| 2020 | Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy. | PLoS Negl Trop Dis | Subclinical infection with Mycobacterium leprae is one potential source of leprosy transmission, and post-exposure prophylaxis (PEP) regimens have been proposed to control this source. Because PEP trials require considerable investment, we applied a sensitive variation of the kinetic mouse footpad (MFP) screening assay to aid in the choice of drugs and regimens for clinical trials.Athymic nude mice were inoculated in the footpad (FP) with 6 x 103 viable M. leprae and treated by gastric gavage with a single dose of Rifampin (SDR), Rifampin + Ofloxacin + Minocycline (SD-ROM), or Rifapentine + Minocycline + Moxifloxacin (SD-PMM) or with the proposed PEP++ regimen of three once-monthly doses of Rifampin + Moxifloxacin (RM), Rifampin + Clarithromycin (RC), Rifapentine + Moxifloxacin (PM), or Rifapentine + Clarithromycin (PC). At various times post-treatment, DNA was purified from the FP, and M. leprae were enumerated by RLEP quantitative PCR. A regression analysis was calculated to determine the expected RLEP value if 99.9% of the bacilli were killed after the administration of each regimen. SDR and SD-ROM induced little growth delay in this highly susceptible murine model of subclinical infection. In contrast, SD-PMM delayed measurable M. leprae growth above the inoculum by 8 months. The four multi-dose regimens delayed bacterial growth for >9months post-treatment cessation.The delay in discernable M. leprae growth post-treatment was an excellent indicator of drug efficacy for both early (3-4 months) and late (8-9 months) drug efficacy. Our data indicates that multi-dose PEP may be required to control infection in highly susceptible individuals with subclinical leprosy to prevent disease and decrease transmission. |
| Evaluation of New Antibacterial Drugs and their Combinations in a Murine Model to Identify Short Duration Alternative Chemotherapy for Leprosy. | Indian J Lepr | The objective of the research is to test the efficacy of new drugs and drug combinations in mice infected with Mycobacterium leprae (M. leprae) as alternative to current WHO MDT. Individual drugs tested were Rifampicin (RMP), Rifapentine (RPT) and Moxifloxacin (MOXI). Drug combinations were RMP, Clarithromycin (CLARI), Minocycline (MINO) and RMP, MINO and Ofloxacin (OFLO). RPT drug combinations were RPT, CLARI,MINO and RPT, OFLO, MINO. Both the drugs and drug combinations were used as daily regimen and intermittent regimen. WHO MB MDT served as a positive control. Mice pre-inoculated with M. leprae were allotted to daily and intermittent groups and administered selected drugs and drug combinations. At the end of 12 months post sub-inoculation, mice were sacrificed and the proportion % of viable bacilli were counted using Spearman and Karber method. It was noted that RMP, RPT and Moxifloxacin indicated a range of 89.99% to 99.99% bactericidal effect when used in daily or intermittent doses in both normal and TR mice. Drug combinations showed bactericidal effect comparable to that of WHO MDT. From the study it was concluded that if the present duration of MDT has to be shortened then daily dose regimen with RMP/MINO/OFLO or RPT/CLARI/MINO are recommended for a clinical trial. |
| Evaluation of anti-bacterial activity of Rifapentine, Clarithromycin, Minocycline, Moxifloxacin, Ofloxacin and their combinations in Murine Model of Rifampicin Resistant Leprosy. | Indian J Lepr | Leprosy, a debilitating disease of the skin and peripheral nerves is caused by Mycobacterium leprae (M. leprae) and is treated by multidrug therapy (MDT) comprising of Dapsone, Rifampicin and Clofazimine. Resistance to any of these drugs poses a threat to the current disease control strategies. With the emergence of Rifampicin resistance in leprosy, it is important that alternative drugs need to be tested to develop a treatment strategy to combat drug resistant leprosy. In the current study, we have investigated WHO MDT, Rifapentine, Clarithromycin, Minocycline, Moxifloxacin, Ofloxacin and their combinations in intermittent and daily dose regimens in rifampicin resistant strains of M. leprae through mouse foot pad experiments in order to determine the loss in viability of M. leprae in response to these drugs and their combinations. Our findings suggest that WHO MDT is still the best combination in Rifampicin resistance cases. Combination of Moxifloxacin with Minocycline and Clarithromycin may also be taken up for clinical trials in cases with Rifampicin resistant leprosy. Rifapentine and Moxifloxacin can be effective alternative drugs to replace Rifampicin where required either in daily dose shorter duration regimens or intermittent dose longer regimen to treat resistant strains. |
