WO2012011917A1 - Administration of rifalazil to immunocompromised patients - Google Patents

Abstract

Compositions and methods for treating a bacterial infection, or disorder associated with a bacterial infection, in a patient being treated for another disorder with a drug metabolized by CYP450, are disclosed. The methods involve administering a therapeutically effective amount of a composition comprising rifalazil or rifalazil analogs that does not modulate CYP450. The bacterial infection may be caused by a bacteria with an active and inactive, latent form, and the rifalazil is administered in an amount and for a duration sufficient to treat both the active and the inactive, latent form of the bacterial infection, which duration is longer than is needed to treat the active form of the bacterial infection. One such bacterial infection is tuberculosis, and the method can be used to treat immunocompromised tuberculosis patients, including those being treated with protease inhibitors and/or NNRTI.

Description

Administration of Rifalazil to Immunocompromised Patients

Field of the Invention

The invention is generally in the area of treating a bacterial infection or disorder associated with a bacterial infection, in a patient being treated for another disorder with a drug which is metabolized by CYP450. The treatment involves administering to the patient a therapeutically effective amount of a composition comprising rifalazil, 3'-hydroxy-5'-(4-methylpiperazinyl)benzoxazinorifamycin), or other rifalazil analogs that does not modulate CYP450. In particular, the bacterial infection may be caused by a bacteria with an active and inactive, latent form, and the rifalazil is administered in an amount and for a duration sufficient to treat both the active and the inactive, latent form of the bacterial infection, which duration is longer than is needed to treat the active form of the bacterial infection. One such bacterial infection is tuberculosis, and the treatment is particularly useful for treating tuberculosis patients who are immunocompromised.

Background of the Invention

There are a variety of disorders, including HIV, HCV, HBV, and cancer, where the disorder and/or treatments for the disorder result in a patient that is immunocompromised. Many of these patients also suffer from tuberculosis ("TB"), often as a result of having one or more of these disorders and being immunocompromised.

Additionally, patients having pre-existent chronic liver disease can also develop tuberculosis. Patients undergoing conventional treatment for tuberculosis can develop hepato toxicity as an adverse reaction to the drugs, and/or can develop fresh liver diseases like acute viral hepatitis. Hepatic dysfunction can also alter absorption and distribution of drugs that are metabolized or excreted in the liver. Accordingly, the presence of co-existent hepatic disease, such as that caused by HCV and HBV, poses a significant challenge in the treatment of tuberculosis.

Rifampicin, pyrazinamide, isoniazid, ethionamide and PAS are all hepatotoxic drugs. Slow acetylators of isoniazid are at a higher risk of hepatotoxicity. The hepatotoxic effects of rifampicin and isoniazide are believed to be additive, whereas the hepatic damage due to pyrazinamide is related to dose and duration. Accordingly, patients with liver disease and who are treated with these agents are at risk of liver damage. If that were not bad enough, patients being treated for viral liver diseases such as HCV and HBV are at a higher risk, as several of these agents are not only hepatotoxic, they are also modulators (primarily inducers) of CYP450, which adversely affects the metabolism of several anti-HCV and anti-HBV agents.

As an example, the ability of isoniazid (INH) to elevate the concentrations in plasma and/or toxicity of co-administered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been well-documented in humans. Based on studies on the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms, it has been determined that INH potently inhibits CYP2C19 and CYP3A in a concentration-dependent manner (Desta et al., "Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A," Antimicrob Agents Chemother., 45(2): 382- 392 (2001)).

Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of certain co-administered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH (i.e., patients with certain single nucleotide polymorphisms of the CYP450 gene) may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent.

Tuberculosis and HIV/AIDS

The World Health Organization has recently doubled its estimate of the ravages tuberculosis (TB) is causing among HIV/AIDS patients. Over nine million people contracted TB in 2007, including around 1.4 million people with HIV/AIDS. More than one death in four of the 1.75 million tuberculosis deaths recorded in 2007 is thought to involve an HIV/ AIDS patient.

It has been estimated that one-third of the more than 40 million people living with HIV/AIDS are also infected with tuberculosis. TB is the leading infectious killer of people with HIV/ AIDS. TB-HIV co-infections are on the rise in sub-Saharan Africa and other areas of the world, particularly Asia and Eastern Europe. In 2005, 2.7 million people were newly infected with HIV/ AIDS. As long as HIV/AIDS continues to spread, TB will remain a constant and deadly threat.

It has been estimated that patients living with HIV have a twenty-fold increase in the risk of developing tuberculosis relative to HIV negative people. The combination of poor diagnosis, rising drug resistance, and the impact on HIV/AIDS patients has heightened alarm among health experts. Drug-resistant strains are believed to have infected an estimated 500,000 people, of whom around 150,000 of which die from the disease, according to the World Health Organization ("WHO"). Furthermore, around 10 percent of the drug resistant strains are almost incurable extra-resistant strains (XDR-TB), and these extra-resistant strains are now found in at least 55 countries.

It is difficult to treat HIV-infected patients, because of the patient's immunologic status, the need for highly active antiretroviral therapy (HAART), and potential drug reactions.

Accordingly, there is an urgent need to find, prevent and treat tuberculosis in people living with HIV and to test for HIV in all patients with TB in order to provide prevention, treatment and care. However, there are severe shortcomings in tackling tuberculosis in HIV/ AIDS patients.

Highly active anti-retroviral therapy (HAART) is today's most effective, available treatment option for controlling the progression of HIV, the virus that causes AIDS. Unfortunately, drug-drug interactions between the current first-line TB regimen and certain commonly used anti-retrovirals complicate treatment for co- infected patients. Rifampin, a cornerstone of the current TB regimen, induces the enzyme cytochrome P450. Cytochrome P450 causes some AIDS drugs to be metabolized too quickly, inhibiting effective HAART therapy. People with HrV/AIDS who contract TB must sometimes change their HAART regimens to avoid this dangerous interaction, or delay needed HAART treatment until their TB is under control.

Widely used antiretroviral drugs available in the United States include protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, invirase, Norvir, viracept, and agenerase) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, efavirenz, and virammune). Protease inhibitors and NNRTIs have substantive interactions with the rifamycins (rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections. These drug interactions principally result from changes in the metabolism of the antiretroviral agents and the rifamycins secondary to induction or inhibition of the hepatic cytochrome CYP450 enzyme system. Rifamycin-related CYP450 induction decreases the blood levels of drugs metabolized by CYP450. For example, if protease inhibitors are administered with rifampin (a potent CYP450 inducer), blood concentrations of the protease inhibitors (all of which are metabolized by CYP450) decrease markedly, and most likely the antiretroviral activity of these agents declines as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered with rifabutin, blood concentrations of rifabutin increase markedly, and most likely rifabutin toxicity increases as well.

Of the available rifamycins, rifampin is the most potent CYP450 inducer; rifabutin has substantially less activity as an inducer; and rifapentine, a newer rifamycin, has intermediate activity as an inducer. The four currently approved protease inhibitors and amprenavir (141W94, an investigational agent in Phase III clinical trials) are all, in differing degrees, inhibitors of CYP450. The rank order of the agents in terms of potency in inhibiting CYP450 is ritonavir (the most potent); amprenavir, indinavir, and nelfinavir (with approximately equal potencies); and saquinavir (the least potent). The three approved NNRTIs have diverse effects on CYP450: nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz is both an inducer and an inhibitor.

In contrast to the protease inhibitors and the NNRTIs, the other class of antiretroviral agents available, nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not metabolized by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the glucuronidation of zidovudine and thus slightly decreases the serum concentration of zidovudine. The effect of this interaction probably is not clinically important, and the concurrent use of NRTIs and rifamycins is not contraindicated.

Because current treatment regimens frequently include two NRTIs combined with a potent protease inhibitor (or, as an alternative, combined with an NNRTI), and the protease inhibitors and NNRTIs are adversely affected by conventional anti-TB agents, the patients receiving dual treatment with these regimens are at risk for developing resistant mutations of HIV. Accordingly, the use of rifampin to treat active TB in a patient who is taking a protease inhibitor or an NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome enzymes than rifampin, and, in modified doses, might not be associated with a clinically significant reduction of protease inhibitors or nevirapine. Rifapentine is not recommended as a substitute for rifampin because its safety and effectiveness have not been established for treating patients with HIV -related TB. Efavirenz is one example of an anti-HIV agent that is incompatible with conventional TB antibiotics. Efavirenz (brand names Sustiva and Stocrin) is a non- nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

Cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism. Accordingly, the administration of CYP450 inducers to treat TB has implications for HIV/AIDS therapy Ward et al., J Pharmacol Exp Ther.;306(l):287-300 (2003).

TB treatment regimens that contain no rifamycins, for example, TB treatment regimens consisting of streptomycin, isoniazid, have been proposed as an alternative for patients who take protease inhibitors or NNRTIs. However, these TB regimens have not been studied among patients with HIV infection.

In addition to the risk that conventional anti-TB agents are incompatible with certain anti-HIV agents, resistance to antituberculosis drugs is an important consideration for some HIV-infected persons with TB. According to the results of a study of TB cases reported to CDC from 1993 through 1996, the risk of drug-resistant TB was higher among persons with known HIV infection compared with others. HIV- positive serostatus is a risk factor for resistance to at least isoniazid, for both isoniazid and rifampin resistance (multidrug-resistant (MDR) TB) and for rifampin monoresistance (TB resistant to rifampin only). The use of rifabutin as prophylaxis for Mycobacterium avium complex may also be associated with the development of rifamycin resistance.

New TB drugs, developed to avoid interactions with anti-retroviral agents, are essential to treat the growing number of people dually infected with TB and HIV.

HCV and Tuberculosis

Estimates by the Centers for Disease Control and Prevention indicate that 1.8% of the U.S. population (approximately 4 million Americans) is currently infected with HCV. The current standard of therapy for hepatitis C is a combination of ribavirin and interferon alfa-2b, but this treatment results in a number of side effects. A number of patients infected with hepatitis C virus (HCV) are also co-infected with TB, and HCV treatment is typically not recommended while taking medications for TB. One reason is that anti-infectives used to treat TB can be hard on the liver, and anti-infectives used to treat HCV can cause liver failure. In combination, the risk of liver damage is higher.

To further complicate matters, if a patient's liver enzymes increase, which is a sign of liver damage, a treating physician might not be able to determine whether the liver damage was due to the treatment for HCV, TB, or both. Further, some treatments for HCV result in immunosuppression, making it more difficult to treat TB. As mentioned above with respect to HIV, some anti-TB drugs, such as rifampicin, rifabutin, and isoniazid, up-regulate the cytochrome P450 function, causing an increase in the metabolism of immunosuppressants and (in this case, serine) protease inhibitors, thus decreasing their levels in the blood, and, subsequently, decreasing the efficacy of the anti-HCV therapy.

Accordingly, there remains a need for effective anti-TB therapy that does not adversely impact anti-HCV treatments.

HBV and Tuberculosis

Therapy is currently recommended for patients with evidence of chronic active hepatitis B (HBV) disease (i.e, high aminotransferase levels, positive HBV DNA findings, HBeAg). In general, for the HBeAg-positive patient population that is identified with evidence of chronic hepatitis B virus (HBV) disease, treatment is advised to be administered when the HBV DNA level is >20,000 IU/mL (10⁵ copies/mL) and when serum ALT is elevated for 3-6 months.

Elevated hepatitis B (as well as hepatitis C) viral load is believed to predispose tuberculosis patients to both drug- and virus-induced hepatotoxicity during antituberculosis treatments. Further, as with the treatment of HIV, HBV infections are commonly treated with nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and protease inhibitors (Pis), and both Pis and NNRTIs are metabolized by CYP450.

