Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

Tuberculosis pharmacotherapy: strategies to optimize patient care

Introduction: The treatment of tuberculosis (TB) is a mature discipline, with more than 60 years of clinical experience accrued across the globe. The requisite Multi-drug treatment of drug-susceptible TB, however, lasts 6 months and has never been optimized according to current standards. Multi-drug resistant TB and TB in individuals coinfected with HIV present additional treatment challenges. Objective: This article reviews the role that existing drugs and new compounds could have in shortening or improving treatment for TB. The key to treatment shortening seems to be sterilizing activity, or the ability of drugs to kill mycobacteria that persist after the initial days of multi-drug treatment. Results: Among existing anti-TB drugs, the rifamycins hold the greatest potential for shortening treatment and improving outcomes, in both HIV-infected and HIV-uninfected populations, without dramatic increases in toxicity. Clinical studies underway or being planned, are supported by in vitro , animal and human evidence of increased sterilizing activity - without significant increases in toxicity - at elevated daily doses. Fluoroquinolones also seem to have significant sterilizing activity. At present, at least two class members are being evaluated for treatment shortening with different combinations of first-line drugs. However, in light of apparent rapid selection for fluoroquinolone-resistant mutants, relative frequency of serious adverse events and a perceived need to ‘reserve’ fluoroquinolones for the treatment of drug-resistant TB, their exact role in TB treatment remains to be determined. Other possible improvements may come from inhaled delivery or split dosing (linezolid) of anti-TB drugs for which toxicity (ethionamide) or lack of absorption (aminoglycosides and polypeptides) precludes delivery of maximally effective, oral doses, once daily. New classes of drugs with novel mechanisms of action, nitroimidazopyrans and a diarylquinoline, among others, may soon provide opportunities for improving treatment of drug-resistant TB or shortening treatment of drug-susceptible TB. Conclusion: More potential options for improved TB treatment currently exist than at any other time in the last 30 years. The challenge in TB pharmacotherapy is to devise well-tolerated, efficacious, short-duration regimens that can be used successfully against drug-resistant and drug-resistant TB in a heterogeneous population of patients     

Derivatives of 3-isoxazolecarboxylic acid esters: a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis

New antituberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains and to shorten the long treatment regimen. A series of isoxazole-based compounds, bearing a carboxy moiety at the C3 position, are highly potent and versatile anti-TB agents. Several members of this compound class exhibit submicromolar in vitro activity against replicating Mtb (R-TB) and thus comparable activity to the current first-line anti-TB drugs. Remarkably, certain compounds also show low micromolar activity in a model for nonreplicating Mtb (NRP-TB) phenotype, which is considered a key to shortening the current long treatment protocol. The series shows excellent selectivity towards Mtb and, in general, shows no cytotoxicity on Vero cells (IC50's > 128 μM). Selected compounds retain their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. The foregoing facts make derivatives of 3- isoxazolecarboxylic acid esters a promising anti-TB chemotype, and as such present attractive lead compounds for TB drug development.     

