Antituberculosis drugs

Newer antituberculosis drugs

Current management of tuberculosis involves taking at least four drugs and a minimum treatment duration of 6 months. Moreover, the emergence of newer strains of tuberculosis-like multidrug resistant organisms (MDR-TB) and extremely resistant organisms (XDR-TB) has focused attention on the development of new antituberculosis drugs. There is now a pipeline of new compounds or classes of compounds that are being specifically tested for their potential effectiveness in the treatment of tuberculosis.

Drug targets

The most important aim in drug development is the identification of novel drug targets involved in vital aspects of bacterial growth, metabolism, and viability, the inactivation of which will lead to bacterial death or inability to persist [ ]. The Mycobacterium tuberculosis genome sequence and mycobacterial genetic tools, such as transposon mutagenesis and signature-tagged mutagenesis, have been used to identify genes essential for growth of the organism in vitro and its survival in vivo [ , ]. Inhibition of the host tissue liquefaction process, which facilitates reduced transmission, represents a novel approach to the design of new drugs [ ]. Targeted knockout of specific genes, whose disruption leads to non-viability of the bacilli, is a valuable approach to identifying essential gene products involved in mycobacterial persistence. Some enzymes, including isocitrate lyase (ICL), PcaA (a methyltransferase involved in the modification of mycolic acid), RelA (ppGpp synthase), and DosR (controlling a 48-gene regulon involved in mycobacterial survival under hypoxic conditions) have been identified as targets for the development of drugs to kill persistent bacilli [ ]. Energy production pathways, such as the electron transport chain, glycolytic pathways (like the Embden–Meyerhof pathway), and fermentation pathways, could be good targets for drug development [ ]. In identifying drugs that kill persistent organisms and thereby shortening the duration of treatment, novel drug screens that mimic in vivo conditions in lesions (i.e. acidic pH and hypoxia) and act against old stationary-phase non-growing bacilli could be important [ , ]. In addition, drug combination screens could be performed to identify drugs that have synergistic effects. The systems biology approach, which proposes using multiple compounds that hit multiple targets in different pathways to achieve the desired outcome, can be used for identifying novel drug combinations against tuberculosis [ ].

In the growing pipeline of potential new antituberculosis drugs there are currently seven novel compounds that are not yet approved for the treatment of tuberculosis and are in various stages of clinical development [ ]. The most advanced of these are the fluoroquinolones, specifically gatifloxacin and moxifloxacin, which are currently being evaluated in phase 2 and 3 clinical trials. Two other compounds (TMC207 and OPC67683) have completed phase 1 clinical trials and early bactericidal activity (EBA) studies, PA824 has completed its phase 1 program, and two other compounds (LL3858 and SQ109) are currently being evaluated in phase 1 clinical studies.

Diarylquinoline (TMC207)

A novel diarylquinoline TMC207 (previously referred to as “R207910”) is being developed by Tibotec, a Johnson & Johnson subsidiary. It has many characteristics, both in vitro and in vivo, that make it a very attractive antituberculosis drug candidate. It has very potent in vitro activity against both multidrug-resistant and drug-susceptible strains of Mycobacterium tuberculosis [ ]. The target for diarylquinoline has been proposed to be mycobacterial F1F0 proton ATP synthase, which is a new drug target in mycobacteria. TMC207 was more active than isoniazid and rifampicin in a mouse model and shortened therapy from 4 months to 2 months in mice with established infection. In phase 1 studies in humans tolerability was good and the pharmacokinetics were linear over the dose range studied. In a phase 1 study of multiple ascending doses there was accumulation, with increases in the AUC by a factor of about two between day 1 and day 14. The “effective half-life” was of the order of 24 hours. TMC207 is about to enter a randomized phase 2 study in a population of patients with MDR-TB [ ].

Nitroimidazoles (PA824 and OPC67683)

Two nitroimidazoles are currently in clinical development, the nitroimidazo-oxazine PA824, which is being developed by the TB Alliance, and the dihydroimidazo-oxazole OPC67683, which is being developed by Otsuka Pharmaceutical [ ].

PA824 has an MIC as low as 0.015–0.250 μg/ml against drug sensitive and multidrug resistant Mycobacterium tuberculosis [ ]. PA824 is a prodrug that requires activation by a bacterial F420-depedent glucose-6-phosphate dehydrogenase (Fgd) and nitroreductase to activate components that then inhibit bacterial mycolic acid and protein synthesis [ ]. Pharmacokinetic studies of PA824 in rats have shown that it has excellent tissue penetration [ ]. In animals, PA824 was active against non-growing bacilli, even in microaerophilic conditions, and its activity is comparable to that of isoniazid, rifampicin, and moxifloxacin [ ]. PA824 had bactericidal activity in mice in the first 2 months of treatment and also in the continuation phase, which suggests that it has significant activity against non-growing persistent bacilli in vivo [ ].