Currently, interferon alfa (IFN-a) and pegylated versions thereof, lamivudine, telbivudine, adefovir, adefovir dipivoxil, entecavir, and tenofovir are the main treatment drugs approved globally for treating HBV. The effectiveness of these therapies is dependent on normal metabolism of these agents. Accordingly, treatment of TB infection with conventional anti-TB therapeutics that also function as CYP450 inducers can result in heptatoxicity while treating the infection, and also reduce the efficacy of the anti-HBV therapeutics and/or result in even higher incidences of side effects.

Accordingly, there remains a need for effective anti-TB therapy that does not adversely impact anti-HBV treatments.

Cancer and Tuberculosis

Patients with cancer are immunocompromised. Because of the cancer and the cancer treatment, the immune system does not function normally, which decreases its ability to fight off infection and disease. Patients with latent, or inactive, TB, are at risk for active TB.

Further, there is an association between lung cancer and TB. The incidence of tuberculous lesions in autopsies unassociated with tumor is around 7%, as compared to around 25 % incidence of association with carcinoma; which is significant. (Dacosta and Kinare, Association of lung carcinoma and tuberculosis, J Postgrad Med, 37: 185 (1991)). Often, lung cancer is diagnosed long after a patient has been infected with tuberculosis, and a patient must be treated for both diseases.

The association of tuberculosis and cancer has been recorded in most of the organs. Pandey et al., "Tuberculosis and metastatic carcinoma coexistence in axillary lymph node: A case report," World Journal of Surgical Oncology, Volume 1: 1-3 (2003)). In one review, 58,245 cancer patients with cancer were evaluated, and 201 cases of coexisting tuberculosis were identified (Kaplan et al., "Tuberculosis complicating neoplastic disease. A review of 201 cases," Cancer. 33(3):850-858 (1974)). The highest prevalence was seen in patients with Hodgkin's disease (96/10,000 cases) followed by lung cancer (92/10,000), lymphosarcoma (88/10,000) and reticulum cell sarcoma (78/10,000). These rates are approximately 1% of all patients, which is a significant correlation.

Patients with hematologic malignancies (leukemias and lymphomas, such as Hogkin's lymphoma) are at increased risk of developing tuberculosis, because of the T-cell immunodeficiency associated with the disease and/or its treatment. For example, in a study of 917 patients observed between 1990 and 2000, 24 cases of tuberculosis (2.6% of patients) were found, and the mortality of the patients was around 70% (Silva et al., "Risk factors for and attributable mortality from tuberculosis in patients with hematologic malignances," Haematologica; 90: 1110-1115 (2005)). Patients at risk include those with

Non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, acute myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, myelodysplasia, and chronic myeloid leukemia.

Cancer patients with TB are difficult to treat, as conventional TB treatments can alter CYP450 metabolism of anti-cancer agents. This alteration of CYP450 metabolism is detrimental for several reasons.

When treating cancer, there is frequently a narrow window between drug toxicity and suboptimal therapy, and inter-individual variation in drug metabolism complicates therapy. Genetic polymorphisms in enzymes such as those in the cytochrome P450 superfamily are at least partially responsible for the observed inter- individual variation in pharmacokinetics and pharmacodynamics of anticancer drugs. For example, there is potential clinically relevant application of CYP450 pharmacogenetics for anticancer therapy, for example, between CYP1A2 and flutamide, CYP2A6 and tegafur, CYP2B6 and cyclophosphamide, CYP2C8 and paclitaxel, CYP2D6 and tamoxifen, and CYP3A5 (van Schaik, "Cancer treatment and pharmacogenetics of cytochrome P450 enzymes," Journal Investigational New Drugs (Springer Netherlands), 23(6): 513-522 (December, 2005), the contents of which are hereby incorporated by reference). In addition to genetic polymorphisms, drugs which modulate CYP450 also have an impact on chemotherapy.

Further, chemical entities which induce cytochrome P450 may be further undesirable, since P450 induction is linked to tumor formation which may further compromise the cancer patient.

Accordingly, there remains a need for effective anti-TB therapy that does not adversely impact cancer treatments.

Patients with Liver Disease

Frequently, patients having pre-existent chronic liver disease also develop tuberculosis. Additionally, patients undergoing treatment for tuberculosis may develop hepato toxicity as an adverse reaction to the drugs, and/or can develop fresh liver diseases like acute viral hepatitis. Hepatic dysfunction can also alter absorption and distribution of drugs that are metabolized or excreted in the liver. Accordingly, the presence of co-existent hepatic disease, such as that caused by HCV and HBV, poses a challenge in the treatment of tuberculosis.

Rifampicin, pyrazinamide, isoniazid, ethionamide and PAS are all hepatotoxic drugs. Slow acetylators of isoniazid are at a higher risk of hepatotoxicity. The hepatotoxic effects of rifampicin and isoniazide are believed to be additive, whereas the hepatic damage due to pyrazinamide is related to dose and duration. Accordingly, patients with liver disease and who are treated with these agents are at risk of liver damage. If that were not bad enough, patients being treated for viral liver diseases such as HCV and HBV are at a higher risk, as several of these agents are not only hepatotoxic, they are also modulators (primarily inducers) of CYP450, which adversely affects the metabolism of several anti-HCV and anti-HBV agents.

Summary of the Invention

In its broadest sense, the invention is directed to a method for treating bacterial infections is patients who are also being treated for a disorder other than the bacterial infection using agents that are metabolized by CYP450. The bacterial infection is treated with rifalazil or a rifalazil analog that is not a CYP450 modulator, so that the antibacterial treatment does not adversely interfere with the other treatments that the patient is undergoing. In this case, rifalazil is quite different than rifampicin and rifabutin, which are modulators of CYP450, and which can be contraindicated for patients taking medications that are metabolized by CYP450.

Compositions and methods for treating tuberculosis ("TB") patients, in particular, immunocompromised patients, are also disclosed. The compositions include rifalazil, derivatives of rifalazil in which the sec-butyl group on the piperidine ring is replaced with methyl (i.e., 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin), and other rifamycin analogs that do not incude CYP450. The compositions optionally include other antimicrobial agents that do not induce CYP450, particularly the CYP3A4 and CYP2C9 isoforms.

The compositions can be used to treat tuberculosis in patients suffering from cancer, and/or from infection from one or more of HIV, HBV, and HCV. Accordingly, in one embodiment, the compositions include a combination of rifalazil and one or more anticancer, anti-HIV, anti-HBV, and/or anti-HCV agents. In another embodiment, the compositions are administered in alternation with therapy for cancer, HP , HBV, and/or HCV. In one embodiment, the methods involve administering to a patient suffering from cancer and from a concomitant TB infection one or more anti-cancer compounds that would be detrimental, or suffer from decreased or lack of efficacy, if an inducer or other modulator of CYP450 (cytochrome P450) were administered. The method further involves administering a composition comprising rifalazil or a derivative thereof to treat the TB infection, alone or in combination with another antimicrobial agent. The administration of rifalazil is continued until such time as the TB infection is effectively treated.

Representative anti-cancer agents that are metabolized by CYP450 include, but are not limited to, cyclophosphamide, docetaxel, doxorubicin, etoposide, ifosfamide, paclitaxel, tamoxifen, anastrazole, teniposide, vinblastine, vindesine, and gefitinib.

In a second embodiment, the methods involve administering to a patient suffering from HIV and from a concomitant TB infection one or more anti-cancer compounds that would be detrimental, or suffer from decreased or lack of efficacy, if an inducer or other modulator of CYP450 (cytochrome P450) were administered. The method further involves administering a composition comprising rifalazil to treat the TB infection, alone or in combination with another antimicrobial agent. The administration of rifalazil is continued until such time as the TB infection is effectively treated.

Representative anti-HIV agents that are metabolized by CYP450 include, but are not limited to, non-nucleoside reverse transcriptase inhibitors and protease inhibitors.

In a third embodiment, the methods involve administering to a patient suffering from HBV and from a concomitant TB infection one or more anti-cancer compounds that would be detrimental, or suffer from decreased or lack of efficacy, if an inducer or other modulator of CYP450 (cytochrome P450) were administered. The method further involves administering a composition comprising rifalazil to treat the TB infection, alone or in combination with another antimicrobial agent. The administration of rifalazil is continued until such time as the TB infection is effectively treated.

Representative anti-HBV agents that are metabolized by CYP450 include, but are not limited to, protease inhibitors and NNRTI. In a fourth embodiment, the methods involve administering to a patient suffering from HCV and from a concomitant TB infection one or more anti-cancer compounds that would be detrimental, or suffer from decreased or lack of efficacy, if an inducer or other modulator of CYP450 (cytochrome P450) is administered. The method further involves administering a composition comprising rifalazil to treat the TB infection, alone or in combination with another antimicrobial agent. The administration of rifalazil is continued until such time as the TB infection is effectively treated.

Representative anti-HCV agents that are metabolized by CYP450 include, but are not limited to, a combination of Pegylated interferon (Pegasys) and ribavirin, polymerase inhibitors such as IDX-375 and IDX-184 (Idenix), PSI-7851 and PSI- 7977 (Pharmasset) danoprevir (InterMune/Genentech), RG7128 (Pharmasset/Genentech), I ANA598 (Anadys Pharmaceuticals), TMN-191 (R7227), combinations of RG7128 and RG7227 (Genentech, Pharmasset and Intermune), ABT- 072 (Abbott), VX-916, VX-759, VX-222, and VX-500 (Vertex), Filibuvir (PF- 00868554) (Pfizer), GS 9190 (Gilead), alone or with boosters such as ritonavir, and serine protease inhibitors such as Boceprevir (SCH 503034) (Schering Plough), BILN-2061, Telaprevir (Vertex), ACH-1625 (Achillion), GS-9256 (Gilead), BI 201335 (Boehringer Ingelheim Pharma), Vaniprevir (MK-7009) (Merck), SCH900518 (Narlaprevir) (Schering / Merck), TMC435 (Medivir/Tibotec). Additional examples of serine protease inhibitors are provided, for example, in Reiser and Timm, "Serine protease inhibitors as anti-hepatitis C virus agents," Expert Review of Anti-infective Therapy, 7(5):537-547 (June 2009), the contents of which are hereby incorporated by reference.

Rifalazil and the rifalazil derivatives described herein are not inducers of cytochrome P450, and in this respect, they differ significantly from other rifamycin derivatives such as rifampicin and rifabutin.

The rifalazil and/or rifalazil derivatives can be administered in conjunction, or in alternation, with other anti-TB compounds, such as pyrazinamide, isoniazid, ethionamide and PAS. Ideally, due to the co-administration of rifalazil and/or rifalazil derivatives, the dosage of these agents can be decreased, which can result in lower incidences of side effects. Additionally, the co-administration of rifalazil and/or rifalazil derivatives can reduce the duration of treatment. In another embodiment, a patient suffering from a bacterial infection caused by a bacteria with an active form as well as an inactive, latent form, and who is also being treated for another disorder with an agent that is metabolized by CYP450, is treated for the bacterial infection by administering rifalazil or a rifalazil analog that does not modulate CYP450. Ideally, the rifalazil or a rifalazil analog is administered for a longer period of time than would be required to treat the active bacteria, so that it can accumulate in the patient's cells, and the drug's persistence will enable it to be present to treat the latent form of the bacteria, when it transitions into the active form. In this manner, one can prevent a relapse of a bacterial infection.

The present invention will be better understood with reference to the following detailed description.

Detailed Description

The invention described herein relates to the discovery that rifalazil, and certain rifalazil derivatives, administered alone or in combination with one or more additional antibiotics suitable for treating tuberculosis (TB) infections and which do not modulate, for example, do not induce CYP450, can be effective to treat a subject suffering from tuberculosis, which patient is also administered one or more active agents which are metabolized by CYP450 in the treatment of another disorder. Examples of such other disorders include, but are not limited to, cancer, HIV, HBV, HCV, and liver disorders.