| 2015 | Drug Susceptibility Testing of 31 Antimicrobial Agents on Rapidly Growing Mycobacteria Isolates from China. | Biomed Res Int | Several species of rapidly growing mycobacteria (RGM) are now recognized as human pathogens. However, limited data on effective drug treatments against these organisms exists. Here, we describe the species distribution and drug susceptibility profiles of RGM clinical isolates collected from four southern Chinese provinces from January 2005 to December 2012.Clinical isolates (73) were subjected to in vitro testing with 31 antimicrobial agents using the cation-adjusted Mueller-Hinton broth microdilution method. The isolates included 55 M. abscessus, 11 M. fortuitum, 3 M. chelonae, 2 M. neoaurum, and 2 M. septicum isolates.M. abscessus (75.34%) and M. fortuitum (15.07%), the most common species, exhibited greater antibiotic resistance than the other three species. The isolates had low resistance to amikacin, linezolid, and tigecycline, and high resistance to first-line antituberculous agents, amoxicillin-clavulanic acid, rifapentine, dapsone, thioacetazone, and pasiniazid. M. abscessus and M. fortuitum were highly resistant to Ofloxacin and rifabutin, respectively. The isolates showed moderate resistance to the other antimicrobial agents.Our results suggest that tigecycline, linezolid, clofazimine, and cefmetazole are appropriate choices for M. abscessus infections. Capreomycin, sulfamethoxazole, tigecycline, clofazimine, and cefmetazole are potentially good choices for M. fortuitum infections. Our drug susceptibility data should be useful to clinicians. |
| 2014 | Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. | J Antimicrob Chemother | Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, Ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies. |
| 2011 | The activity of several newer antimicrobials against logarithmically multiplying M. leprae in mice. | Lepr Rev | Moxifloxacin, rifampicin, rifapentine, linezolid, and PA 824, alone and in combination, have been previously administered, as single doses and five times daily doses, to M. leprae infected mice during lag phase multiplication and were each found to have some bactericidal activity.The fluroquinolones, Ofloxacin, moxifloxacin and gatifloxacin, (50 mg/kg, 150 mg/kg and 300 mg/kg) and the rifamycins (5 mg/kg, 10 mg/kg, and 20 mg/kg), rifampicin and rifapentine, were evaluated alone and in combination for bactericidal activity against M. leprae using the mouse footpad model during logarithmic multiplication. Linezolid and PA 824 were similarly evaluated alone and linezolid in combination with rifampicin, minocycline and Ofloxacin.The three fluroquinolones and rifamycins were found alone and in combination to be bactericidal at all dosage schedules. PA 824 had no activity against M. leprae, while linezolid at a dose of 25 mg/kg was bacteriostatic, and progressively more bactericidal at doses of 50 mg/kg and 100 mg/kg. No antagonisms were detected between any of these drugs when used in combinations.Moxifloxacin, gatifloxacin, rifapentine and linezolid were found bactericidal against rapidly multiplying M. leprae. |
| 2008 | [Effects of two treatment regimens for drug-resistant tuberculosis in tuberculosis control project areas: a comparative study]. | Zhonghua Yi Xue Za Zhi | To search for an ideal therapeutic regimen for multidrug resistant tuberculosis conforming to the situation of China.One hundred and fifty-four patients with rifampin-resistant tuberculosis, 114 multi-drug resistant (MDR-TB) and 40 resistant to other drugs, in Heilongjiang, Zhejiang, and Shenzhen, 107 males and 47 females, aged 39 (19-77), were randomly divided into 2 groups: 85 patients in the group of drug-resistant regimen, 3RFT AM Ofx Pto PAS-INH/5RFT Ofx Pto PAS-INH regimen, including rifapentine (RFT), amikacin (Am), Ofloxacin (Ofx), protionamide (Pto), para-aminosalicylic acid-isoniazid (PAS-INH) for 3 months and then RFT, Ofx, Pto, and PAS-INH for 5 months, and 69 in the retreatment regimen group undergoing 3 H3R3Z3E3S3/5 H3R3E3, including isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S) for 3 months and then H, R, and E for 5 months. Sputum smear was checked and the sputum smear conversion rate was calculated as an effective treatment indicator 3, 6, and 8 months later.One hundred and fourteen of the 154 patients were treated for a good 8 months. The sputum smear conversion rate 8 months after treatment of the drug-resistant regimen group was 65.9% (56/85), significantly higher than that of the retreatment regimen group [40.6% (28/69), chi2 = 9.834, P = 0.002]. Eighty-five of the 114 MDR-TB patients had been treated for a good 8 months with a sputum smear conversion rate of 61.8% (42/68), significantly higher than that of the retreatment regimen group [39.1% (18/46), chi2 = 5.638, P = 0.018]. Sputum smear conversion at the end of the 8th month was related to age, course of disease, therapeutic regimen, and the type of drug-resistance (all P < 0.05). The side-effect rate of the drug-resistant regimen group was 23.9% (17/71), higher than that of the retreatment regimen group [18.6% (8/43)], but not significantly (chi2 = 0.446, P = 0.504).The drug-resistant regimen recommended above is more effective than the retreatment regimen and should be considered in the areas where the WHO guideline fails to be followed or drug sensitivity test (DST) cannot be conducted and adjusted according to the results of DST and treatment. |
