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Rifampicin can induce hypothyroidism. We report a case of pulmonary tuberculosis and tuberculous pleurisy that was complicated by rifampicin-induced hypothyroidism. The patient received rifampicin-based tuberculosis treatment and experienced persistent appetite loss, which led us to pro- vide concomitant hypothyroidism treatment. An 85-year-old woman with no underlying thyroid-related disease presented to her local hospital with a 3-month history of appetite and weight loss. A chest radiograph revealed pleural effusions and infiltrative shadows in the lower fields of both lungs, and we also detected high levels of lympho- cytes and adenosine deaminase levels (49.6 IU/1) in the pleu- ral effusion, with positive results from a polymerase chain reaction assay of a sputum sample. Thus, we diagnosed the patient with pulmonary tuberculosis and tuberculous pleurisy, and initiated treatment using isoniazid, rifampicin, etham- butol, and pyrazinamide. Her clinical course was good and her anorexia was improved. However, she subsequently experienced recurrent appetite loss, malaise, and bilateral lower-leg edema. Follow-up laboratory testing revealed that she had developed hypothyroidism. We started treatment using levothyroxine without interrupting the tuberculosis treatment. The loss of appetite and other thyroid-related symptoms were improved. The patient's thyroid function had been normal at her admission, and there were no findings of Hashimoto's thyroiditis or other thyroid conditions. Based on the clinical course, we conclude that the rifampicin induced the hypothyroidism. Therefore, rifampicin-induced hypothyroidism should be considered in cases with persistent appetite loss, even if the patient appears to be experiencing anorexia as an adverse drug reaction.

To investigate the outcome of rifam- picin (RFP) monotherapy for latent tuberculosis infection (LTBI) and the incidence of RFP-induced liver toxicity. [Method] We conducted a retrospective chart review of patients who received RFP monotherapy as LTBI treatment at the Daiichi Dispensary Clinic. [Result] Of 61 patients who received RFP monotherapy, the treatment completion rate was 88.5%, self-termination rate was 3.3%, abandonment rate due to adverse drug effects was 8.2% (5 cases: 3 cases of skin eruption and 2 cases of liver dysfunction). Among the 2 cases of liver dysfunction, I was not associated with abnormal alkaline phosphatase (ALP) or gamma-glutamyl transferase (y GTP) levels. Among patients with liver dysfunction who did not discontinue RFP mono- therapy, no cases-of severely abnormal ALP and/or y GTP levels were reported. [Conclusion] The incidence of liver toxicity due to RFP is lower than that observed with isoniazid, and liver dysfunction due to RFP was not always associated with abnormal of ALP and/or yGTP levels.

Objectives: To clarify whether rifabutin (RBT) can be used for treating tuberculosis in elderly Japanese patients in the clinical setting., Method: We performed a clinical chart review from Oct 2008 to Dec 2011, for patients who were diagnosed with tuberculosis and were prescribed rifabutin, at the Fukujuji Hospital (180 beds for respiratory medicine, including 60 for TB). Primarily, we focused on characteristics of patients, the cause for RBT indication, and success rate of treatment., Results: During the study period, 1129 patients were diagnosed with tuberculosis, and among these, 42 (3.7%) patients were prescribed RBT. Of these, 39 patients were included in this study (3 were excluded because their prescription was terminated within 2 weeks because of reasons other than adverse effects). In all, 69% patients were male. Mean age was 69 years, and mean body mass index was 19.1 +/- 3.4 kg/m2. RFP-related adverse effects were observed in 28 patients (72%; age, 73 years); these included gastrointestinal complications in 16, liver dysfunction in 7, skin rashes in 6, and renal dysfunction and thrombocytopenia in 1 each). Additional medication was required in 6 patients, and RBT-resistant TB was noted in 5 patients (28%; age, 60 years). A success rate of 71.4% was observed in cases of RFP-related adverse effects, and that of 81.8% was observed in cases of other reasons. Except for the patient who experienced renal dysfunction, RBT could be used in all patients who experienced RFP-related adverse effects., Conclusion: RBT showed a relatively good success rate, even in patients who experienced RFP-related adverse effects. Thus, RBT could be an alternative in cases of RFP-related adverse effects, even in elderly patients.