The use of anti-tuberculosis agents which do not induce or otherwise modulate CYP450 can be useful for patients who might otherwise have to put therapies for treating other disorders on hold until the tuberculosis treatment is completed.

The present invention will be better understood with reference to the following detailed description, and with respect to the following definitions.

Definitions

The term "an effective amount" refers to the amount of rifalazil, alone or in combination with one or more additional antibiotics, needed to eradicate tuberculosis or other bacterial infection from the subject, or to prevent an infection of tuberculosis or other bacterial infection, as determined by a diagnostic test that detects tuberculosis or other infection. Disorders commonly treated with rifampicin and rifabutin include Mycobacterium infections, including tuberculosis and leprosy, as well as inactive meningitis. These agents are typically administered in conjunction with isoniazid, ethambutol, pyrazinamide and/or streptomycin. When used to treat TB, these agents are commonly administered daily for several months without a break in treatment, to minimize the risk of drug-resistant tuberculosis is greatly increased. Drug resistance is one of the main reasons that rifabutin is administered in tandem with the three aforementioned drugs, particularly isoniazid.

When used to treat leprosy, rifampicin is typically used in combination with dapsone and clofazimine to avoid eliciting drug resistance.

Rifampicin has also been used to treat methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid, and in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.

Rifampicin is an effective liver enzyme-inducer, promoting the upregulation of hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4), increasing the rate of metabolism of many other drugs that are cleared by the liver through these enzymes. As a consequence, rifampicin can cause a range of adverse reactions when taken concurrently with other drugs. For instance, patients undergoing long term anticoagulation therapy with warfarin have to be especially cautious and increase their dosage of warfarin accordingly. Failure to do so could lead to under-treating with anticoagulation resulting in serious consequences of thromboembolism.

Rifabutin is now recommended as first- line treatment for tuberculosis. Rifampicin is more widely used because of its cheaper cost.

Rifabutin is used to treat mycobacterium avium complex disease, a bacterial infection most commonly encountered in late-stage AIDS patients. Rifabutin is also used in trials for treating Crohn's Disease as part of the anti-MAP therapy. Its main usefulness lies in the fact that it has lesser drug interactions than rifampicin. It has also found to be useful in the treatment of (Chlamydia) pneumoniae (Cpn) Infection.

An "effective amount" of rifalazil or rifalazil derivatives, alone or in combination with one or more additional antibiotics that do not induce or otherwise modulate CYP450, in particular, the CYP3A4 and CYP2C9 isoforms. As used herein, tuberculosis is a disorder caused by mycobacterium tuberculosis, but the compositions and methods described herein can also be used to treat mycobacterial non-tuberculosis, and mycobacterium para-tuberculosis, as well as other disorders caused by these bacteria.

Chlamydia trachomatis is a bacteria, and methods for treating the bacterial infection are described. Chlamydia trachomatis, and other Chlamydial infections, are also known to cause various disorders. For example, Chlamydia trachomatis can cause urogenital infections, trachoma, conjunctivitis, pneumonia and lymphogranuloma venereum (LGV). Chlamydophila pneumoniae can cause bronchitis, sinusitis, pneumonia and atherosclerosis, and Chlamydophila psittaci can cause pneumonia (psittacosis). The treatment of the infections, as well as the underlying disorders, is within the scope of the invention described herein.

I. Rifalazil

As used herein, "Rifalazil" refers to 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin, also known as KRM-1648 or ABI1648. Methods of making rifalazil and microgranulated formulations thereof are described in U.S. Pat. Nos. 4,983,602 and 5,547,683, respectively. The invention as previously discussed contemplates the use of Rifalazil derivatives that are similar or superior in therapeutic effect to Rifalazil, for example, 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin.

Rifalazil is a synthetic antibiotic designed to modify the parent compound, rifamycin. Compared to other antibiotics in the rifamycin class, it has extremely high antibacterial activity. However, while it has a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes, it is not an inducer of CYP450, like rifabutin and rifampicin.

II. Rifalazil Analogs

There are a variety of rifalazil analogs that can be used in addition to or in place of rifalazil. Principal among these is 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin. Other rifalazil analogs include those described in U.S. Patent No. 7,078,399, U.S. Patent No. 7,342,011, U.S. Patent No. 7,220,738, U.S. Patent No. 7,271,165, U.S. Patent No. 7,488,726, U.S. Patent No. 7,547,692, and U.S. Patent No. 11/638738, the contents of each of which are hereby incorporated by reference. Those rifalazil derivatives in these patents and pending applications that induce CYP450, such as the CYP3A4 and CYP2C9 isoforms, can be identified using no more than routine experimentation using routine assays. One such assay is described in Burczynski et al., "Cytochrome P450 Induction in Rat Hepatocytes Assessed by Quantitative Real-Time Reverse-Transcription Polymerase Chain Reaction and the RNA Invasive Cleavage Assay," DMD 29(9): 1243-1250 (September 1, 2001).

III. Pharmaceutical Compositions

The pharmaceutical compositions described herein include rifalazil, and, optionally, one or more other anti-TB agents that do not induce or otherwise modulate CYP450. The compositions can also include, or be administered in combination or alternation with, agents useful for treating the patient for cancer, HIV, HBV, HCV, liver disease, and the like.

Rifalazil Formulations

The rifalazil used in the invention described herein can be in any suitable form that provides suitable bioavailability. Acceptable forms include microgranulated crystals, and combinations of rifalazil with micelle-forming surfactants, and, optionally, lipophilic antioxidants. Such formulations are described, for example, in U.S. Serial No. 10/950,917 and 11/784,051, the contents of which are hereby incorporated by reference in their entireties.

The formulations in U.S. Serial No. 10/950,917 generally fall within the following description. The pharmaceutical compositions are intended for oral administration in unit dosage form, and include rifalazil and an amount of micelle- forming excipient sufficient to produce, upon administration to fasted patients, a coefficient of variation in Cmax of less than 60%, a coefficient of variation in AUCinfinity of less than 40%, and/or a mean bioavailability of greater than 30%. The composition can be in the form of a liquid-filled capsule, which capsule includes rifalazil and a micelle-forming excipient.

Examples of micelle-forming excipients include, but are not limited to, polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters-glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, sorbitan fatty acid esters, lower alcohol fatty acid esters, and ionic surfactants.

The micelle-forming excipients can also be selected from sodium lauryl sulfate, polyoxyl-40 stearate, PEG-3 castor oil, PEG-5, 9, and 16 castor oil, PEG-20 castor oil, PEG-23 castor oil, PEG-30 castor oil, PEG-35 castor oil, PEG-38 castor oil, PEG-40 castor oil, PEG-50 castor oil, PEG-60 castor oil, PEG- 100 castor oil, PEG- 200 castor oil, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG- 10 hydrogenated castor oil, PEG-20 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-30 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-45 hydrogenated castor oil, PEG-50 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-80 hydrogenated castor oil, and PEG- 100 hydrogenated castor oil. PEG-35 castor oil can be preferred.

The capsules can also include a hydrophilic polymer, such as PEG 300, PEG 400, and PEG 600, and a gelling agent, such as a polyoxyethylene-polyoxypropylene block copolymer. The capsules can also include between 0.5% and 10% (w/w) water, and, optionally, a liquid that is 65% to 85% (w/w) PEG-35 castor oil, 8% to 25% PEG 400, 4% to 6% (w/w) water, and 0.2% to 1.5% Pluronic® F68. The capsules can be hard capsules or soft capsules.

The pharmaceutical compositions typically include between around 0.1 and around 100 mg of rifalazil, for example, between 0.1 and 25 mg of rifalazil, and can include, for example, between about 20% and about 90% (w/w) micelle-forming excipient.

The formulations described in U.S. Serial No. 11/784,051 are also intended for oral administration in unit dosage form, and also include rifalazil and one or more surfactants. They also include a lipophilic antioxidant. The surfactants are typically from about 20% to about 99% (w/w) of the composition, for example, between 75% to 95% (w/w) of the composition. Examplary lipophilic antioxidants include carotenoids, tocopherols and esters thereof, tocotrienols and esters thereof, retinol and esters thereof, ascorbyl esters, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, and mixtures thereof. The lipophilic antioxidant can be an antioxidant surfactant, for example, retinyl palmitate, ascorbyl palmitate, or tocopheryl- PEG- 1000-succinate. The pharmaceutical composition can include from 1 to 50 % (w/w) of a first lipophilic antioxidant selected from retinol, retinyl palmitate, ascorbyl palmitate, tocopherol, tocotrienol and tocopheryl-PEG-1000-succinate and less than 0.1% (w/w) of a second lipophilic antioxidant selected from tocopherol, tocopherol acetate, tocopherol nicotinoate, tocopherol succinate, tocotrienol, tocotrienol acetate, tocotrienol nicotinoate, tocotrienol succinate, carotenoids, BHT, BHA, and propylgallate. The composition can also include from 1 to 20 % (w/w) of said first lipophilic antioxidant, and can also include a hydrophilic co- solvent selected from alcohols, polyethylene glycols, and mixtures thereof, such as ethanol, propylene glycol, glycerol, and mixtures thereof. One type of hydrophilic co-solvent is a polyethylene glycol with a molecular weight of between 200 and 10,000 Da. The compositions can also include PEG-35 castor oil.

One representative formulation includes from 0.2 to 2.5% (w/w) rifalazil, from 75 to 85% (w/w) PEG-35 castor oil, from 0.5 to 1.5% (w/w) pluronic F68, from 8 to 15% PEG-400, from 1.5 to 2.5% (w/w) ascorbyl palmitate, from 0.01 to 0.05% (w/w) BHT, and from 1.5 to 2.5% (w/w) water.

In one embodiment, the compositions include PEG-35 castor oil, PEG-8 caprylic/capric glycerides, and PEG-6 apricot kernel oil, and in one aspect of this embodiment, the composition includes from 0.2 to 2.5% (w/w) rifalazil, from 22 to 28% (w/w) PEG-35 castor oil, from 45 to 50% (w/w) PEG-6 apricot kernel oil, from 20 to 25% PEG-8 caprylic/capric glycerides, from 1.5 to 2.5% (w/w) ascorbyl palmitate, and from 0.01 to 0.05% (w/w) BHT.

Ideally, in both formulations (i.e., with and without the lipophilic antioxidant), the solubility of the rifalazil or rifalazil derivative in the one or more surfactants is greater than 16 mg/mL, for example, greater than 20 mg/mL.

In one embodiment, the pharmaceutical compositions include between 0.1 and 100 mg of rifalazil, more particularly between 1 and 30 mg of rifalazil.

The presence of the lipophilic antioxidant can be useful in inhibiting the conversion of rifalazil to rifalazil N-oxide.

Various salt forms of Rifalazil also can be used in the broad practice of the present invention. Ideally, the rifalazil is administered in a composition that is administered orally, but the rifalazil can alternatively be administered parenterally, for example, intraveneously.

The dosage of Rifalazil in various specific embodiments can range from about 0.01 to 1000 mg., although any specific dosage that is advantageous in a given application can be employed. The dosage of Rifalazil in various emobodiments can be any suitable amount, e.g., about 1 to 1000 mg (desirably about 1 to 100 mg, more desirably about 1 to 50 mg, and even more desirably about 1 to 25 mg). The Rifalazil may be given daily (e.g., once, or twice daily) or less frequently (e.g., once every other day, once or twice weekly, or twice monthly), or in any other dosing regimen that provides therapeutic benefit. The administration of rifalazil can be by any suitable means that results in an effective amount of the compound reaching the target region.

The compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. In one embodiment, the composition is provided in a dosage form that is suitable for oral administration, e.g., a tablet, capsule, pill, powder, granulate, suspension, emulsion, solution, or gel.

The pharmaceutical composition can generally be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, N.Y.).

The pharmaceutical compositions used to deliver the rifalazil can be formulated to release rifalazil at a predetermined time period, or set of criteria (i.e., upon reaching a certain pH).

