Biomedical subjects
Publications and source records attributed to M D Iseman.
Multiply resistant tuberculosis is on the rise throughout the world. It poses the risk that an increasing percentage of patients will have disease that cannot be cured in economically limited nations and, thus, resistant tubercle bacilli will be spread in an exponential manner. For such patients in the United States, aggressive chemotherapy, coupled with surgery in cases of localized disease, is the best hope for cure.
We studied the activity of amikacin against Mycobacterium avium complex strain 101 by using continuous-level, changing concentrations which simulated levels in serum in a patient, and pulsed exposures. Amikacin at a concentration of 5 or 15 micrograms/ml showed rapid bactericidal action following constant exposure of the organisms. With the in vitro model, using a peak concentration of 10 or 20 micrograms/ml, complete sterilization was obtained by day 7. In pulsed-exposure studies, a minimum period of contact of 72 or 96 h at a concentration of 10 micrograms/ml was needed for complete sterilization.
The in vivo activity of amikacin, used alone or in combination with rifabutin or clofazimine or both, was assessed in the treatment of early and established Mycobacterium avium complex infections in beige mice. Amikacin given alone at a dose of 50 mg/kg, in one, two, or three divided doses, showed remarkable activity. Addition of clofazimine increased the activity significantly, but addition of the third drug, rifabutin, did not further improve the results. Amikacin-containing regimens are worthy of consideration for investigations in patients with M. avium complex infections.
Ethambutol, when combined with rifampin or rifabutine (ansamycin, LM427), produced an additive inhibitory effect against most of the tested M avium complex strains (12 of 16 with rifampin, 13 of 16 with rifabutine). The inhibitory effect was synergistic for the remaining 4 of 16 and 3 of 16 strains. This relationship reduced the minimal inhibitory concentrations for each drug in combination. In addition, the minimal bactericidal concentrations of all 3 drugs were reduced because of synergistic bactericidal activity in 6 of 6 strains tested.
The minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of rifabutine (ansamycin LM427, spiropiperidyl rifamycin) against rifampin-susceptible and rifampin-resistant strains of Mycobacterium tuberculosis were determined. The MICs for 17 rifampin-susceptible strains were low, falling in a narrow range of 0.06 microgram/ml or less when determined by either the agar-dilution method (in 7H10 or 7H11 agar) or in 7H12 broth (radiometrically or by sampling and colony-forming units [CFU/ml] determination). The MICs of rifabutine for 21 rifampin-resistant strains were much higher, ranging from 0.25 to 16.0 micrograms/ml. The MBCs of rifabutine were 0.125 or 0.25 microgram/ml for rifampin-susceptible strains, and were 4.0 and 32.0 micrograms/ml for two tested rifampin-resistant strains. The MIC/MBC ratio was 1:4 for rifampin-susceptible strains.
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Rifabutin (ansamycin LM 427) when given alone in doses of 5, 10, or 20 mg/kg showed limited in vivo activity against acute or chronic Mycobacterium intracellulare infections studied in beige C57B1/6, or S/W mice. Prophylactic studies in S/W mice in which chemotherapy was given for 3 wk prior to challenge showed slight improvement. Combination chemotherapy consisting of rifabutin (10 mg/kg) and clofazimine (20 mg/kg) achieved complete sterilization of M. intracellulare infections in spleen and lung when initiated immediately after challenge. Inclusion of ethambutol did not offer additional benefit. If chemotherapy is initiated 3 wk after challenge (established infections), the activity of this double drug combination is less effective.
In order to understand the discrepant results between in vitro and in vivo activity of rifabutin (LM 427) against Mycobacterium intracellulare, we studied its effects upon the phagocytosis of M. intracellulare by resident and activated mouse peritoneal and alveolar macrophages and upon growth of M. intracellulare inside these cells. Rifabutin (ansamycin, LM 427) had no effect on the viability of resident or activated peritoneal or alveolar macrophages or on the phagocytosis of M. intracellulare by resident peritoneal macrophages. In activated peritoneal and alveolar macrophages, it had a dose-related effect on the phagocytic index and intracellular growth of M. intracellulare. Macrophages from mice pretreated with 10 or 20 mg/kg of rifabutin either orally or intraperitoneally for 4 to 10 days showed inhibition of intracellular growth of M. intracellulare in a dose-related manner. The route of administration or further addition of the drug did not enhance the inhibitory activity of these macrophages. These results indicate that rifabutin has the potential of killing M. intracellulare persisters inside macrophages.
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Seventy-five patients with pulmonary infection caused by Mycobacterium avium-intracellulare were studied to determine whether results of therapy correlated with in vitro susceptibility testing of mycobacterial isolates. Fifty patients responded to therapy and 25 were nonresponders. The total number of drugs received by responders did not differ significantly from the total number of drugs received by nonresponders. However, responders received significantly more drugs to which their isolate was susceptible in vitro than did nonresponders (2.4 +/- 1.2 versus 1.4 +/- 1.0, p less than 0.001). We conclude that patients with pulmonary M. avium-intracellulare infection should receive chemotherapeutic agents to which their isolate is susceptible in vitro.