This is a review of non-clinical and clinical study results of rifabutin (Mycobutin, RBT) which was approved as a new anti-mycobacterial agent 38 years after rifampicin (RFP) was approved in Japan. The anti-bacterial actions of RBT were similar to those of RFP, but its potency was stronger (4 to 32 times in MIC90). RBT showed excellent penetration in cells (9 times in neutrophil, 15 times in monocyte, against plasma concentration) and in tissues (5 to 10 times in pulmonary tissue). Clinical efficacy of RBT (150 mg, as well as 300 mg daily) was comparable to that of RFP 600 mg daily, in the treatment of newly diagnosed tuberculosis, drug-resistant tuberculosis, and the NTM diseases. In addition, RBT 300 mg showed significant prophylactic effect on the development of disseminated MAC infection in HIV positive subjects. Most of the adverse events of RBT were the same as those of RFP, including drug-drug interactions related to the induction of CYP3A4. The concomitant use of RBT (over 450 mg) with clarithromycin induces uveitis, which warrants special attention. It is expected that the efficacy and safety of RBT in Japanese subjects will be evaluated in Japan through the accumulation of clinical experience.

A case was 38 years old male. He was pointed out abnormal shadow on chest X-ray and complained respiratory infection symptoms. He had not past history of tuberculosis. He was diagnosed as multi-drug resistant tuberculosis (MDR-TB) in a certain hospital and was referred to our hospital to undergo treatment. His drug sensitivity test by Ogawa medium was resistant to all anti-tuberculosis drugs except for kanamycin (KM) and enviomycin (EVM). His chest X-ray revealed large cavities in the right upper field and infiltrations in the right lower field and small cavitary lesions in the left lower field. The right pneumonectomy was done because he took anti-tuberculosis drugs but his sputum examinations continued to be smear and culture positive without improvement of the lesions. After the surgical treatment (right pneumonectomy), he continued anti-tuberculosis drugs therapy and the chest X-ray improved including the collapse of left lower cavitary lesions. This case was a difficult case to treat because of bilateral cavitary lesions. However he was successfully treated by the surgical treatment.

Purpose: Buruli ulcer is a human skin disease caused by Mycobacterium ulcerans infection, which is characterized by massive skin ulceration and persistent necrotic change. In recent years Buruli ulcer has rapidly emerged as an increasingly important cause of human morbidity around the world. The disease is endemic at least 32 countries in Africa, Western Pacific, Asia and South America, and it is considered the third most common mycobacterial infection of humans after tuberculosis and leprosy. An effective chemotherapeutic regimen against Buruli ulcer disease has not been established to date. In this study, the inhibitory effect of rifalazil (RLZ) against M. ulcerans was assessed in experimentally infected mice and compared to that of rifampicin (RFP)., Materials and Methods: Five-week-old BALB/c female mice were challenged with 25 microliters (CFU = 4 x 10(4) of M. ulcerans cultured in Middlebrook 7H9 broth in bilateral hind footpads. Mice were administered per os with a suspension of RLZ or RFP at 2.5, 5, or 10 mg/kg once daily 5 times per week starting from one day up to 6 weeks after infection. During the treatment, mice were observed weekly for footpad skin lesions and examined for footpad swelling. In addition, CFU enumeration was done on both hind footpads and spleen at 2, 4, and 6 weeks after initiating treatment., Results: In the infected control mice group, slightly erythematous lesions and moderate swelling of footpads were observed 4 weeks after the infection. Ulcerative lesion was observed 6 weeks after the infection. Mean log10 CFU/footpad (FP) was 5.22 on day 1 after the infection and increased to 5.56, 6.29, and 7.33 at 2, 4, and 6 weeks after treatment was initiated in the treated groups. On the other hand, no visible erythema, swelling or ulcerative lesion in footpads were observed in RLZ-administered groups. Furthermore, log10 CFU/FP decreased to 4.14 after only 2 weeks of initiating treatment in 2.5 mg/kg administered group, i.e. the lowest dose employed group. Log10 CFU/FP decreased to < 2.1 in 6 weeks in the 10 mg/kg administered group, which was close to the detection limit (< 1.7) of the CFU assay. By contrast, inhibitory effect on disease progression and reduction of CFU were observed only in the group of mice given 10 mg/kg among RFP-administered groups: the reduction of CFU was not observed in the early period but 6 weeks after initiating treatment., Conclusion: These results clearly demonstrate that the in vivo anti-M.ulcerans activity of RLZ is much higher than RFP. RLZ activity against M. ulcerans can be expected to control the disease progression in the clinical applications.