Solid Dosage Forms for Oral Use

Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

The tablets may be uncoated or they may be coated by known techniques, preferably to delay disintegration and absorption in the gastrointestinal tract until the tablets reach the colon. The coating can be adapted to not release the rifalazil until after passage through the stomach, for example, by using an enteric coating (e.g., a pH-sensitive enteric polymer).

The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or a coating based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose. Furthermore, a time delay material such as, for example, glyceryl monostearate or glyceryl distearate, may be employed.

The solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes (e.g., chemical degradation prior to the release of the active drug substance). The coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin). Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Controlled Release Oral Dosage Forms Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance.

Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, camauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl inethacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

Combination or Alternation Therapy

In addition, the rifalazil or rifalazil derivative described herein can be administered in combination or alternation with one or more anti-retrovirus, anti-HBV, interferon, anti-cancer or antibacterial agents, including but not limited to other compounds of the present invention.

For example, when used to treat or prevent tuberculosis infection in an HIV, HBV, or HCV-positive patient, the rifalazil, rifalazil derivative, or pharmaceutically acceptable salt can be administered in combination or alternation with an antiviral agent, such as anti-HIV, anti-HBV, or anti-HCV agent, including, but not limited to, those of the formulae below.

In general, in combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially. The dosage will depend on absorption, inactivation and excretion rates of the drug, as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

Certain compounds described herein may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds, and as such, are coadministered for this intended effect. For example, the rifalazil, rifalazil derivative, or pharmaceutically-acceptable salt thereof is administered because it does not impact the metabolism of anti-HIV, HBV, HCV, or cancer agents that are metabolized by CYP450.

The combination therapy may be administered as (a) a single pharmaceutical composition which comprises rifalazil (or a rifalazil derivative), at least one additional pharmaceutical agent described herein, and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising rifalazil (or a rifalazil derivative) as described herein and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions can be administered simultaneously or sequentially and in any order.

Combination Anti-TB Therapy

For combination anti-TB therapy, the rifalazil and/or rifalazil derivative can be combined with an additional antibiotic that is effective at treating TB, and which does not induce or otherwise modulate CYP450. Examples include one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol.

The rifalazil and the other antibiotic can be administered simultaneously or sequentially. For sequential administration, the rifalazil can be administered before, during, or after administration of the additional antibiotic, or any combination thereof.

For combination therapy, the dosage and the frequency of administration of each component of the combination can be controlled independently. For example, one of the compounds (i.e., rifalazil or the additional antibiotic) may be administered three times per day, while the second compound may be administered once per day. The compounds may also be formulated together such that one administration delivers both compounds.

Combination Therapy For Treating HIV and Tuberculosis

The rifalazil can be administered in combination or alternation with one or more anti-HIV agents, one of which is ideally an NNRTI or a protease inhibitor, or other anti-HIV agent that is metabolized by CYP450 or a subtype thereof.

Combination Therapy For Treating HBV and Tuberculosis

Non-limiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include those in the tables below.

Combination Therapv For Treating HCV and Tuberculosis

Antiviral agents suitable for treating the HCV infection include, but are not limited to, NRTI, NNRTI, protease inhibitors, such as serine protease inhibitors, interferons, pegylated interferons, IMPDH (inosine monophosphate dehydrogenase) inhibitors, vaccines, monoclonal and polyclonal antibodies, such as anti-CD20 monoclonal antibodies, immunomodulators, antisense therapeutics, caspase inhibitors, anti-fibrotics, and polymerase inhibitors. Specific anti-HCV compounds include the following.

Combination Therapy For Treating Cancer and Tuberculosis

In use in treating or preventing cancer, the rifalazil or rifalazil derivative described herein can be administered together with at least one chemotherapeutic agent as part of a unitary pharmaceutical composition. Alternatively, the rifalazil or rifalazil derivative can be administered apart from the anticancer chemotherapeutic agent. In this embodiment, the rifalazil or rifalazil derivative and the at least one anticancer chemotherapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels for a period of time in the blood.

Combination therapy involves administering the rifalazil or rifalazil derivative, as described herein, or a pharmaceutically acceptable salt or prodrug of a compound described herein, in combination with at least one anti-cancer chemotherapeutic agent (i.e., VEGF inhibitors, alkylating agents, and the like).

Examples of known anticancer agents which can be used for combination therapy include, but are not limited to alkylating agents, such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents, such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and topotecan; topo II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5- fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; and antibodies, such as Herceptin® and Rituxan®. Other known anti-cancer agents, which can be used for combination therapy, include arsenic trioxide, gamcitabine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine. Other classes of anti-cancer compounds that can be used in combination with the rifalazil or rifalazil derivatives are described below.

The rifalazil or rifalazil derivatives can be combined with alpha- 1- adrenoceptor antagonists, such as doxazosin, terazosin, and tamsulosin., which can inhibit the growth of prostate cancer cell via induction of apoptosis (Kyprianou, N., et al., Cancer Res 60:4550 4555, (2000)).

Sigma-2 receptors are expressed in high densities in a variety of tumor cell types (Vilner, B. J., et al., Cancer Res. 55: 408 413 (1995)) and sigma-2 receptor agonists, such as CB-64D, CB-184 and haloperidol, activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. (Kyprianou, N., et al., Cancer Res. 62:313 322 (2002)). Accordingly, the rifalazil or rifalazil derivatives can be combined with at least one known sigma-2 receptor agonists, or a pharmaceutically acceptable salt of said agent.

The rifalazil or rifalazil derivatives can be combined with lovastatin, a HMG- CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice, can potentiate antitumor effects (Giermasz, A., et al., Int. J. Cancer 97:746 750 (2002)). Examples of known HMG-CoA reductase inhibitors, which can be used for combination therapy include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin, and pharmaceutically acceptable salts thereof.

Certain HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma (Sgadari, C, et al., Nat. Med. 8:225 232 (2002)). Accordingly, the rifalazil or rifalazil derivatives can be combined with HIV protease inhibitors, or a pharmaceutically acceptable salt of said agent. Representative HIV protease inhibitors include, but are not limited to, amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.

Synthetic retinoids, such as fenretinide (N-(4-hydroxyphenyl)retinamide, 4HPR), can have good activity in combination with other chemotherapeutic agents, such as cisplatin, etoposide or paclitaxel in small-cell lung cancer cell lines (Kalemkerian, G. P., et al., Cancer Chemother. Pharmacol. 43: 145 150 (1999)). 4HPR also was reported to have good activity in combination with gamma-radiation on bladder cancer cell lines (Zou, C, et al., Int. J. Oncol. 13: 1037 1041 (1998)). Representative retinoids and synthetic retinoids include, but are not limited to, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, alpha- difluoromethylornithine, ILX23-7553, fenretinide, and N-4-carboxyphenyl retinamide.

Proteasome inhibitors, such as lactacystin, exert anti-tumor activity in vivo and in tumor cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis (Almond, J. B., et al., Leukemia 16:433 443 (2002)). Representative proteasome inhibitors include, but are not limited to, lactacystin, MG- 132, and PS-341.

Tyrosine kinase inhibitors, such as STI571 (Imatinib mesilate, Gleevec®), have potent synergetic effects in combination with other anti-leukemic agents, such as etoposide (Liu, W. M., et al. Br. J. Cancer 86: 1472 1478 (2002)). Representative tyrosine kinase inhibitors include, but are not limited to, Gleevec®, ZD 1839 (Iressa®), SH268, genistein, CEP2563, SU6668, SU11248, and EMD121974.

Prenyl-protein transferase inhibitors, such as farnesyl protein transferase inhibitor Rl 15777, possess antitumor activity against human breast cancer (Kelland, L. R., et. al., Clin. Cancer Res. 7:3544 3550 (2001)). Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines also has been reported (Adjei, A. A., et al., Clin. Cancer. Res. 7: 1438 1445 (2001)). Prenyl-protein transferase inhibitors, including farnesyl protein transferase inhibitor, inhibitors of geranylgeranyl-protein transferase type I (GGPTase-I) and geranylgeranyl-protein transferase type-II, or a pharmaceutically acceptable salt of said agent, can be used in combination with rifalazil or the rifalazil analogs described herein. Examples of known prenylprotein transferase inhibitors include, but are not limited to, Rl 15777, SCH66336, L-778,123, BAL9611 and TAN-1813.

Cyclin-dependent kinase (CDK) inhibitors, such as flavopiridol, have potent, often synergetic, effects in combination with other anticancer agents, such as CPT-11, a DNA topoisomerase I inhibitor in human colon cancer cells (Motwani, M., et al., Clin. Cancer Res. 7:4209 4219, (2001)). Representative cyclin-dependent kinase inhibitors include, but are not limited to, flavopiridol, UCN-01, roscovitine and olomoucine.

Certain COX-2 inhibitors are known to block angiogenesis, suppress solid tumor metastases, and slow the growth of implanted gastrointestinal cancer cells (Blanke, C. D., Oncology (Hunting) 16(No. 4 Suppl. 3): 17 21 (2002)). Representative COX-2 inhibitors include, but are not limited to, celecoxib, valecoxib, and rofecoxib.

ΙκΒ-α phosphorylation inhibitors, such as BAY- 11-7082 (an irreversible inhibitor of ΙκΒ-α phosphorylation) are also known to induce apoptosis, or to enhance the effectiveness of other agents at inducing apoptosis. These inhibitors can also be used in combination with the compounds described herein.

Among the anti-cancer agents are therapeutics specifically being pursued for treating liver cancer, which can be important given the co-incidence of liver cancer and tuberculosis, and the hepatotoxicity of existing anti-TB and cancer treatments. Examples include ALN-VSP, an RNAi therapeutic (Alnylam), PV-10 (Provectus), ZIO-101 (Arsenic) (ZIOPHARM), 4SC-201 (Resminostat), an HDAC inhibitor (4SC AG), PI-88 (Progen Industries), GV1001 (Heptovax) (Pharmexa), Doxorubicin, including Doxorubicin Transdrug®, a treatment presented in the form of nanoparticles delivered via hepatic intra- arterial route, and Doxorubicin (ThermoDox) Celsion), a heat-activated liposome therapy, Nexavar (sorafenib) Onyx Pharmaceuticals (Bayer and Onyx), alone or in combination with Tarceva (Genentech).

Any of the above-mentioned compounds can be used in combination therapy with the rifalazil or rifalazil derivatives.

The compounds can also be administered in conjunction with surgical tumor removal, by administering the compounds before and/or after surgery, and in conjunction with radiation therapy, by administering the compounds before, during, and/or after radiation therapy.

The appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers. By "effective amount", "therapeutic amount" or "effective dose" is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder.

When treating cancers, an effective amount of the anticancer agent is an amount sufficient to suppress the growth of the tumor(s), shrink the tumor, and, more ideally, to destroy the tumor. Cancer can be prevented, either initially, or from re- occurring, by administering the compounds described herein in a prophylactic manner. Preferably, the effective amount is sufficient to obtain the desired result, but insufficient to cause appreciable side effects.

The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the cancer, and the manner in which the pharmaceutical composition is administered. The effective dose of compounds will of course differ from patient to patient, but in general includes amounts starting where desired therapeutic effects occur but below the amount where significant side effects are observed.

The compounds, when employed in effective amounts in accordance with the method described herein, are selective to certain cancer cells, but do not significantly affect normal cells.

For human patients, the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, often at least about 10, and frequently at least about 25 μg/ 24 hr/ patient. The effective dose generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 μg/ 24 hr/ patient. In addition, administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/mL and frequently does not exceed 100 ng/mL.

V. Methods of Treating Immunocompromised Patients Suffering from Tuberculosis Infection

The compositions described herein can be used to treat immunocompromised patients, including cancer patients, HIV-positive patients, HBV patients, and HCV patients, suffering from a tuberculosis infection or at risk for being infected with tuberculosis.