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A 48-year-old woman with profound, rapidly progressive dyspnea requested a second opinion regarding the diagnosis and management of an undiagnosed interstitial process. One year prior to this evaluation, she had been placed on therapy with exogenous estrogens for the treatment of osteoporosis. During this therapy, she had a marked deterioration of her pulmonary status. Review of her open lung biopsy, which was obtained five years previously, revealed lymphangioleiomyomatosis. Discontinuation of estrogen therapy and treatment with tamoxifen were successful in stopping the progressive course. This patient's clinical course suggested an association between estrogen therapy and clinical deterioration during the menopause.
The aim of this study was to search for new drugs active against the Mycobacterium avium complex and to re-examine the activity of some conventional antituberculosis drugs against these species. This progress report describes the protocol and phases of in vitro experiments in a search which included 57 different compounds tested against numerous strains of M. avium clinical isolates. The preliminary screening and MIC determination of these drugs were conducted in 7H12 broth by the radiometric method (BACTEC system). Of the total of 57 drugs, 23 were discarded after preliminary screening and 17 after MIC determination. The remaining 17 drugs were considered sufficiently promising for more detailed in vitro studies. These, now in progress, include MIC determination by two additional methods (in broth by sampling and plating and in 7H11 agar plates), MBC determination and drug combination studies. The following drugs are currently undergoing these detailed studies: isoniazid, rifampin, rifabutine (ansamycin LM427), amikacin, streptomycin, ethambutol, ethionamide, cycloserine, clofazimine (CF), CF derivative B746, CF derivative B1865, ofloxacin, ciprofloxacin, cephalosporin BMY 28142, trimethoprim-sulfamethoxazole, spectinomycin derivative U6633F(B), and dihydromycoplanecin.
We determined the MICs of ethambutol for both Mycobacterium avium and Mycobacterium tuberculosis strains by using broth dilution (7H12 broth, radiometric method) and agar dilution (7H11 agar) methods. We found the MICs to be much lower in liquid than in solid medium. The broth-determined MICs for susceptible M. tuberculosis and most of the M. avium strains were comparable to the levels in blood of patients, being lower than the peak levels. We propose that the MICs, determined radiometrically in in 7H12 broth, be considered as tentative criteria for susceptibility testing of M. avium isolates in future clinical trials. The use of these values instead of critical concentrations should also be considered as an alternative to the conventional susceptibility testing method in chemotherapy of tuberculosis. Ethambutol produced bactericidal effects against both M. tuberculosis and M. avium, and the MIC/MBC ratios were in the same range for both species when MICs and MBCs were tested in 7H12 broth by conventional sampling and plating.
Susceptibility testing and serotyping were performed on 57 isolates of Mycobacterium avium-M. intracellulare from patients with acquired immunodeficiency syndrome (AIDS) and 75 isolates from patients without AIDS. Susceptibility patterns and serotypes of AIDS isolates were significantly different from those of non-AIDS isolates. These results may partially explain the poor therapeutic response of M. avium-M. intracellulare infections in AIDS patients.
The propensity of systemic beta-adrenergic blockers to cause bronchoconstriction in patients with reactive airway disease is well recognized. A study was carried out to determine the prevalence of sensitivity to ophthalmic timolol in 24 asthmatic subjects at our institution and to determine the effect of ophthalmic betaxolol, a cardioselective beta-blocker efficacious in the treatment of glaucoma, in 8 subjects who were timolol-sensitive. Subjects received topical timolol 0.5%; ventilatory function, blood pressure, and heart rate were monitored over a 90-min period. The mean FEV1 fell from 2.47 to 1.93 L by 30 min after drug treatment to a minimal value of 1.86 L (-27.8%). There was a corresponding fall in FVC from 3.68 to 3.09 L by 30 min with a minimal value of 3.00 L(-20.7%). FEV1/FVC ratio also fell from 66.9 to 61.0% by 30 min, reaching a minimum of 60.0%. In 14 subjects (58.3%), the fall in FEV1 was greater than or equal to 20%, with a mean fall of 38.7% by 30 min and a maximal fall of 44.9%. The severity of timolol-sensitivity correlated with the extent of reduction in baseline percent predicted FEV1 and FVC and with exercise-induced bronchospasm. In addition, the administration of timolol reduced the bronchodilator response to below the pretimolol value. In 8 of the timolol-sensitive patients who underwent a double-blind crossover challenge with ocular instillation of betaxolol 1% and saline, betaxolol was well-tolerated and did not affect ventilatory function over a 4-h observation period. In addition, it did not prevent the FEV1 response to inhaled bronchodilator.(ABSTRACT TRUNCATED AT 250 WORDS)