Studied were made on the profiles of the therapeutic efficacy of KRM-1648 (KRM) against Mycobacterium avium complex (MAC) infection, which was induced in mice at different challenge doses, in reducing bacterial growth in the visceral organs and altering the profiles of cytokine mRNA expression at the sites of infection. First, bacterial growth in the lungs of mice infected with either high or low challenge doses of MAC, was reduced due to KRM treatment. This effect was noted even in the early phase of infection (week 4) in mice, that were given a high-dose infection. Second, marked therapeutic efficacy of KRM was observed in mice, that were given low-dose MAC infection, in terms of the reduction in bacterial loads in the spleen. However, in mice given a high-dose bacterial challenge, KRM did not exhibit such an efficacy. Third, the expression of both proinflammatory cytokines (TNF-alpha, IFN-gamma) and anti-inflammatory cytokines (IL-10, TGF-beta) in mRNA levels were increased at 4 weeks after infection. Notably, all of the cytokines tested for the mRNA expression levels were higher in mice given a low-dose MAC infection as compared to those in mice given a high-dose infection. KRM treatment increased the mRNA levels of these cytokines at week 4, while TGF-beta mRNA expression at week 8 was conversely decreased by KRM treatment. These findings suggest that the profiles of the therapeutic efficacy of KRM vary in mice given low- or high-dose MAC infection.

M. avium complex (MAC) is one of the important causative agents of opportunistic infections among AIDS patients. Recent evidence showed that the entry of infection is through the gastrointestinal tract. In the present study, we compared the prophylactic effect of some antimicrobials against MAC infection induced in mice. Different groups of beige mice were fed with pellets containing 0.0067% (10 mg/kg) of KRM-1648, rifabutin (RFB) and clarithromycin (CAM). Seven days after the administration of drugs, the mice were infected with M. intracellular N-241 (5 x 10(8) CFU) orally, five times, every other day and killed one and 126 days after the last infection. The effect of drug was evaluated using the frequency and severity of gross lung lesions in the mice and by the total CFU recovered from the lungs and spleen. MAC infection was not likely to be established since there was no macroscopic evidence of lesion in organs and the recovery of cultures from lungs and spleen tested was negative, in 3 of 10 mice in the control group, 2 of 9 in the CAM group, 4 of 9 in the RFB group and 4 of 10 in the KRM group. These mice were excluded from the analysis of the study results. Thus, we examined 7 mice in the control group, 7 in the CAM group, 5 in the RFB group, and 6 in the KRM group. Tubercle-like lesions were observed in the lungs of all 7 mice in the control group (severity: 3+ in 5 mice; 4+ in 2 mice), in 5 of 7 mice (71%) in the CAM group (severity: 2+ in 1 mouse; 3+ in 4 mice), and in 4 of 5 mice (80%) in the RFB group (severity: 1+ in 1 mouse; 2+ in 1 mouse; 4+ in 2 mice), while only slight lesions (severity: 1+) were observed in 4 of 6 mice (67%) in the KRM group. There was no macroscopic evidence of lesion in spleen, liver and kidneys. The log CFU was determined at the next day of the completion of the last infection. The log CFU of the lungs was 2.49 and 2.28 in the control group and the CAM group, respectively. The bacteria were not recovered either from the lungs in the RFB and KRM groups, nor from the spleen in all the groups. The order of efficacy of the drugs on the basis of the CFUs recovered from the lungs and spleen in each group determined 126 days after the completion of the last infection was as follows; KRM > CAM > RFB in the lungs and KRM > CAM [symbol: see text] RFB in the spleen, although there was no significant difference among the three drugs (P < 0.05). However, the significantly preferable effect was obtained in the three drug groups as compared with the control group.

We previously examined the effects of a Chinese medicine "Mao-Bushi-Saishin-To" (MBST) which has anti-inflammatory activity on the therapeutic efficacies of a benzoxazinorifamycin, KRM-1648 (KRM), against, Mycobacterium avium complex (MAC) infection induced in mice. MBST potentiated the therapeutic activity of KRM against MAC infection. In the present study, we examined the effects of another anti-inflammatory drug Glycyrrhizin, which is effective for chronic hepatitis, on the therapeutic efficacy of KRM against MAC infection induced in mice. First, KRM significantly inhibited the bacterial growth in the lungs and spleen of MAC-infected mice. Glycyrrhizin exhibited no therapeutic activity against MAC infection and did not affect the expression of the therapeutic efficacy of KRM. Secondly, treatment of murine peritoneal macrophages (M phi s) with Glycyrrhizin caused no significant changes in the M phi anti-MAC activity.