When the immunocompromised patients have an HIV, HBV, and/or HCV infection, and are co-infected with tuberculosis, by using the compositions described herein, the patients can continue their existing HIV, HBV, and/or HCV treatments without fear of complications resulting from induction of CYP450.

Treatment of HIV-Positive Patients

Ideally, the management of TB among HIV-infected patients taking antiretroviral drugs includes directly observed therapy, and the availability of experienced and coordinated TB/HIV care givers (CDC, Recommendations and Reports, October 30, 1998 / 47(RR20);1-51, Prevention and Treatment of Tuberculosis Among Patients Infected with Human Immunodeficiency Virus: Principles of Therapy and Revised Recommendations). As described herein, the management of TB also includes the use of a TB treatment regimen that includes rifalazil instead of rifampin The same holds true for patients with cancer, HBV, HCV, and various liver disorders.

Because the use of rifalazil as an alternative to the use of rifampin or rifabutin for antituberculosis treatment is now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin or rifabutin for TB treatment is no longer needed for patients with HIV-related TB.

The use of the anti-tuberculosis regimens described herein may further include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy restores immune function.

Short-course (i.e., 2 months) multidrug regimens (e.g., rifalazil or a rifalazil derivative, combined with pyrazinamide or other anti-TB agents) can be used to prevent TB in persons with HIV infection.

The co-treatment of mycobacterium tuberculosis infection and HIV infection can take into consideration the frequency of co-existing TB and ΗΓ infection and rates of drug-resistant TB among patients infected with HIV; the co-pathogenicity of TB and HIV disease; the potential for a poorer outcome of TB therapy and paradoxical reactions to TB treatment among HIV-infected patients; and therapies to prevent TB among HIV-infected persons. Effective treatments for TB patients co- infected with HIV can not only help reduce new cases of TB in general, but also help decrease further transmission of drug-resistant strains and new cases of drug-resistant TB.

The Use of Rifalazil in Combination with Anti-Retro viral Agents

Widely used antiretroviral drugs available in the United States include protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, and efavirenz). Protease inhibitors and NNRTIs have substantive interactions with certain rifamycins (rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections. These drug interactions principally result from changes in the metabolism of the antiretroviral agents and the rifamycins secondary to induction or inhibition of the hepatic cytochrome CYP450 enzyme system. Rifamycin-related CYP450 induction decreases the blood levels of drugs metabolized by CYP450. For example, if protease inhibitors are administered with rifampin (a potent CYP450 inducer), blood concentrations of the protease inhibitors (all of which are metabolized by CYP450) decrease markedly, and most likely the antiretroviral activity of these agents declines as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered with rifabutin, blood concentrations of rifabutin increase markedly, and most likely rifabutin toxicity increases as well. These undesirable side effects are avoided by using rifalazil or the other rifamycin analogs described herein, instead of rifampin, rifabutin, or rifapentine.

In contrast to the protease inhibitors and the NNRTIs, the other class of antiretroviral agents available, nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not metabolized by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the glucuronidation of zidovudine and thus slightly decreases the serum concentration of zidovudine. The effect of this interaction probably is not clinically important, and the concurrent use of NRTIs and rifamycins is not contraindicated.

Because current treatment regimens frequently include two NRTIs combined with a potent protease inhibitor (or, as an alternative, combined with an NNRTI), and the protease inhibitors and NNRTIs are adversely affected by conventional anti-TB agents, the patients receiving dual treatment with these regimens are at risk for developing resistant mutations of HIV. Accordingly, the use of rifampin to treat active TB in a patient who is taking a protease inhibitor or an NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome enzymes than rifampin, and, in modified doses, might not be associated with a clinically significant reduction of protease inhibitors or nevirapine. Rifapentine is not recommended as a substitute for rifampin because its safety and effectiveness have not been established for treating patients with HIV -related TB.

TB treatment regimens that contain no rifamycins, for example, TB treatment regimens consisting of streptomycin, isoniazid, have been proposed as an alternative for patients who take protease inhibitors or NNRTIs. However, these TB regimens have not been studied among patients with HIV infection. For this reason, the treatment regimens using rifalazil or rifalazil derivatives described herein overcome the limitations of the prior TB treatment for HIV-infected individuals.

In one embodiment, the initial phase of a 9-month TB regimen consists of rifalazil or a rifalazil derivative, along with one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment involves administration of rifalazil or a rifalazil derivative, along with one or more of isoniazid, streptomycin, and pyrazinamide, 2-3 times a week for 7 months.

Another option is a 6-month regimen that includes rifalazil or a rifalazil derivative, along with one or more of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by 2-3-times-per-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment includes a) isoniazid and rifalazil or a rifalazil derivative administered daily or 2-3 times a week for 4 months. Rifalazil or a rifalazil analog, and one or more of isoniazid, pyrazinamide, and ethambutol (or streptomycin) also can be administered three times a week for 6 months

Pyridoxine (vitamin B6) (25-50 mg daily or 50-100 mg twice weekly) can be administered to all HIV-infected patients who are undergoing TB treatment with isoniazid, to reduce the occurrence of isoniazid-induced side effects in the central and peripheral nervous system.

The CDC's most recent recommendations for the use of treatment regimens is 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12 induction doses (two doses per week for 6 weeks) plus 36 continuation doses (two doses per week for 18 weeks). While the use of rifalazil and/or rifalazil derivatives may obviate the need for such lengthy treatment, the CDC guidelines can be useful in determining an appropriate baseline treatment modality, and patient monitoring can be used to determine whether the treatment duration can be shortened.

The minimum duration of short-course rifampin-containing TB treatment regimens can be, for example, 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12-18 induction doses (two to three doses per week for 6 weeks) plus 36- 54 continuation doses (two to three doses per week for 18 weeks)

Three-times-per-week rifalazil regimens can include at least 78 doses administered over 26 weeks.

The final decision on the duration of therapy should consider the patient's response to treatment. For patients with delayed response to treatment, the duration of rifalazil-based regimens should be prolonged from 6 months to 9 months (or to 4 months after culture conversion is documented).

Interruptions in therapy because of drug toxicity or other reasons should be taken into consideration when calculating the end-of-therapy date for individual patients. Completion of therapy is typically based on the total number of medication doses administered, rather than on duration of therapy alone.

Reinstitution of therapy for patients with interrupted TB therapy might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) or a complete renewal of the regimen. In either situation, when therapy is resumed after an interruption of greater than or equal to 2 months, sputum samples (or other clinical samples as appropriate) should be taken for smear, culture, and drug- susceptibility testing.

When caring for persons with HIV infection, clinicians should make aggressive efforts to identify those who also are infected with M. tuberculosis. Because the reliability of the tuberculin skin test (TST) can diminish as the CD4+ T- cell count declines, it can be important to screen for TB with TST as soon as possible after HIV infection is diagnosed. Because the risk of infection and disease with M. tuberculosis is particularly high among HIV-infected contacts of persons with infectious pulmonary or laryngeal TB, these persons should be evaluated for TB as soon as possible after learning of exposure to a patient with infectious TB.

Monthly Monitoring of Patients During TB Preventive Treatment

Patients undergoing preventive treatment for TB can optionally receive a periodic, for example, a monthly clinical evaluation of their adherence to treatment and medication side effects.

In one embodiment, the preventive therapy regimens include the use of a combination of at least two antituberculosis drugs that the infecting strain is believed to be susceptible to (e.g., rifalazil or a rifalazil derivative, in combination with ethambutol pyrazinamide, levofloxacin or ethambutol). The clinician can review the drug- susceptibility pattern of the M. tuberculosis strain isolated from the infecting source-patient before choosing a preventive therapy regimen.

Follow-up of HIV-infected Persons Who Have Completed Preventive Therapy Follow-up care, including chest x-rays and medical evaluations, may not be necessary for patients who complete a course of TB preventive treatment, unless they develop symptoms of active TB disease or are subsequently re-exposed to a person with infectious TB disease.

These examples are provided to illustrate two potential combinations for sequential therapy. They are not intended to limit the invention in any way.

Treatment of Cancer Patients

Where the immunocompromised patients have cancer, the patients can continue their existing cancer treatments without fear of complications resulting from induction of CYP450. The types of cancer treatments that are implicated by this treatment modality specifically include the treatment of liver cancers, lung cancer, lymphoma and leukemia. However, patients suffering from tuberculosis and which are inflicted with other cancers can also benefit from this treatment. For example, patients with the following cancers can benefit from the treatment described herein when they are infected with tuberculosis: human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g., plasma cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), including NF-KB mutant and Velcade Resistant lymphoma cells, multiple myeloma, PI3 kinase deficient myeloma, Waldenstrom's macro globulinemia, and heavy chain disease, and malignant forms of these cancers.

When treating cancer, there is frequently a narrow window between drug toxicity and suboptimal therapy, and inter-individual variation in drug metabolism complicates therapy. Genetic polymorphisms in enzymes such as those in the cytochrome P450 superfamily are at least partially responsible for the observed inter- individual variation in pharmacokinetics and pharmacodynamics of anticancer drugs. For example, there is potential clinically relevant application of CYP450 pharmacogenetics for anticancer therapy, for example, between CYP1A2 and flutamide, CYP2A6 and tegafur, CYP2B6 and cyclophosphamide, CYP2C8 and paclitaxel, CYP2D6 and tamoxifen, and CYP3A5 (van Schaik, "Cancer treatment and pharmacogenetics of cytochrome P450 enzymes," Journal Investigational New Drugs (Springer Netherlands), 23(6): 513-522 (December, 2005), the contents of which are hereby incorporated by reference). In addition to genetic polymorphisms, drugs which modulate CYP450 also have an impact on chemotherapy.

Representative chemotherapeutic agents metabolized by CYP450 include cyclophosphamide, docetaxel, doxorubicin, etoposide, ifosfamide, paclitaxel, tamoxifen, anastrazole, teniposide, vinblastine, vindesine, and gefitinib.

The compositions described herein can be used as therapy for treating tuberculosis and other bacterial disorders treatable with rifalazil and rifalazil derivatives described herein, in any and all of these patients, in combination or alternation with existing therapies used to manage the aforementioned types of cancers, liver disorders, HIV, HBV, and HCV.

VII. Methods of Treating Disorders Other than Tuberculosis The compositions described herein can be used to treat bacterial infections other than tuberculosis, and disorders mediated by such infections, in immunosuppressed patients.

The compositions can be used to treat immunocompromised patients suffering from respiratory tract infections, acute bacterial otitis media, bacterial pneumonia, urinary tract infections, complicated infections, noncomplicated infections, pyelonephritis, intra-abdominal infections, deep-seated abcesses, bacterial sepsis, skin and skin structure infections, soft tissue infections, bone and joint infections, central nervous system infections, bacteremia, wound infections, peritonitis, meningitis, infections after burn, urogenital tract infections, gastro-intestinal tract infections, pelvic inflammatory disease, endocarditis, and other intravascular infections.

Patients can also be treated for gastrointestinal disorders, such as inflammatory bowel disease, irritable bowel syndrome, Clostridium difficile infections and the associated disorder (CD AD), and Crohn's Disease, as well as hepatic encephalopathy, particularly where such patients are co-infected with another disease where the treatment requires the use of the p450 pathway, such as HIV, HBV, HCV, and cancer.

The compositions can also be used to treat diseases associated with bacterial infection. For example, bacterial infections can produce inflammation, resulting in the pathogenesis of atherosclerosis, multiple sclerosis, rheumatoid arthritis, diabetes, Alzheimer's disease, asthma, cirrhosis of the liver, psoriasis, meningitis, cystic fibrosis, cancer, or osteoporosis. Accordingly, the present invention also features a method of treating the diseases associated with bacterial infection listed above.

