr (p=0.0002). Conclusions: Sunitinib is a reference standard for first-line treatment of mRCC, with significant improvement in PFS and ORR compared to IFN-a. The benefit of sunitinib extends across all subgroups of pts with mRCC. Previously defined MSKCC risk factors for mRCC predict longer PFS with sunitinib. No significant financial relationships to disclose.

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