The role of fluoroquinolones in tuberculosis today

Tuberculosis is a growing international health concern; it is the leading infectious cause of death in the world today. The fluoroquinolones are the most recent class of drugs offering hope in the fight against this disease. Ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin are currently the most commonly used agents used against Mycobacterium tuberculosis (TB), with in vitro minimum inhibitory concentrations (MICs) of 0.1 to 4 mcg/ml. Resistance in TB to fluoroquinolones may occur spontaneously or may be acquired, especially when these agents are used inappropriately. Cross-resistance among the fluoroquinolones has been shown in TB. The fluoroquinolones offer a favourable pharmacokinetic profile for the treatment of TB. Most demonstrate excellent oral bioavailability and achieve maximum (peak) serum concentrations well above the MIC. They are also distributed widely, including intracellularly. The fluoroquinolones are cleared renally and/or hepatically, with varying serum half-lives. Fluoroquinolones are most effective when the peak concentration (Cmax) to MIC ratio is maximised. Fluoroquinolones such as ciprofloxacin and ofloxacin have been used in regimens for the prevention of TB, but have been poorly tolerated when used in combination with pyrazinamide. Favourable responses with fluoroquinolones in regimens used in the treatment of clinical TB disease have been seen. They, however, are not to be considered as equal replacements for isoniazid or rifampicin (rifampin) and should be used with at least 2 other antituberculous agents. Therapeutic drug monitoring of fluoroquinolones is beneficial in assuring that maximum Cmax to MIC ratios are being achieved, especially in patients at risk for malabsorption, such as those infected with HIV. Higher, once-daily doses of most fluoroquinolones are becoming more common in treating TB. Fluoroquinolones are generally well tolerated with long term use in treating TB, but rare, serious adverse effects have been reported with general fluoroquinolone use. The most common drug interactions with fluoroquinolones in TB therapy include the malabsorption interactions associated with multivalent cations and cytochrome P450 interactions with ciprofloxacin. An increased risk of central nervous system effects with concomitant cycloserine has been reported and seen clinically. When using fluoroquinolones to treat TB, careful consideration of individual susceptibility patterns, pharmacokinetic and toxicity profiles should be taken. The aid of a TB expert may also be warranted. The exact role of the fluoroquinolones in treating TB remains to be determined.     

Phenothiazines as anti-multi-drug resistant tubercular agents

Pulmonary tuberculosis (TB) has again become a global problem: it infects 2.2 billion people world-wide, caused the deaths of over 3 million last year and will produce over 8 million new cases of TB this coming year. Although effective therapy is widely available for antibiotic susceptible strains of Mycobacterium tuberculosis, current drugs are relatively useless against multi-drug resistant infections (MDRTB). Mortality is almost complete within two years regardless of therapy, and in the case of co-infection with HIV/AIDS, mortality is 100% within a few months of diagnosis especially the M. tuberculosis strain in XDRTB. As of the time of this writing no new effective anti-TB drugs have been made available by the pharmaceutical industry and XDRTB. Because TB is an intracellular infection of the non-killing macrophage of the lung, any agent that is to prove effective must have activity against MDRTB and XDRTB strains that have been phagocytosed by the human macrophage. This review intents to provide cogent in vitro, ex vivo and in vivo evidence that supports the use of a variety of commonly available phenothiazines for the therapy of MDRTB and XDRTB, especially when the prognosis of the infection is poor and the use of the recommend agents can take place along lines of "compassionate therapy". In addition, we will describe the macrophage assay as indispensable when an agent is to be further studied for its effectiveness as an anti-TB drug. In vitro studies if not complemented by ex vivo studies will for the most part be dead-ended since few agents that have activity in vitro have any activity against phagocytosed M. tuberculosis.     

Challenges Facing Antitubercular Therapy: New Drugs and Delivery Systems

Tuberculosis (TB) has again emerged as a challenging disease, victimizing a large section of the world population. Long duration of therapy, drug resistance, side effects associated with large doses of number of drugs, and economic reasons have resulted in poor patient compliance and in ineffective anti-TB therapy. In addition, drug-resistant strains of tubercle bacilli have further compounded the problem. In this article challenges facing present therapy, the mode of tuberculosis infection, challenges facing fixed-dose combination (FDC) formulation, new anti-TB molecules from the modification of existing anti-TB drugs for better activity, new molecules acting on the novel targets for reducing bacterial pathogenicity, antibiotics and nonantibiotics exhibiting anti-TB activity, and new drug delivery systems are discussed.     

Drug resistance in Mycobacterium tuberculosis and targeting the l,d-transpeptidase enzyme

Tuberculosis (TB) is a disease that has afflicted mankind for thousands of years, but in the last seven decades, much progress has been made in anti-TB therapy. Early drugs, such as para-aminosalicylic acid, streptomycin, isoniazid, and rifamycins were very effective in combatting the disease, giving rise to the hope that TB would be eradicated from the face of the earth by 2010. Despite that optimism, TB continues to kill more than a million people annually worldwide. A major reason for our inability to contain TB is the emergence drug resistance in Mycobacterium tuberculosis. This commentary is based on our recent publication on the structure of l ,d -transpeptidase enzyme, relevant to drug resistance. As a background, we briefly outline the history and development of anti-TB therapy. Based on the crystal structure, we suggest a potential direction for designing more potent drugs against TB.     