Immunocompromised patients can be treated for microbial infections cause by bacterium such as Anaplasma bovis, A. caudatum, A. centrale, A. marginale A. ovis, A. phagocytophila, A. platys, Bartonella bacilliforrnis, B. clarridgeiae, B. elizabethae, B. henselae, B. henselae phage, B. quintana, B. taylorii, B. vinsonii, Borrelia afielii, B. andersonii, B. anserina, B. bissettii, B. burgdorferi, B. crocidurae, B. garinii, B. hermsii, B. japonica, B. miyamotoi, B. parkeri, B. recurrentis, B. turdi, B. turicatae, B. valaisiana, Brucella abortus, B. melitensis, C. psittaci, C. trachomatis, Cowdria ruminantium, Coxiella burnetii, Ehrlichia canis, E. chaffeensis, E. equi, E. ewingii, E. muris, E. phagocytophila, E. platys, E. risticii, E. ruminantium, E. sennetsu, Haemobartonella canis, H. felis, H. muris, Mycoplasma arthriditis, M. buccale, M. faucium, M. fermentans, M. genitalium, M. hominis, M. laidlawii, M. lipophilum, M. ovale, M. penetrans, M. pirum, M pneumoniae, M. salivarium, M. spermatophilum, Rickettsia australis, R. conorii, R. felis, R. helvetica, R. japonica, R. massiliae, R. montanensis, R. peacockii, R. prowazekii, R. rhipicephali, R. rickettsii, R. sibirica, and R. typhi.

More specifically, bacterial infections such as C. difficile, S. aureus, B. anthracis, leprosy, MAC, C. pneumoniae, and Chlamydia trachomatis can be treated.

Immunocompromised patients may also be treated for chronic diseases associated with a bacterial infection, particularly chronic diseases caused by bacteria capable of establishing a cryptic phase. The chronic disease may be an inflammatory disease, such as asthma, coronary artery disease, arthritis, conjunctivitis, lymphogranuloma venerum (LGV), cervicitis, and salpingitis. The chronic disease can also be an autoimmune disease (e.g., systemic lupus erythematosus, diabetes mellitus, or graft versus host disease).

Immunocompromised patients diagnosed as being infected with a bacterium having a multiplying form and a non-multiplying form can be treated, for example, by administering to the patient (i) rifalazil or a rifalazil derivative as described herein, and (ii) a second antibiotic that is effective against the multiplying form of the bacterium, wherein the two antibiotics are administered in amounts and for a duration that, in combination, effectively treat the patient.

Immunocompromised patients can be treated for persistent intracellular bacterial infections caused by one of the following: Chlamydia spp. (e.g., C. trachomatis, C. pneumoniae, C. psittaci, C. suis, C. pecorum, C. abortus, C. caviae, C. felis, C. muridarum), N. hartmannellae, W. chondrophila, S. negevensis, or P. acanthamoeba.

Where a patient is suffering from a bacterial infection caused by one of the above-listed bacteria, which have an active form as well as an inactive, latent form, and is also being treated for another disorder with an agent that is metabolized by CYP450, the patient can be treated for the bacterial infection by administering rifalazil or a rifalazil analog that does not modulate CYP450. Ideally, the rifalazil or a rifalazil analog is administered for a longer period of time than would be required to treat the active bacteria, so that it can accumulate in the patient's cells, and the drug's persistence in the blood stream and within the cells will enable it to be present to treat the latent form of the bacteria, when it transitions into the active form. In this manner, one can prevent a relapse of a bacterial infection. The compositions can be used to treat drug resistant Gram-positive cocci, such as methicillin-resistant S. aureus and vancomycin-resistant enterococci, and are useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital- acquired lung infections, bone and joint infections, and other bacterial infections.

The compositions can be administered to the ear (e.g., the tympanic membrane or the external auditory canal of the ear) to treat or prevent bacterial infections associated with otitis media (e.g., an infection of H. influenza, M. catarhalis, or S. pneumoniae) or otitis externa (e.g., an infection of S. intermedins, Streptococcus spp., Pseudomonas spp., Proteus spp., or E. coli). The compositions can also be used to treat infections associated with otic surgical procedures such as tympanoplasty, stapedectomy, removal of tumors, or cochlear implant surgery. The compositions may also be used prophylactically, prior to therapies or conditions that can cause ear infections. In such a use, the compositions can be applied to an area of the ear to which the surgical intervention will be performed, within at least seven days (before or after) of the surgical intervention.

The time sufficient to treat a bacterial infection ranges from one week to one year, but it can also be extended over the lifetime of the individual patient, if necessary. In more preferable embodiments, the duration of treatment is at least 30 days, at least 45 days, at least 100 days, or at least 180 days. Ultimately, it is most desirable to extend the treatment for such a time that the bacterial infection is no longer detected.

VII. Methods of Treating Patients Other Than Immunocompromised Patients

Enzyme induction is the process by which exposure to certain substrates (e.g., drugs, environmental pollutants) results in accelerated biotransformation with a corresponding reduction in unmetabolized drug. Most drugs can exhibit decreased efficacy due to rapid metabolism, but drugs with active metabolites can display increased drug effect and/or toxicity due to enzyme induction. Enzyme inhibition occurs when 2 drugs sharing metabolism via the same isozyme compete for the same enzyme receptor site. The more potent inhibitor will predominate, resulting in decreased metabolism of the competing drug. For most drugs, this can lead to increased serum levels of the unmetabolized entity, leading to a greater potential for toxicity. For drugs whose pharmacological activity requires biotransformation from a pro-drug form, inhibition can lead to decreased efficacy.

Cytochrome P450 3A (CYP3A) is involved in biotransformation of more than half of all drugs currently available. Drug interactions by inhibition of CYP3A are of major interest in patients receiving combinations of drugs. Some interactions with CYP3A inhibitors also involve inhibition of the multidrug export pump, P- glycoprotein.

Various rifamycin analogs, including rifampicin and rifabutin, are CYP3A inducers. When patients taking drugs that are metabolized by CYP3A4 also have bacterial infections commonly treated with rifampicin or rifabutin, it can be advantageous to use rifalazil or rifalazil derivatives that do not induce CYP3A4. A number of adverse drug reactions can be avoided by adopting this approach.

Accordingly, in addition to immunocompromised patients, there are patients treated for chronic disorders, where the patients have to undergo treatment on a daily basis for the rest of their lives. Where the treatment involves administration of agents metabolized by CYP450, in particular, the CYP3A4 and CYP2C9 isoforms, and such patients additionally suffer from one or more of the above-mentioned bacterial infections and/or disorders associated with these bacterial infections, it is preferable to administer rifalazil or a rifalazil derivative that is not an inducer of CYP450, in particular CYP3A4 or CYP2C9. Accordingly, the rifalazil or rifalazil-containing compositions can be particularly useful for treating patients being treated for chronic disorders, such as the following:

Calcium Channel Blockers

Most calcium channel blockers decrease the force of contraction of the myocardium (muscle of the heart). Calcium channel blockers work by blocking voltage-gated calcium channels (VGCCs) in cardiac muscle and blood vessels. This decreases intracellular calcium leading to a reduction in muscle contraction. The decrease in cardiac contractility decreases cardiac output. Since blood pressure is determined by cardiac output and peripheral resistance, the result is a lowering of blood pressure. Lower blood pressure can help ameliorate symptoms of ischemic heart disease such as angina pectoris. Representative calcium channel blockers include diltiazem, nifedipine, felodipine, amlodipine, verapamil, There are two main classes of calcium channel blockers, dihydropyridines and non-dihydropyridines.

Dihydropyridines

Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina (with the exception of amlodipine and nifedipine, which carry an indication to treat chronic stable angina as well as vasospastic angina) because the vasodilation and hypotension can lead to reflex tachycardia. This CCB class is easily identified by the suffix "- dipine".

Representative dihydropyridines include Amlodipine (Norvasc), Aranidipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa), Benidipine (Coniel) , Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Efonidipine (Landel), Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin), and Pranidipine (Acalas)

Non-Dihvdropyridines

Among non-dihydropyridines, there are two main classes, phenylalkylamines and benzothiazepines.

(Phenylalkylamines)

Phenylalkylamine calcium channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines, and therefore cause less reflex tachycardia, making it appealing for treatment of angina, where tachycardia can be the most significant contributor to the heart's need for oxygen. Representative phenylalkylamines include Verapamil (Calan, Isoptin) and Gallopamil (Procorum, D600).

Benzothiazepines Benzothiazepine calcium channel blockers are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. Diltiazem is a representative benzothiazepine.

Many of the estimated 50 million Americans with high blood pressure receive medications for hypertension and for other conditions, placing them at risk for adverse drug interactions. The risk for hypertension and for adverse drug reactions is highest in the elderly, who have the greatest need for pharmacologic therapy. The most important class of drug interactions involves the cytochrome P450 microsomal enzyme system, which handles a variety of xenobiotic substances. Because of the potential for interactions with rifampicin and rifabutin, the present invention provides an effective alternative for treating bacterial infections in these patients.

In addition to ordinary heart patients, heart disease and high blood pressure are major health concerns for people with HIV. Standard treatment for these illnesses often includes calcium channel blockers (CCBs). There is already a potential for significant drug interactions between CCBs and HIV protease inhibitors (Pis) that may influence the dosing, monitoring, and choosing of CCBs and Pis when used in people infected with HIV. Additional interactions with rifabutin and rifampicin can be avoided when such patients are treated for bacterial infections.

Anti-Fungals

Azole anti-fungals, such as voriconazole, are metabolized by the CYP450 isoenzymes 2C19 and 3A4 and, to a lesser extent, by CYP2C9. Several drug-drug interactions with voriconazole can be expected, because many other drugs are also transformed by these enzymes, leading to a contraindication for co-administration of voriconazole with some other drugs. Representative azole antifungals include ketoconazole, itraconazole, and clotrimazole.

When co-administered with voriconazole, rifampin, a CYP450 inducer, decreased the Cmax (maximum plasma concentration) and AUCx (area under the plasma concentration-time curve within a dosing interval) of voriconazole by 93% and 96%, respectively. Geist, "Induction of Voriconazole Metabolism by Rifampin in a Patient with Acute Myeloid Leukemia: Importance of Interdisciplinary Communication To Prevent Treatment Errors with Complex Medications," Antimicrob Agents Chemother. September; 51(9): 3455-3456 (2007). In this case, an immunocompromised patient with acute myeloid leukemia was treated with voriconazole for antifungal prophylaxis. The patient was also treated with rifampin, to treat a Staphylococcus epidermidis infection, without recognizing the potential for drug-drug interactions. The result was a loss of effectiveness of voriconazole caused by rifampin.

In immunocompromised patients suffering from both fungal and bacterial infections, co-administration of voriconazole to treat the fungal infection and rifalazil to treat the bacterial infection can be useful for maintaining the therapeutic efficacy of voriconazole. Unlike co-administration of rifabutin or rifampicin, there will not be a massive reduction of systemic voriconazole exposure due to induced metabolism. The same is true for other azole antifungal agents.

Birth Control

Rifampin (Rifadin®, Rimactane®) is an inducer of CYP3A4, and can cause clinically significant drug interactions with oral contraceptives. Rifampin significantly reduces the efficacy of oral contraceptives as a result of decreased plasma concentrations of estradiol (a substrate of CYP3A4), which can be reduced when rifampin induces CYP3A4 enzymes. The rifalazil and rifalazil derivatives described herein can avoid these side effects, maintaining the efficacy of birth control when women taking such birth control medicines are treated for bacterial infections.

Representative birth control agents include estradiol (estrogen), levonorgestrel (female sex hormone, oral contraceptive), ethinylestradiol (hormonal contraceptive), toremifene (SERM), mifepristone (antiprogesterone, anti-implantation agent), testosterone (androgen), and finasteride (antiandrogen).