OPC67683 is extremely potent in vitro and in vivo against Mycobacterium tuberculosis [ ]. In a mouse model of chronic infection, OPC67683 was more efficacious that currently used antituberculosis drugs. The effective plasma concentration was 100 mg/l, which was achieved with an oral dose of 0.625 mg/kg. OPC67683 showed no cross-resistance with any of the currently used antituberculosis drugs. MICs against multiple clinically isolated tuberculosis strains were of the order of 6 mg/l [ ].

New fluoroquinolones

C-8-methoxy-FQ, moxifloxacin, and gatifloxacin have a longer half-life and are more active against M. tuberculosis than the older quinolones. Moxifloxacin, in combination with rifampicin and pyrazinamide, killed tubercle bacilli in mice more effectively than the standard regimen of isoniazid + rifampicin + pyrazinamide and achieve stable cures in 4 months without relapse [ , ]. Moxifloxacin has early bactericidal activity against tubercle bacilli comparable to that of isoniazid and was well tolerated in a preliminary human study [ ]. In a clinical trial conducted by the TB Trials Consortium in patients with pulmonary tuberculosis substitution of moxifloxacin for ethambutol did not influence 2-month sputum culture status but did result in a higher frequency of negative cultures at earlier times, which suggests that moxifloxacin has good sterilizing activity [ ]. There is a current trial by the TB Trials Consortium, in which moxifloxacin replaces isoniazid in patients with pulmonary tuberculosis. In addition, at the Tuberculosis Research Centre in Chennai, patients are being recruited for a randomized clinical study of the efficacy and tolerability of 3- and 4 month regimens containing moxifloxacin.

Pyrrole (LL3858)

Pyrrole LL3858, developed by Lupin, is being evaluated in a multidose phase 1 trial in healthy volunteers in India. It has submicromolar MICs and was be very active in a mouse model of tuberculosis. In combination with currently used antituberculosis drugs, LL3858 is reported to sterilize the lungs and spleens of infected animals more quickly than conventional therapy [ ].

Diamine (SQ109)

The most recent compound to enter phase 1 clinical trials for tuberculosis is SQ109, which is being developed by Sequella. In in vitro and mouse in vivo studies the MIC against Mycobacterium tuberculosis was 100–630 mg/l [ ]. SQ109 has recently entered phase 1 studies in human volunteers.

General adverse effects and adverse reactions

Adverse reactions are often due to the combined effects of two or more drugs used simultaneously [ ]. Hypersusceptibility reactions can occur even to more than one agent. The incidence of adverse reactions to drugs used in the treatment of tuberculosis is higher in elderly patients, who are more likely to have intercurrent illnesses and a lower lean body mass than younger patients. In two studies from Hong Kong in patients being treated for tuberculosis with rifampicin, the incidence of adverse reactions was higher with regimens containing rifampicin; furthermore, patients taking rifampicin had a higher steady-state plasma concentration of isoniazid [ , ].

Some simple rules about which drugs are more likely to cause which reactions reflect the principle that the most probable causative agent (or agents) must be stopped.

Observational studies

An increasing number of patients with multidrug-resistant tuberculosis are being treated with second-line drugs worldwide, often in places with poor resources. The number of drugs used is large (4–9) and treatment is prolonged (1–2 years). There is justifiable concern over patients’ tolerance of such regimens and their adverse effects, which determine adherence to treatment. Treatment has to be individualized according to the WHO guidelines for a DOTS-plus strategy.

It is therefore encouraging to read a report from Lima, Peru, where 60 patients from a shanty town tolerated a median of eight antituberculosis drugs fairly well for a median duration of 20 months [ ]. All received a parenteral aminoglycoside daily for 6 months, cycloserine, and a fluoroquinolone, and most also took para -aminosalicylic acid and ethionamide. Of 60 patients, 23 took clofazimine, 23 pyrazinamide, 25 isoniazid, and 3 rifampicin. Commonly encountered adverse effects included dermatological effects, including bronzing of the skin (many of these patients were taking clofazimine and fluoroquinolones), depression, anxiety, and peripheral neuropathy. All complained of mild gastritis. There were no cases of serious hepatic or renal toxicity. This may have been because only a few patients took rifampicin. Absence of eighth nerve toxicity was striking, and can be attributed to close monitoring of patients by physicians with experience of DOTS-plus regimens.

In a similar report from Turkey, adverse reactions to drugs led to withdrawal of one or more drugs in 62 of 158 patients (39%) [ ]. Outcomes were favorable and cultures became negative in 95% of the patients within 2 months.