| 2006 | Antituberculosis drugs and hepatotoxicity. | Respirology | Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like Ofloxacin/levOfloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity. |
| 2001 | Newer drugs in leprosy. | Int J Lepr Other Mycobact Dis | During the last 15 years, new drugs active against Mycobacterium leprae have been identified. All of them belong to the fluoroquinolone, cycline and macrolide drug families. In the mouse model and in humans, minocycline, Ofloxacin, and clarithromycin have demonstrated, individually or in combination, antileprosy activities much superior to those of the standard drugs dapsone and clofazimine. In humans, a single dose of the combination Ofloxacin 400 mg + minocycline 100 mg was able to kill 68% to 98% of viable M. leprae and a single dose of ROM, a three-drug combination of rifampin 600 mg + Ofloxacin 400 mg + minocycline 100 mg, was killing more than 99% of viable M. leprae. As a result of a double-blind, control, clinical trial, the Seventh Report of the WHO Expert Committee on Leprosy recommended in 1997 the use of single-dose ROM for the treatment of patients with single-lesion paucibacillary leprosy. Recently moxifloxacin, a new fluoroquinolone, and rifapentine, a long-lasting rifamycin derivative, have demonstrated in the mouse model highly promising antileprosy activities, justifying their assessment in humans. |
| 2000 | Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy. | Lepr Rev | To further the development of a multidrug regimen for treatment of leprosy that is suitable for monthly administration and fully supervisable, the bactericidal activities against Mycobacterium leprae of HMR 3647 (HMR), moxifloxacin (MXFX) and rifapentine (RPT) were measured by the proportional bactericide technique in the mouse footpad system, and compared with those of the established antileprosy drugs clarithromycin (CLARI), Ofloxacin (OFLO) and rifampicin (RMP). Administered in five daily doses of 100 mg per kg body weight, HMR appeared slightly more bactericidal than CLARI, but the difference did not attain statistical significance. Administered as single doses, MXFX in a dosage of 150 mg per kg was more active than OFLO in the same dosage, and displayed the same level of activity as RMP in a dosage of 10 mg per kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT in a dosage of 10 mg per kg was more bactericidal than RMP administered in the same dosage, and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae, and was slightly more bactericidal than was RPT alone, indicating that the combination PMM showed an additive effect against M. leprae. These promising results justify a clinical trial among lepromatous patients, in which MM is being compared with OM, and PMM with ROM, in terms of efficacy and tolerance. |
| 2000 | Bactericidal activities of HMR 3647, moxifloxacin, and rifapentine against Mycobacterium leprae in mice. | Antimicrob Agents Chemother | Bactericidal activities of HMR 3647 (HMR), moxifloxacin (MXFX), and rifapentine (RPT) against Mycobacterium leprae, measured by the proportional bactericidal technique in the mouse footpad system, were compared with those of the established antileprosy drugs clarithromycin (CLARI), Ofloxacin (OFLO), and rifampin (RMP). Administered in five daily doses of 100 mg/kg of body weight, HMR appeared slightly more bactericidal than CLARI. In a single dose, MXFX at 150 mg/kg was more active than the same dose of OFLO and displayed exactly the same level of activity as RMP at 10 mg/kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT at 10 mg/kg was more bactericidal than the same dose of RMP and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae and was slightly more bactericidal than RPT alone, indicating that the combination PMM showed an additive effect against M. leprae. |