We examined the effects of such drugs having anti-inflammatory activity as half-sized secretory leukocyte protease inhibitor (1/2 SLPI) and Chinese traditional medicines, Yokuinin (YOK) and Mao-Bushi-Saishin-To (MBST), on therapeutic efficacies of benzoxazinorifamycin KRM-1648 against Mycobacterium avium complex (MAC) infection induced in mice, since it is possible that these agents inhibit the increase in tissue levels of immunosuppressive cytokines due to MAC infection. First, Zymosan A-induced murine peritoneal macrophages treated with either 1/2 SLPI, YOK or MBST at 37 degrees C for 2 days were infected with M. avium N-444 and further cultivated in the medium with or without addition of 1/2 SLPI, YOK or MBST at 37 degrees C for up to 7 days. Treatment of macrophages with these drugs caused some decrease in the intracellular growth of the organisms. Secondly, we evaluated effects of 1/2 SLPI, YOK and MBST on the therapeutic efficacy of benzoxazinorifamycin KRM-1648 against M. avium infection induced in mice. When MAC-infected mice were given KRM-1648 (20 mg/kg) alone, or in combination with 1/2 SLPI (100 mg/kg), YOK (50 mg/kg), or MBST (50 mg/kg), by gavage, except for 1/2 SLPI which was given via i.p. route, once a week, from day 1 for up to 8 weeks after infection, these drugs did not affect the expression of therapeutic activity of KRM-1648. When MAC-infected mice were given KRM-1648 alone (once a week), or in combination with YOK (five times per week) or MBST (five times per week), MBST increased the expression of therapeutic activity of KRM-1648. These findings indicate that suppression of inflammatory reactions using MBST is capable to improve the therapeutic efficacy of KRM-1648 in MAC infection. Moreover, these results also mean that combined use of these drugs in MAC patients receiving KRM-1648 therapy may not cause any disadvantages to the therapeutic efficacy of KRM-1648.

Disseminated Mycobacterium avium-intracellulare complex (DMAC) infection is a common complication of AIDS. The cumulative incidence is 40% in patient surviving 2 years after diagnosis of AIDS. AIDS patients with DMAC reduced life expectancy compared with those without. Antimycobacterial therapy with Clarithromycin (CAM) can significantly reduce bacteremia and improve symptoms, quality of life, and survival of patients with DMAC. Prophylactic therapy with Rifabutin, CAM and Azithromycin is effective and Synergic effect can be expected as Rifabutin and Azithromycin are administered together. But it is serious problem to get resistance to CAM when prophylactic therapy with CAM failed because we lose one of the most effective medicines against DMAC. It is recommended to start prophylactic therapy when CD4 Lymphocyte count falls below 50-75/microliters in patients who had opportunistic infection. In Japan, 32 cases of AIDS with NTM are reported. All of them are male and mean count of CD4+lymphocyte was 11/microliters. Twenty three out of 32 were MAC and 6 were M. kansasii. Cases of NTM bacteremia were 9 (69.2%) and cases of those without bacteremia were 4 (30.8%). Three out of 4 were cases of M. kansasii.

Objectives: This study aims to compare in vivo activity of benzoxazinorifamycin KRM-1648 (KRM) with those rifampicin (RFP) and rifabutin (RBT) against experimental murine tuberculosis., Study Design: Mice were infected with Mycobacterium tuberculosis or M. bovis by the intratracheal (i.t.) or intravenous (i.v.) routes, and treated for 10 days with various doses of each drug starting from the 9th or 11th day after the TB-infection., Results: (A) A rapid test for in vivo evaluation of three rifamycins was conducted by examining the survival days of treated mice infected with 106 cfu of M. bovis Ravenel. Mice treated with KRM exhibited 2.13.7 times longer survival times, in comparison with those treated with RFP or RBT. (B) In the i.t.-model of M. bovis Ravenel infection, three rifamycin derivatives gave "distinctive dose-response curves" in the correlation of dose sizes with the mean survival times or "log10CFU/lungs reductions". (C) In M. tuberculosis Kurono infection models, the ranking of the anti-TB activity of the three rifamycins in each organ was as follows: i.t.-and i.v.-lungs: KRM >> RFP not equal to RBT, i.v.-spleen: KRM not equal to RBT > RFP, i.v.-liver: KRM not equal to RBT > RFP. (D) Based on the results of "log10CFU reduction" in different organs in M. tuberculosis Kurono infection models, "characteristic in vivo activity patterns of each rifamycin" were obtained. (E) The therapeutic efficacy of KRM in lungs was greater than in spleen and liver with any dose. In contrast, RBT exhibited more remarkable in vivo activity in the spleen and liver than in lungs., Conclusion: The prominent in vivo activity of KRM may allow small dose for effective therapy; 1/3 dose or less in comparison with those of RFP or RBT, or intermittent therapy of tuberculosis.