Emerging therapeutic targets in tuberculosis: post-genomic era

Every minute, somewhere in the world four people die from tuberculosis (TB), yet it has been nearly 40 years since a novel drug was introduced to treat this disease. The ever increasing number of TB cases together with the advent of multi-drug resistant (MDR) TB, has stimulated the search for novel anti-TB agents. An array of novel drug targets is provided by the mycobacterial cell wall, whose integrity is essential for bacterial viability. Over the years researchers have identified potential drug targets that are associated with the synthesis of various cell wall constituents. This classic approach, together with the unravelling of the Mycobacterium tuberculosis genome sequence, has placed TB drug research in an unprecedented position. An entire new set of genetic and bioinformatic tools for probing potential drug targets is now available. As therapies using first-line drugs like isoniazid (INH) or rifampin in combination with second-line drugs, like ethambutol (EMB) still continues, a number of substituted fluoroquinolones are being considered as the new generation of anti-TB drugs for their favourable pharmacokinetic profile and excellent oral bioavailability. In this review, the future of anti-TB drugs is discussed with reflection on the structure and biosynthesis of cell wall constituents that are potential drug targets. The importance and relevance of the M. tuberculosis genome sequence for the development of novel anti-TB drugs, have also been underscored.     

Drug-resistant tuberculosis: what are the treatment options?

Drug-resistant tuberculosis (DR-TB) is an emerging global health threat as treatment involves complex multiple drug regimens, which are longer and more toxic than standard therapy and yet have worse outcomes. In the presence of resistance to one or more first-line drugs, an alternative regimen should be designed. A major problem is the almost complete lack of published evidence regarding the optimal drug combinations and duration of treatment for the different types of DR-TB. Current principles, some of which are based on expert opinion, are that at least three new anti-TB agents should be added to a failing regimen and four agents when multidrug resistance is suspected. All first-line oral anti-TB agents to which the Mycobacterium tuberculosis strains are susceptible should be used, plus one fluoroquinolone. In addition, one injectable anti-TB agent and one or more second-line oral anti-TB agents should be added to the regimen until the target number of drugs is reached. The duration of treatment depends on the type of drug resistance, the type and number of drugs used in the regimen, and the extent of the disease. All forms of DR-TB should receive daily, not intermittent, therapy and all doses should be directly observed. Because of the high rate of adverse drug effects, careful monitoring and appropriate management of these adverse reactions are important to achieve successful treatment. Supportive measures, such as adequate nutrition along with emotional and social supports, are an important part of the treatment. Careful consideration is required when dealing with pregnant or lactating women and HIV co-infected patients, as well as in treatment of extrapulmonary DR-TB.     

Adverse reactions of anti-tuberculosis drugs in hospitalized patients: incidence, severity and risk factors

BACKGROUND: Tuberculosis (TB) has been a common chronic infectious disease in human communities. Besides disease-related complications, there could be serious adverse reactions due to anti-tuberculosis (anti-TB) drug therapy. OBJECTIVES: To assess the incidence and severity of adverse drug reactions (ADRs) induced by anti-TB drugs. To determine possible covariates associated with detected ADRs. METHODS: All patients with respiratory TB admitted to a teaching hospital who received anti-TB drugs during the research period entered the study and were monitored for ADRs. Socio-demographic and medical history of patients were used as independent covariates. The relationship between independent covariates with frequency and severity of ADRs was analysed using multivariate logistic regression. Preliminary analyses of the Mann-Whitney, Chi-square, Kruskal-Wallis and the Fisher's exact tests were applied to determine factors unlikely associated with the independent variables. RESULTS: Among 204 patients admitted, there were 92 patients (45.1%) with ADRs induced by anti-TB drugs. Patients with a previous history of anti-TB drugs usage (OR = 5.81, 95% confidence interval [95%CI]: 1.31-25.2), patients with a history of drug allergy (OR = 6.68, CI: 1.28-36.2), those from Afghani ethnic (OR = 4.91, 95%CI: 1.28-18.30) as well as smoker patients with concurrent diseases (OR = 19.67, CI: 1.24-341.51) had a higher rate of ADR incidence. Being female (OR = 1.63, 95%CI: 1.96-36.40) and having previous history of ADR (OR = 17.46, 95%CI: 1.96-20.42) were identified as risk factors. CONCLUSION: Anti-TB drugs could cause severe and frequent adverse effects. Females, those with a previous history of ADRs to anti-TB drugs and Afghani patients, should be considered as high-risk groups.     