Immunosuppressants

Immunosuppressant therapy is critical for transplant recipients. Representative immunosuppressants include cyclosporine, tacrolimus, and sirolimus. All are substrates for CYP450, so it can be important to treat bacterial infections, such as those described herein, with rifalazil and the rifalazil derivatives described herein.

Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors (SSRIs) Many patients suffering from depression will take antidepressants such as tricyclic antidepressants and SSRIs for the rest of their lives. Representative tricyclic antidepressants include amitriptyline, imipramine, and clomipramine. Representative SSRIs include citalopram, escitalopram, fluoxetine, and norfluoxetine, sertraline,

SNRIs

In addition to SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depression and other mood disorders. They are sometimes also used to treat anxiety disorders, obsessive- compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

SNRIs act upon and increase the levels of two neurotransmitters in the brain that are known to play an important part in mood, these being serotonin and norepinephrine. Representative SNRIs include Venlafaxine and Desvenlafaxine (Pristiq), the active metabolite of Venlafaxine (Wyeth), Duloxetine (Cymbalta, Yentreve, Eli Lilly and Company), Milnacipran (Dalcipran, Ixel, Savella) and Levomilnacipran (F2695), the levo- isomer of milnacipran, Sibutramine (Meridia, Reductil), Bicifadine (DOV-220,075, DOV Pharmaceutical), and SEP-227162 (Sepracor).

In addition to these anti-depressants, anxiolytics such as spiperone and buspirone are often used, and both are metabolized by CYP450. Further, various antipsychotics, such as haloperidol, risperidone, ziprasidone, and aripiprazole, are also metabolized by CYP450. Benzodiazepines are frequently used to treat patients suffering from sleep disorders and other CNS disorders. Representative benzodiazepines include flunitrazepam, midazolam, alprazolam, triazolam, and clonazepam pimozide.

Additional agents used to treat depression and psychosis, and which are incompatible with CYP450 inducers, include Mirtazapine (NaSSA), nefazodone (psychoactive and antidepressant), pimozide (antipsychotic), reboxetine (antidepressant) and zopiclone (hypnotic). All of these patients will benefit from treatment with rifalazil and rifalazil derivatives that are not inducers of CYP450 when they also suffer from bacterial infections.

Opiate Analgesics

Opiates are highly susceptible to changes in CYP3A4 activity, and interact with other drugs that inhibits or induce CYP3A4. Drugs that increase CYP3A4 activity (enzyme inducers) reduce opiate plasma concentrations.

If a patient is being treated with rifampacin or rifabutin, which are CYP3A4 inducers, they may not respond adequately to opiates such as oxycodone, alfentanil, fentanyl, sufentanil, codeine, methadone and tramadol. (See, for example, Nieminen et al., "Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone," Anesthesiology.;110(6): 1371-1378) (2009).

In patients undergoing opiate therapy, including oxycodone therapy, it is preferable to avoid using rifampacin or rifabutin to treat bacterial infections, and instead, to use rifalazil or rifalazil derivatives that do not incude CYP450.

Statins

Representative statins include atorvastatin, lovastatin, and simvastatin. These agents are administered daily for the life of the patient, and are incompatible with CYP450 inducers. Accordingly, when such patients are treated for bacterial infections, the compositions described herein can be safely used.

Antiarrhythmic s

Amiodarone, quinidine, and digoxin are representative antiarrhythmic agents. Lidocaine, a local anesthetic, also functions as an antiarrhythmic agent. These agents are substrates for CYP450, and, as such, patients taking these agents and suffering from bacterial infections should be prescribed rifalazil and rifalazil derivatives that do not induce CYP450 rather than rifampicin or rifabutin.

Phosphodiesterase Type 5 (PDE5) Inhibitors and Kinins

Kinins and PDE5 inhbitors are frequently used as vasodilators and smooth muscle contractors, and as such are frequently used to treat erectile dysfunction. Sildenafil is a representative PDE5 inhibitor. Patients taking these agents and suffering from bacterial infections should be prescribed rifalazil and rifalazil derivatives that do not induce CYP450 rather than rifampicin or rifabutin.

HI Antagonists

Astemizole is a representative HI antagonist, and is used as an anti-pruritic. HI antagonists are frequently incompatible with CYP450 inducers.

Anti-Coagulants

Warfarin is a representative anticoagulant. It is known to be incompatible with rifampicin and rifabutin, but is compatible with the rifalazil and rifalazil derivatives described herein.

Anticonvulsants

Representative anticonvulsants that are substrates for CYP3A4 include carbamazepine and valproate.

Proton Pump Inhibitors

Representative proton pump inhibitors include omeprazole and esomeprazole. These agents are metabolized by CYP450, and as such, are incompatible with rifampicin and rifabutin, but compatible with rifalazil and rifalazil derivatives described herein.

Miscellaneous Agents

Other substrates for CYP3A4 include ergot alkaloids (circulation, neurotransmission), ivabradine (used to treat angina pectoris), montelukast (a leukotriene receptor antagonist), ondansetron (a 5-HT3 antagonist), paracetamol (an analgesic and antipyretic), quinine (an antipyretic, anti-smallpox agent, and analgesic), theophylline (a stimulant), glibenclamide (an antidiabetic), cisapride (a 5-HT4 receptor agonist), terfenadine (an Hl-receptor antagonist), barbituates such as phenobarbital. These agents are metabolized by CYP450, and as such, are incompatible with rifampicin and rifabutin, but compatible with rifalazil and rifalazil derivatives described herein.

VIII. Methods of Treating Patients with Liver Disease Frequently, patients having pre-existent chronic liver disease also develop tuberculosis. Additionally, patients undergoing treatment for tuberculosis may develop hepato toxicity as an adverse reaction to the drugs, and/or can develop fresh liver diseases like acute viral hepatitis. Hepatic dysfunction can also alter absorption and distribution of drugs that are metabolized or excreted in the liver. Accordingly, the presence of co-existent hepatic disease, such as that caused by HCV and HBV, poses a challenge in the treatment of tuberculosis.

Rifampicin, pyrazinamide, isoniazid, ethionamide and PAS are all hepatotoxic drugs. Slow acetylators of isoniazid are at a higher risk of hepatotoxicity. The hepatotoxic effects of rifampicin and isoniazide are believed to be additive, whereas the hepatic damage due to pyrazinamide is related to dose and duration. Accordingly, patients with liver disease and who are treated with these agents are at risk of liver damage. If that were not bad enough, patients being treated for viral liver diseases such as HCV and HBV are at a higher risk, as several of these agents are not only hepatotoxic, they are also modulators (primarily inducers) of CYP450, which adversely affects the metabolism of several anti-HCV and anti-HBV agents.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims

Claims:

1. A method for treating an immunocompromised patient infected with tuberculosis, wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the tuberculosis infection.

2. The method of Claim 1, wherein the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) is co-administered with an antibiotic selected from the group consisting of streptomycin, isoniazid, pyrazinamide, ethionamide, PAS, and ethambutol.

3. The method of Claim 2, wherein the treatment is carried out over an approximately 9-month time period.

4. The method of Claim 3, wherein the patient is treated daily for approximately 8 weeks or daily for at least the first 2 weeks, followed by twice-a- week dosing for 6 weeks, to complete a 2-month induction phase, followed by treatment 2-3 times a week for approximately 7 months.

5. The method of Claim 2, wherein the treatment is carried out over an approximately 6-month time period.

6. The method of Claim 5, wherein the treatment is administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by 2-3-times-per-week dosing for 6 weeks, to complete a 2-month induction phase, followed by a second phase of treatment wherein the patient is administered isoniazid and rifalazil or 3 '-hydroxy- 5'- (4-methylpiperazinyl)benzoxazinorifamycin) daily or 2-3 times a week for 4 months.

7. The method of Claim 5, wherein rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin), and one or more of isoniazid,

pyrazinamide, ethambutol, or streptomycin is administered three times a week for 6 months.

8. The method of any of Claims 1-6, wherein the patient is also treated with one or more of Efavirenz, Virammune, Invirase, Norvir, Viracept, or Agenerase.

9. A method of preventing tuberculosis in an immunocomprised individual suspected of being at risk of developing tuberculosis, wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co- infected with one or more of HIV, HBV, and HCV,

and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a prophylactically-effective amount of a composition comprising rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to prevent the tuberculosis infection.

10. The method of Claim 9, wherein the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) is co-administered with an antibiotic selected from the group consisting of streptomycin, isoniazid, pyrazinamide, ethionamide, PAS, and ethambutol.

11. The method of Claim 9, wherein the duration of treatment is approximately two months.

12. The method of Claims 10 or 11, wherein the patient is also treated with one or more of Efavirenz, Virammune, Invirase, Norvir, Viracept, or Agenerase.

13. A composition for use in treating a tuberculosis patient who is immunocompromised as a result of being infected with HIV, comprising rifalazil or 3'-hydroxy-5'-(4-methylpiperazinyl)benzoxazinorifamycin), along with one or more antiviral agents suitable for treating the HIV infection.

14. The composition of Claim 13, wherein the one or more antiviral agents suitable for treating the HIV infection are selected from the group consisting of NRTI, NNRTI, protease inhibitors, entry inhibitors, including fusion inhibitors, integrase inhibitors, cellular inhibitors, and immune-based therapies.

15. The composition of Claim 13, wherein the one or more antiviral agents suitable for treating the HIV infection are selected from the group consisting of NNRTI and protease inhibitors.

16. The composition of Claim 13, wherein the one or more antiviral agents suitable for treating the HIV infection are selected from the group consisting of Efavirenz, Virammune, Invirase, Norvir, Viracept, or Agenerase.

17. A composition for use in treating a tuberculosis patient who is immunocompromised as a result of being infected with HBV, comprising rifalazil or 3'-hydroxy-5'-(4-methylpiperazinyl)benzoxazinorifamycin), along with one or more antiviral agents suitable for treating the HBV infection.

18. The composition of Claim 13, wherein the one or more antiviral agents suitable for treating the HIV infection are selected from the group consisting of NRTI, NNRTI, protease inhibitors, interferons, pegylated interferons, HBV DNA vaccines, ara-AMP prodrugs, hammerhead ribozymes, glycosidase inhibitors, and human or humanized monoclonal antibodies.

19. The composition of Claim 13, wherein the one or more antiviral agents suitable for treating the HIV infection are substrates for CYP450.

20. A composition for use in treating a tuberculosis patient who is immunocompromised as a result of being infected with HCV, comprising rifalazil or 3'-hydroxy-5'-(4-methylpiperazinyl)benzoxazinorifamycin), along with one or more antiviral agents suitable for treating the HCV infection.

21. The composition of Claim 20, wherein the one or more antiviral agents suitable for treating the HCV infection are selected from the group consisting of NRTI, NNRTI, protease inhibitors, such as serine protease inhibitors, interferons, pegylated interferons, IMPDH (inosine monophosphate dehydrogenase) inhibitors, vaccines, monoclonal and polyclonal antibodies, such as anti-CD20 monoclonal antibodies, immunomodulators, antisense therapeutics, caspase inhibitors, anti- fibrotics, and polymerase inhibitors.

22. The composition of Claim 20, wherein the one or more antiviral agents suitable for treating the HCV infection are selected from the group consisting of NNRTI and protease inhibitors, such as serine protease inhibitors.

23. A composition for use in treating a tuberculosis patient who is immunocompromised as a result of having cancer, comprising rifalazil or 3'-hydroxy- 5'-(4-methylpiperazinyl)benzoxazinorifamycin), along with one or more antitumor agents.

24. The composition of Claim 23, wherein the one or more antitumor agents are selected from the group consisting of alkylating agents, such as busulfan, cis- platin, mitomycin C, and carboplatin; antimitotic agents, such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and topotecan; topo II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies, such as Herceptin® and Rituxan®, arsenic trioxide, gamcitabine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine.