We evaluated the in vivo therapeutic activities of benzoxazinorifamycin KRM-1648, clarithromycin (CAM) and levofloxacin (LVFX) against Mycobacterium avium infection induced in mice. Mice infected intravenously with M. avium (1.4 x 10(7)) were given KRM-1648 (20 mg/kg), CAM (10 mg/kg), or LVFX (5 mg/kg) alone, or combination of KRM-1648 with diclofenac sodium (1.25 mg/kg) by gavage, once daily, five times per week, from day 1 for up to 8 weeks. The bacterial loads in the lungs and spleens were determined by counting colony forming units of the organisms in the tissue homogenates of the visceral organs using 7H11 agar plates. Both KRM-1648 and CAM caused significant levels of bacteriological response in mice treated with these drugs, while LVFX exerted no appreciable therapeutic effect. The therapeutic efficacies of test antimicrobials were in the order, KRM-1648 > CAM > > LVFX. The combined use of diclofenac sodium with KRM-1648 did not affect the expression of therapeutic activity of KRM-1648. This excludes the possibility that cyclooxygenase-dependent inflammatory reactions may be involved in the establishment of persistent bacterial growth of M. avium organisms at the sites of infection in mice. Furthermore, the present study showed that the parameters of in vitro antimicrobial activities of drugs such as MIC and MBC values are not useful in predicting their therapeutic outcome in M. avium-infected mice.

Although various antimicrobial drugs show appreciable bactericidal activity in the early phase (2 to 4 weeks after infection) of Mycobacterium avium complex (MAC) infections in mice, no drug, as far as we know, can continue to exert the growth inhibiting activity against the bacteria at the site of infection in the progressed stage. Here, we studied the mechanisms of the bacterial regrowth which usually starts around 2-4 weeks after infection. First, the changes in the level of TNF-alpha, IFN-gamma, IL-6 and IL-10 in the lungs and spleen during the course of MAC infections was examined. Tissue levels of TNF-alpha and IL-10 increased around weeks 2 to 4, then rapidly decreased thereafter, and returned to the normal levels by week 8, while levels of IFN-gamma and IL-6 remained very low throughout the observation period. In this experiment, the bacterial CFUs rapidly decreased during the first 2 weeks of the treatment with a rifamycin derivative, KRM-1648, and thereafter the regrowth of the organisms was observed even in mice treated continuously with KRM-1648, although the rate of bacterial growth in the treated mice was much lower than in untreated control mice. Second, effect of either anti-TGF-beta or anti-IL-10 antibody on intracellular growth of MAC in human monocytes cultured in vitro in the medium with or without addition of TNF-alpha or IFN-gamma were examined. Anti-TGF-beta and anti-IL-10 antibodies potently reduced the bacterial growth in monocytes. Effects of TNF-alpha and IFN-gamma in reducing the bacterial growth was potentiated by the addition of either anti-TGF-beta or anti-IL-10 antibody. Third, anti-IL-10 antibody augmented to some extent the chemotherapeutic efficacy of KRM-1648 against MAC infection, when the drug was given to mice at weeks 2 and 4 after infection. From these results, it is suggested that IL-10 derived from MAC-infected macrophages in response to stimulation with some bacterial components, such as lipoarabinomannan, might downregulate the antimicrobial function of host macrophages against MAC.

A 46-years-old male was admitted to our hospital because of productive cough and infiltrates on the chest roentogenogram. The patient had a history of left upper bullectomy ten years prior to the admission. The CT scan of the chest on admission showed infiltrats with cavitation in the left apex and multiple bullae in almost whole lung. Microscopical examination of smears of sputum and bronchoalveolar lavage fluid revealed acid-fast bacilli. They were identified as Mycobacterium szulgai by DNA-DNA hybridization method. The patient was treated with isoniazid, streptomycin and rifampicin. After treatment for about a month, the culture of sputum converted to negative for M. szulgai. After about three months hospitalization, the infiltrates decreased and the cavity wall became thin, and no recurrence sign has been observed after the discharge. There are a few case reports of pulmonary infection due to M. szulgai associated with bullous disease of the lung in Japan.