The epidemiology of antibiotic resistance in Streptococcus pneumoniae and the clinical relevance of resistance to cephalosporins, macrolides and quinolones

Invasive non-meningeal pneumococcal infections remain a major cause of morbidity and mortality worldwide. The factors affecting the epidemiology and mortality of pneumococcal infections are discussed. The increase and spread of resistance to antimicrobial agents among pneumococci is a cause of concern to the clinician. There are links between the usage of antibacterial agents and the development of resistance. Resistance to penicillin and other beta-lactams has become widespread but this does not appear to have decreased the efficacy of some of these agents against non-meningeal infections. There is evidence that the good pharmacokinetic and pharmacodynamic features of the third generation cephalosporins (cefotaxime and ceftriaxone) contribute to their efficacy in vivo. New breakpoints for cefotaxime and ceftriaxone against non-meningeal pneumococcal isolates were proposed by the National Committee for Clinical Laboratory Standard (NCCLS, US), based on the clinical evidence of the efficacy of these drugs. In contrast there is increasing evidence that resistance to macrolides can lead to a poor clinical response. Fluoroquinolones have been widely used to treat respiratory tract infections among others, and pneumococcal resistance to these agents in vitro, although currently low, is increasing. There are reports that resistance to fluoroquinolones can develop during treatment and may be reflected in a lack of clinical response. Several clinical and epidemiological variables (e.g. prior antibiotic use) can be useful to identify patients at risk from infections with antibiotic-resistant pneumococci. These patients would be those who would benefit the most from a pneumococcal vaccination programme.     

Stereochemistry at the forefront in the design and discovery of novel anti-tuberculosis agents

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.     

Emerging drugs and alternative possibilities in the treatment of tuberculosis

Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB.

Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB.

Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment.

The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation.

Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.     

Antidepressant, anxiogenic, and antinociceptive properties of levofloxacin in rats and mice

Levofloxacin, an optically active isomer of ofloxacin, is a fluorinated quinolone with a broad spectrum of antibacterial activity. Fluoroquinolones have been used for the treatment of bacterial infections for many years. Although they were considered as relatively safe drugs, various adverse effects have recently been reported along with increase in the usage of new-generation fluoroquinolones. In the present study, some of the central nervous system (CNS)-related side effects of levofloxacin were clarified in animals. Our results suggested that: levofloxacin (10-20-40 mg/kg i.p.) had no depression-like effect in the forced swimming test (FST) in rats; exerted anxiety-like effect in the elevated plus maze test in rats; did not alter the locomotor activity in rats; had no apparent effect on sleep latency but shortened the sleeping time on pentobarbital sleeping time in mice; and showed analgesic activity in acetic acid writhing and hot plate test in mice.     

结核分枝杆菌对氟喹诺酮类药物的耐药性研究进展

氟喹诺酮类药物在耐多药结核治疗中的应用日益广泛，但结核分枝杆菌对其耐药性也逐渐增加，特别是当不合理用药时更易发生。因此，研究其耐药机制，加强合理应用以控制耐药性的增长是非常有必要的。本文对氟喹诺酮类药物耐药状况、耐药机制等研究近况作一综述，为临床合理用药提供一定参考。     

Design, synthesis, and biological evaluation of new cinnamic derivatives as antituberculosis agents