25. The composition of Claim 23, wherein at least one tumor agent is a substrate for CYP450.

26. Use of rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) and one or more antiviral agents suitable for treating an HIV infection in the preparation of a medicament for treating a tuberculosis patient who is immunocompromised as a result of being infected with HIV, and is being treated for the HIV infection with a drug which is metabolized by CYP450.

27. The use of Claim 26, wherein the one or more antiviral agents suitable for treating the HIV infection are selected from the group consisting of NRTI, NNRTI, protease inhibitors, entry inhibitors, including fusion inhibitors, integrase inhibitors, cellular inhibitors, and immune-based therapies.

28. The use of Claim 26, wherein the one or more antiviral agents suitable for treating the HIV infection are selected from the group consisting of NNRTI and protease inhibitors.

29. Use of rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) and one or more antiviral agents suitable for treating an HBV infection in the preparation of a medicament for treating a tuberculosis patient who is immunocompromised as a result of being infected with HBV.

30. The use of Claim 21, wherein the one or more antiviral agents suitable for treating the HBV infection are selected from the group consisting of NRTI, NNRTI, protease inhibitors, interferons, pegylated interferons, HBV DNA vaccines, ara-AMP prodrugs, hammerhead ribozymes, glycosidase inhibitors, and human or humanized monoclonal antibodies.

31. The use of Claim 30, wherein the one or more antiviral agents suitable for treating the HBV infection are selected from the group consisting of NNRTI and protease inhibitors.

32. Use of rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) and one or more antiviral agents suitable for treating an HCV infection in the preparation of a medicament for treating a tuberculosis patient who is immunocompromised as a result of being infected with HCV, and is being treated for the HCV infection with a drug which is metabolized by CYP450 .

33. The use of Claim 32, wherein the one or more antiviral agents suitable for treating the HCV infection are selected from the group consisting of NRTI, NNRTI, protease inhibitors, such as serine protease inhibitors, interferons, pegylated interferons, IMPDH (inosine monophosphate dehydrogenase) inhibitors, vaccines, monoclonal and polyclonal antibodies, such as anti-CD20 monoclonal antibodies, immunomodulators, antisense therapeutics, caspase inhibitors, anti-fibrotics, and polymerase inhibitors.

34. The use of Claim 32, wherein at least one of the antiviral agents suitable for treating the HCV infection is an NNRTI or a protease inhibitor, such as a serine protease inhibitor.

35. Use of rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) and one or more antitumor agents in the preparation of a medicament for treating a tuberculosis patient who is immunocompromised as a result of having a cancer, and is being treated with an antitumor agent that is metabolized by CYP450.

36. The use of Claim 35, wherein at least one of the antitumor agents is selected from the group consisting of alkylating agents, such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents, such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and topotecan; topo II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5- fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies, such as Herceptin® and Rituxan®, arsenic trioxide, gamcitabine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine.

37. A method for treating an immunocompromised patient suffering from gastrointestinal disorders, such as inflammatory bowel disease, irritable bowel syndrome, Clostridium difficile infection and the associated disorder (CDAD), Crohn's Disease, or hepatic encephalopathy, wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the gastrointestinal disorder.

38. A method for treating an immunocompromised patient suffering from a disease associated with a bacterial infection, such as atherosclerosis, multiple sclerosis, rheumatoid arthritis, diabetes, Alzheimer's disease, asthma, cirrhosis of the liver, psoriasis, meningitis, cystic fibrosis, cancer, or osteoporosis,

wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the disease associated with the bacterial infection.

40. A method for treating an immunocompromised patient suffering from leprosy,

wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the leprosy.

41. The method of Claim 40, wherein the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) is co-administered with one or more of isoniazid, ethambutol, pyrazinamide, streptomycin, dapsone or clofazimine.

42. A method for treating an immunocompromised patient suffering from a bacterial infection caused by methicillin-resistant Staphylococcus aureus (MRS A), Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae, Legionella pneumophila, or (Chlamydia) pneumoniae (Cpn),

wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection.

43. The method of Claim 42, wherein the bacterial infection is and MRS A infection, and the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) is administered in combination with fusidic acid.

44. Use of rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) in combination with fusidic acid in the preparation of a medicament for treating a methicillin-resistant Staphylococcus aureus (MRSA) infection.

45. A composition comprising rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) in combination with fusidic acid.

46. A method for treating an patient taking warfarin as anti-coagulant therapy, and suffering from a bacterial infection traditionally treated with a rifamycin analog that is a modulator of CYP450, and which would otherwise adversely affect the warfarin therapy,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection.

47. A method for treating an HIV positive patient suffering from mycobacterium avium complex disease, comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3'-hydroxy- 5'-(4-methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the mycobacterium avium complex disease.

48. A method for treating an immunocompromised patient suffering from a bacterial infection selected from the group consisting of respiratory tract infections, acute bacterial otitis media, bacterial pneumonia, urinary tract infections, complicated infections, noncomplicated infections, pyelonephritis, intra-abdominal infections, deep-seated abcesses, bacterial sepsis, skin and skin structure infections, soft tissue infections, bone and joint infections, central nervous system infections, bacteremia, wound infections, peritonitis, meningitis, infections after burn, urogenital tract infections, gastro-intestinal tract infections, pelvic inflammatory disease, endocarditis, and other intravascular infections,

wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection.

49. A method for treating an immunocompromised patient suffering from a microbial infection caused by a bacterium selected from the group consisting of Anaplasma bovis, A. caudatum, A. centrale, A. marginale A. ovis, A. phagocytophila,

A. platys, Bartonella bacilliforrnis, B. clarridgeiae, B. elizabethae, B. henselae, B. henselae phage, B. quintana, B. taylorii, B. vinsonii, Borrelia afielii, B. andersonii, B. anserina, B. bissettii, B. burgdorferi, B. crocidurae, B. garinii, B. hermsii, B. japonica,

B. miyamotoi, B. parkeri, B. recurrentis, B. turdi, B. turicatae, B. valaisiana, Brucella abortus, B. melitensis, C. psittaci, C. trachomatis, Cowdria rurninantium, Coxiella burnetii, Ehrlichia canis, E. chaffeensis, E. equi, E. ewingii, E. muris, E. phagocytophila, E. platys, E. risticii, E. rurninantium, E. sennetsu, Haemobartonella canis, H. felis, H. muris, Mycoplasma arthriditis, M. buccale, M. faucium, M. fermentans, M. genitalium, M. hominis, M. laidlawii, M. lipophilum, M. orale, M. penetrans, M. pirum, M pneumoniae, M. salivarium, M. spermatophilum, Rickettsia australis, R. conorii, R. felis, R. helvetica, R. japonica, R. massiliae, R. montanensis, R. peacockii, R. prowazekii, R. rhipicephali, R. rickettsii, R. sibirica, and R. typhi, wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the microbial infection.

50. A method for treating an immunocompromised patient suffering from a persistent intracellular bacterial infection caused by a bacteria selected from the group consisting of Chlamydia spp. (e.g., C. trachomatis, C. pneumoniae, C. psittaci, C. suis, C. pecorum, C. abortus, C. caviae, C. felis, C. muridarum), N. hartmannellae, W. chondrophila, S. negevensis, or P. acanthamoeba),

wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the persistent bacterial infection.

51. A method for treating an immunocompromised patient suffering from an infection selected from the group consisting of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital- acquired lung infections, or bone and joint infections,

wherein the patient is immunocompromised as a result of having cancer or liver disease, or being co-infected with one or more of HIV, HBV, and HCV, and wherein the patient is treated for the cancer, liver disease, or HIV, HBV, or HCV infection with a drug which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the infection.

52. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also being treated with calcium channel blockers,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

53. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also being treated with azole anti-fungals metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

54. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking birth control medication which is metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

55. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking immunosuppressants which are metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

56. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antipsychotics, anticonvulsants, or anxiolytics which are metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

57. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking one or more opiate analgesics which are metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

58. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking one or more statin drugs which are metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

59. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking one or more antiarrhythmic agents, kinins, or PDE5 inhbitors which are metabolized by CYP450,

comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection or associated disorder.

60. A method for treating a patient suffering from a bacterial infection, or associated disorder, normally treated with rifamycin analogs that are modulators of CYP450, which patient is also taking one or more HI antagonists or proton pump inhibitors which are metabolized by CYP450, comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3 '-hydroxy- 5'- (4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection.

61. A method for treating a bacterial infection, or disorder associated with a bacterial infection, in a patient being treated for another disorder with a drug which is metabolized by CYP450, comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin), in an amount and for a duration sufficient to treat the bacterial infection.

62. The method of Claim 61, wherein the drug which is metabolized by CYP450 is a protease inhibitor, an NNRTI, a calcium channel blocker, an azole antifungal, an oral contraceptive, an immunosuppressant, a tricyclic antidepressant, a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), an anxiolytic, an antipsychotic, an opiate analgesic, a statin, an antiarrhythmic agent, a phosphodiesterase type 5 (PDE5) inhibitor, a kinin, an HI antagonist, an anti-coagulant, an anticonvulsant, a proton pump inhibitor, an ergot alkaloid, a barbiturate, ivabradine, montelukast, ondansetron, paracetamol, quinine, theophylline, glibenclamide, cisapride, or terfenadine.

63. The method of Claim 61, wherein the drug which is metabolized by CYP450 is selected from the group consisting of diltiazem, nifedipine, felodipine, amlodipine, verapamil, Amlodipine (Norvasc), Aranidipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa), Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Efonidipine (Landel), Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin), Pranidipine (Acalas), Verapamil (Calan, Isoptin), Gallopamil (Procorum, D600), Diltiazem, ketoconazole, itraconazole, clotrimazole, voriconazole, estradiol (estrogen), levonorgestrel (female sex hormone, oral contraceptive), ethinylestradiol (hormonal contraceptive), toremifene (SERM), mifepristone (antiprogesterone, anti-implantation agent), testosterone (androgen), finasteride (antiandrogen), cyclosporine, tacrolimus, Sirolimus, amitriptyline, imipramine, clomipramine, citalopram, escitalopram, fluoxetine, norfluoxetine, sertraline, Venlafaxine, Desvenlafaxine (Pristiq), the active metabolite of Venlafaxine (Wyeth), Duloxetine (Cymbalta, Yentreve, Eli Lilly and Company), Milnacipran (Dalcipran, Ixel, Savella) Levomilnacipran (F2695), the levo- isomer of milnacipran, Sibutramine (Meridia, Reductil), Bicifadine (DOV-220,075, DOV Pharmaceutical), SEP-227162 (Sepracor), spiperone, buspirone, haloperidol, risperidone, ziprasidone, aripiprazole, flunitrazepam, midazolam, alprazolam, triazolam, clonazepam pimozide, Mirtazapine (NaSSA), nefazodone, pimozide, reboxetine, zopiclone, oxycodone, alfentanil, fentanyl, sufentanil, codeine, methadone, tramadol, atorvastatin, lovastatin, simvastatin, amiodarone, quinidine, digoxin, lidocaine, Sildenafil, Astemizole, Warfarin, carbamazepine, valproate, omeprazole, esomeprazole, saquinavir, indinavir, ritonavir, nelfinavir, invirase, Norvir, viracept, Agenerase, nevirapine, delavirdine, efavirenz, and virammune.

61. A method for treating a bacterial infection or disorder associated with a bacterial infection, in a patient being treated for another disorder with a drug which is metabolized by CYP450, comprising administering to the patient a therapeutically effective amount of a composition comprising rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin),

wherein the bacterial infection is caused by a bacteria with an active and inactive, latent form, and

wherein the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) is administered in an amount and for a duration sufficient to treat both the active and the inactive, latent form of the bacterial infection, which duration is longer than is needed to treat the active form of the bacterial infection.

62. The method of Claim 61, wherein the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) is administered chronically in a manner that permits accumulation of the rifalazil or 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) within the cells of the patient.