The authors of an observational study in 367 HIV-infected patients with 372 episodes of culture-confirmed tuberculosis analysed the factors that complicate antituberculosis therapy [ ]. In 25% there was hepatic disease at the time of the diagnosis of tuberculosis or during antituberculosis therapy, and there were rises in serum transaminases to at least twice the upper limits of the reference ranges during the first month of antituberculosis therapy in 116 (31%) of the episodes. The most commonly reported adverse effects were rash (28%), nausea (26%), leukopenia or neutropenia (20%), diarrhea (19%), vomiting (19%), and raised temperature (17%). There was co-prescription of rifampicin with medications that interact with rifampicin during 270 episodes (72%).

Nervous and sensory systems

Ethambutol is the most likely drug to cause visual disturbances. Isoniazid is associated with polyneuritis and reactions of the central nervous system. Streptomycin can cause eighth nerve toxicity.

Liver

Hepatotoxicity is the most important adverse effect of antituberculosis drug therapy [ ]. The hepatotoxic potential of isoniazid, pyrazinamide, and rifampicin during antituberculosis chemotherapy has been reviewed [ ]. Hepatic necrosis is the most important adverse effect of first-line antituberculosis drug therapy [ ]. Asymptomatic rises in aminotransferases are common and are not by themselves justification for withdrawing medication, since they settle spontaneously in most patients while treatment continues. All patients taking antituberculosis drugs should be told to report all new illnesses, especially when associated with vomiting. Hepatitis B carriers were no more likely to react adversely to antituberculosis drugs than non-carriers [ ].

If liver damage occurs, isoniazid is probably an important factor and it should be stopped before rifampicin or pyrazinamide [ ]. Prediction of hepatotoxicity is possible [ ]. In a case-control study of 60 patients in India, conducted in order to identify features predicting hepatotoxicity, the body mass index was significantly lower (17.2 kg/m ² ) in patients who experienced hepatotoxicity than in controls (19.5 kg/m ² ) [ ].

There is wide variability in the risk of hepatotoxic reactions reported from different parts of the world or in different populations (for example African–American women in the postpartum period) [ ]. The EIDOS and DoTS descriptions of hepatotoxicity due to antituberculosis drugs are shown in Figure 1 .

The American Thoracic Society has issued a statement on the hepatotoxicity of antituberculosis drugs [ ]. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of drug-induced liver injury range from hepatic adaptation to hepatocellular injury. Systematic steps for preventing and managing liver damage include patient and regimen selection to optimize the benefits to harm balance, staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent tuberculosis, alanine transaminase monitoring is recommended for those who chronically take alcohol or concomitant hepatotoxic drugs, have viral hepatitis or other pre-existing liver disease or abnormal baseline transaminase activity, have had prior isoniazid-induced hepatitis, are pregnant, or are within 3 months post-partum. Treatment should be withdrawn and a modified or alternative regimen used for those with raised transaminase activity more than three times the upper limit of normal in the presence of hepatitis symptoms and/or jaundice, or five times the upper limit in the absence of symptoms.

In a retrospective comparison of isoniazid for 9 months (n = 770) and rifampicin for 4 months (n = 1379) for latent tuberculosis the respective percentages of patients who completed 80% or more of their prescribed treatment were 53% and 72% [ ]. Clinically recognized adverse reactions resulted in permanent treatment withdrawal in 4.6% and 1.9% respectively. Clinically recognized hepatotoxicity was more common with isoniazid (1.8%) than rifampicin (0.08%).

Continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampicin have been compared with regimens containing isoniazid and rifampicin in a case–control study in 3007 Chinese patients with active tuberculosis [ ]. The cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when the serum AlT activity exceeded three times the upper limit of the reference range. There was hepatotoxicity in 48 (1.6%) patients. The adjusted odds ratio (95% CI) for regimens incorporating pyrazinamide along with isoniazid and/or rifampicin relative to standard regimens was 2.8 (1.4, 5.9). There was a significant association between hepatotoxicity and hepatitis B, previous hepatotoxicity, and treatment regimens. The authors concluded that the addition of pyrazinamide to isoniazid and rifampicin during the continuation phase increases the risk of hepatotoxicity appreciably.

Treatment of latent tuberculosis in liver transplant candidates with compensated cirrhosis has been investigated in a prospective study in California in nine patients who took isoniazid for 9 months and in five who took rifampicin for 4 months [ ]. Four of those who took isoniazid had mild asymptomatic rises of AsT or AlT activity compared with none of those who took rifampicin. In two cases the enzyme changes were attributed to isoniazid and in the other two to alcoholism or active chronic hepatitis B. There were no deaths and no cases of fulminant hepatic failure.