| 1998 | [Nontuberculous mycobacteriosis; the present status and in the future. 3--(1). The view of development of new drugs against nontuberculous mycobacterial infections]. | Kekkaku | It is obvious that the number of patients with pulmonary nontuberculous mycobacterial infections is increasing gradually in Japan. Of these infections, M. avium complex (MAC) is the most common cause, and is known to be resistant to many antimicrobial drugs. At present, no standard regimen which is able to control MAC infections completely is established. For these reasons, the development of new drugs with strong antimycobacterial activity which are not cross-resistant to conventional antimycobacterial drugs is urgently desired. Thus, we studied in vitro activities of various drugs which are expected to be a new promising drug against nontuberculous mycobacterial infections, and reviewed clinical impact of these drugs. 1) New quinolones New quinolones including Ofloxacin, ciprOfloxacin, levOfloxacin and sparfloxacin (SPFX), are considered to be active against M. tuberculosis, M. kansasii, M. fortuitum, but are inactive against MAC, M. chelonae, M. abscessus, M. scrofulaceum. Both AM-1155 and Du-6859a, newer quinolones, seemed to be comparable to or more active than SPFX which is considered to be most active now. 2) New macrolides Clarithromycin (CAM) has in vitro activities against various nontuberculous mycobacteria including MAC, and also has proven to have clinical potential not only for disseminated MAC infections in AIDS but also for pulmonary MAC infections. Therefore, CAM seems to be a candidate for one of the key drugs in the treatment of MAC infections. 3)Rifamycins Rifabutin (RBT) and rifapentine exhibited more potent in vitro and in vivo antimycobacterial activities than rifampicin. RBT has already demonstrated clinical effect against intractable tuberculosis and MAC infections. Thus, RBT is recommended for the prophylaxis of M. tuberculosis and MAC infections in AIDS patients in US. KRM-1648 displayed much more potent in vitro and in vivo activities than rifampicin against both M. tuberculosis and MAC. It is needed an effort to confirm its therapeutic efficacies. Now clinical phase study is going on in US. 4) Phenazines Clofazimine (CFZ), an effective antileprosy drug, is known to be active in vitro against various mycobacteria including MAC, and often used as a component of combination chemotherapy for disseminated MAC infections in AIDS patients in US. Recently, CFZ new analogs have been developed, and it is necessary to evaluate its activities against nontuberculous mycobacteria. |
| 1995 | New drugs for tuberculosis. | Eur Respir J Suppl | Since the late 1960s, tuberculosis has been successfully cured with antibiotics. With the introduction of rifampin, "short course" regimens using isoniazid and rifampin together with either streptomycin, ethambutol or pyrazinamide, for 6-9 months, have been successfully adopted. The spread of drug resistant M. tuberculosis strains in large urban areas has made this armamentarium of drugs insufficient, calling for the development of new drugs. Among rifamycin derivatives, rifabutin is more active than rifampin in vitro and in experimental animals, and allows sputum conversion rats of 95-100%. It is effective in treating multidrug-resistant tuberculosis. Rifapentine is more active than rifampin in vitro and has a longer half-life, but it is not active against rifampin-resistant strains. Fluoroquinolones concentrate within macrophages, are effective against M. tuberculosis and act synergistically with rifampin and isoniazid. Ofloxacin, ciprOfloxacin, sparfloxacin and lomefloxacin have been evaluated as antimycobacterial agents, and no cross-resistance with major antituberculous drugs has been found. Several other drugs, including new inhibitors of beta-lactamase and new beta-lactamase-resistant antibiotics, the aminoglycoside antibiotic, paromomycin, and the new nitroimidazole, 2-ethyl-5-intro-2.3-dihydro imidazo-oxazole, have been found to be active in vitro against M. tuberculosis. |
| 1994 | Antimycobacterial drugs. | Semin Respir Infect | This review consists of the following three sections: (1) General principles in selecting antimycobacterial drugs for the treatment regimens, (2) The antimicrobial activity in vitro with an emphasis on inhibitory and bactericidal potency of various agents, and (3) Drug susceptibility testing including methodology and interpretation of the test results. Each of these sections addresses three groups of antimycobacterial agents: (1) against tuberculosis, (2) against Mycobacterium avium complex infections, and (3) against infections caused by M. fortuitum and M chelonae. The following are the drugs examined in the sections and subsections of this review: isoniazid, ethionamide, thiacetazone, rifampin, rifabutin, rifapentine, KRM-1648, pyrazinamide, streptomycin, kanamycin, amikacin, capreomycin, gentamicin, tobramycin, ethambutol, para-aminosalicylic acid, D-cycloserine, Ofloxacin, levOfloxacin, ciprOfloxacin, sparfloin, clofazimine, clarithromycin, azithromycin, erythromycin, cefoxitin, cefmetazole, imipenem, sulfamethoxazole, sulfisoxazole, sulfadiazine, sulfathiazole, trimethoprim, and doxycycline. |