Tuberculosis, HIV coinfection with TB, emergence of multidrug-resistant TB, and extensively drug-resistant TB are the major causes of death from infectious diseases worldwide. Because no new drug has been introduced in the last several decades, new classes of molecules as anti-TB drugs are urgently needed. Herein, we report the synthesis and structure-activity relationships of a series of thioester, amide, hydrazide, and triazolophthalazine derivatives of 4-alkoxy cinnamic acid. Many compounds exhibited submicromolar minimum inhibitory concentrations against Mycobacterium tuberculosis strain (H(37)Rv). Interestingly, compound 13e, a 4-isopentenyloxycinnamyl triazolophthalazine derivative, was found to be 100-1800 times more active than isoniazid (INH) when tested for its ability to inhibit the growth of INH-resistant M. tuberculosis strains. The results also revealed that 13e does not interfere with mycolic acid biosynthesis, thereby pointing to a different mode of action and representing an attractive lead compound for the development of new anti-TB agents.     

Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections

Uncomplicated urinary tract infections (UTI) are treated with beta-lactams, co-trimoxazole, quinolones and fosfomycin tromethamine. Due to increasing resistance of causative pathogens, antibiotics should be used by considering their pharmacodynamic and pharmacokinetic characteristics. beta-lactams have time-dependent activity and should not be used once-daily. Co-trimoxazole should be restricted due to increasing chemoresistance. Fluoroquinolones play a primary role in the treatment of serious and complicated infections. Fosfomycin tromethamine is active against most urinary tract pathogens. In vitro time-kill kinetics of fosfomycin against Escherichia coli and Proteus mirabilis showed primarily concentration-dependent activity, with a prolonged post-antibiotic effect (3.4 to 4.7h). Based on these results a single 3g dose of fosfomycin guarantees optimal efficacy against common uropathogens with an AUC(urine)/MIC ratio of 500.     

The hunt for new tuberculosis vaccines: anti-TB immunity and rational design of vaccines

Tuberculosis (TB) remains to be a leading infectious cause of death worldwide. Apparently, the current BCG vaccine that has been used for 80 years, has failed to control the TB epidemic. Hunting for improved TB vaccine formulations represents a daunting task to TB research community. Anti-TB host defense requires T cell-mediated immunity and we are in desperate need of enhanced understanding of how to develop a new generation of TB vaccines that are able to provoke potent and long-lasting protective cell-mediated immunity, different from almost all of the vaccines currently in use. It is of importance to successful TB vaccine development to identify the key cellular and molecular events governing the generation of anti-TB immunity, but unfortunately little has been understood as to why 90% of infected humans never develop active TB. However, waiting would not help us to win the battle and an ever-intensifying effort is being made to develop various new formulations according to the immunology that we have been learning, in large part, from experimental models. This review article attempts to unite the current understanding of anti-TB immunity with the rational design of anti-TB vaccines. It examines what may have confounded the immunogenicity of current BCG vaccine and the major obstacles to successful development of TB vaccines. It also discusses about antigen presentation, activation of Th1 and Tc1 cells, anti-TB immune effectors and the generation of memory T cells. The vaccine section describes four types of major TB vaccines under development: mycobacterial-, subunit-, plasmid DNA- and viral-based vaccines. A special section is dedicated to the rationale and current design of cytokine-based adjuvant formulations for TB vaccines. We also take this opportunity to introduce our recent development in cytokine transgene adjuvanted BCG vaccination and recombinant adenoviral-based TB vaccines.     

Transition metals in organic synthesis - Part 83#: Synthesis and pharmacological potential of carbazoles

A series of carbazole derivatives with promising pharmacological properties has been prepared using either an iron-mediated or a palladium-catalyzed synthetic approach. The carbazole alkaloids carbazoquinocin C, carbazomadurin A and B, epocarbazolin A and B, neocarazostatin B, and carquinostatin A are antioxidants acting as free-radical scavengers. Thus, they represent potential lead compounds for the development of novel drugs against diseases initiated by oxygen-derived free radicals. Initiated by the first naturally occurring carbazole alkaloids with antituberculosis (anti-TB) activity, clausine K and micromeline, a study on the structure–activity relationships for anti-TB-active carbazole derivatives has been carried out. The 6-oxygenated carbazoles glycozoline and glycozolinine show antibiotic activity towards several microorganisms. The 7-oxygenated carbazole siamenol exhibits anti-HIV activity.