Because of the recent AIDS endemic, there is a worldwide increase in intractable mycobacterial infections including extrapulmonary tuberculosis due to multidrug-resistant M. tuberculosis and disseminated M. avium complex (MAC) infections. Therefore, development of new anti-tuberculous drugs having an excellent antimycobacterial activity and protocols for clinical use of presently available antimicrobials are urgently desired. In this study, we performed in vitro and in vivo experiments to assess the chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin derivative, KRM-1648 (KRM), against experimental infections due to MAC and M. tuberculosis. In addition, we attempted to improve the therapeutic efficacy of the KRM against MAC infections by changing its administration protocols and timing or by combined use with other antimicrobials, including clarithromycin (CAM), clofazimine (CFZ), sparfloxacin (SPFX), streptomycin (SM), and ethambutol (EB). Furthermore, we examined therapeutic efficacy of KRM against rifampicin (RFP)-resistant M. tuberculosis in details. KRM showing much more potent in vitro activity against the MAC organisms compared to rifabutin (RBT) and RFP, also exerted markedly greater therapeutic efficacy against the MAC infections induced in mice or rabbits in terms of reducing the incidence and the extent of gross pulmonary lesions and the bacterial loads in the lungs and spleens. However, in the case of mouse experimental infections, regrowth of the organisms was initiated after week 4 to 6 even in the animals given KRM. Since KRM-resistant organisms could not be isolated from infected mice given continuous KRM administrations, some unknown mechanisms other than the acquisition of drug resistance by infected organisms may be important for the establishment of the regrowth of MAC organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic efficacy of KRM-1648 was studied in BALB/c mice infected with Mycobacterium intracellulare. Mice were infected intravenously with 1.0 x 10(7) CFU of the organisms/mouse and then given 0.2 mg or 0.4 mg of KRM-1648 emulsified in 2.5% gum arabic-0.2% Tween 80 by gavage, once daily, 6 days per week, from day 1 to the death of mice. The therapeutic efficacy of the drug was evaluated on the basis of survival times, incidence and degree of gross lung lesions and bacterial loads in the lungs and spleen. The lung lesions were not observed in any experimental groups at 4 weeks after the infection. At 8 weeks after the infection, the lung lesions were observed in all control mice, but 2 of 5 mice treated with 0.2 mg of KRM and 4 of 5 mice treated with 0.4 mg of KRM did not show any lung lesions, and the degree of the lesions was much milder in KRM-1648-treated mice than in the control mice. All mice of treated and untreated groups died, and median survival times were 141 days for the control mice, 216 days for mice treated with 0.2 mg of KRM-1648 and 220 days for mice treated with 0.4 mg of KRM-1648. At the death, lung lesions were observed in all mice. The CFUs of M. intracellulare in the lungs and spleen in mice treated with KRM-1648 were fewer than those in the control mice at 4 and 8 weeks after the infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, administered at the different periods of infection in Mycobacterium intracellulare-infected mice was studied. Mice were infected intravenously with M. intracellulare (9.8 x 10(6) CFU/mouse) and then were given 0.4 mg of KRM-1648 emulsified in 2.5% gum arabic-0.2% Tween 80 by gavage, once daily six times per week, from day 1 to week 4, week 2 to week 6, week 4 to week 8, and week 8 to the end of experiment (week 12). Judgement of the therapeutic efficacy of the drug against the infection was done on the basis of incidence and degree of gross lung lesions, % organ weight (organ weight/body weight x 100), and bacterial loads in the lungs and spleen. The lung lesions were not observed in the control and KRM-treated mice at 4 weeks after infection (KRM treatment: day 1 to week 4). At 6 weeks after infection (KRM treatment: week 2 to week 6), the lung lesions were observed in all control mice, whereas 3 of the 5 mice given KRM-1648 did not show the lesions. At 8 weeks after infection (KRM treatment: week 4 to week 8), the lung lesions were observed in all control and KRM-1648-treated mice, but the degree of the lung lesions was much more slight in mice given KRM-1648 than in control mice. The incidence and the degree of the lung lesions at 12 weeks after infection (KRM treatment: week 8 to week 12) was not different in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)