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PubMedDate not supplied

Clinical pharmacokinetics of the antituberculosis drugs.

The quantitative aspects of the disposition in man of 12 antituberculosis drugs [isoniazid, rifampicin, (rifampin), ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Isoniazid appears to be the only agent for which plasma concentrations and clearance are related to hereditary differences in acetylator status and for which there is an appreciable 'first-pass' effect. Recent data cast doubt on the suggestion that isoniazid may be more hepatotoxic for rapid as opposed to slow acetylators. Continuous administration of rifampicin leads to induction of enzymes in the liver with a concomitant decrease in maximum plasma concentrations, the time required to achieve this level, elimination half-life, and area under the plasma concentration-time curve (AUC). Coadministration of para-aminosalicylic acid leads to increases in the serum concentrations and elimination half-life of isoniazid. With a few exceptions, the metabolites of the antituberculosis drugs are devoid of antimicrobial activity; the exceptions are 25-desacetylrifampicin which accounts for approximately 80% of the drug's antimicrobial activity in human bile, the acetylated and glycylated metabolites of para-aminosalicylic acid, and the sulphoxide metabolites of ethionamide. The effect of renal impairment is relatively unimportant for the excretion of isoniazid, rifampicin and para-aminosalicylic acid, but the elimination half-life of streptomycin increases to 100 hours when the blood urea nitrogen level is greater than 100mg/100ml, and ototoxicity is strikingly more frequent. In states of malnutrition, such as kwashiorkor, the protein binding of para-aminosalicylic acid decreases from 15% to essentially zero and in the case of ethionamide and streptomycin binding decreases by 6% and 16% respectively. Of the data concerning age-related effects, most notable are the prolonged elimination half-life of isoniazid in neonates (up to 19.8 hours), and the lower peak serum concentrations of rifampicin in children of one-third to one-tenth those of adults following a similar dose on a weight basis. For kanamycin, the maximum plasma concentration varies inversely with age but is not influenced by birthweight; however, the clearance is directly dependent upon birthweight and postnatal age. For the elderly, age is an insignificant factor for the elimination of isoniazid when compared with young adults of similar acetylator status, and the metabolism of rifampicin may be considered globally unaltered in this age group.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗
PubMed1980

New antibiotics, carbazomycins A and B. I. Fermentation, extraction, purification and physico-chemical and biological properties.

An unidentified Streptomyces, designated as Strain H 1051-MY 10, was proved to produce viomycin and two new antibiotics. The new antibiotics were extracted from the cultured mycelia with acetone and transferred to ethyl acetate after acetone was removed in vacuo. The extracted antibiotics were separated into two components by alumina column chromatography and named carbazomycins A and B, because both antibiotics were proved to contain a carbazole nucleus. The molecular formulae of carbazomycins A and B were determined to be C16H17NO2 and C15H15NO2, respectively. Further, carbazomycin B was methylated with diazomethane to give carbazomycin A. Carbazomycins inhibited the growth of phytophathogenic fungi and further showed weak antibacterial and antiyeast activities.

Animals↗
PubMed1981

Ribosomal proteins S9 and L6 participate in the binding of [3H]dibekacin to E. coli ribosomes.

The degrees of binding of [3H]dibekacin to LiCl-treated cores of E. coli ribosomes were reduced by increasing LiCl concentrations. The 1.15 M LiCl core lost 70 approximately 80% of the original binding capacity. The antibiotic attachment to the 1.15 M LiCl core was restored by reconstitution with the split proteins (SP), which were obtained by the treatment of 70S ribosomes with LiCl at concentrations of 0.8 approximately 1.15 M. The basic proteins, split off during the transition from 0.4 M LiCl core to 0.8 approximately 1.15 M LiCl core, seemed to be involved in the drug binding. SP0.4 approximately 1.15, which was obtained by the treatment of the 0.4 M LiCl core with 1.15 M LiCl, was fractionated by CM-Sephadex C-25 column chromatography, and each fraction was assayed for protein composition and the capability of restoring the ability of the 1.15 M LiCl core to bind the drug. Of ribosomal proteins eliminated with 1.15 M LiCl, the addition of either S9 or L6 alone to the 1.15 M LiCl core was observed to restore approximately 50% of the binding as compared to the 70S ribosome alone, and both proteins restored about 70% of the binding. The results suggested that ribosomal proteins S9 and L6 were involved in the attachment of [3H]dibekacin to the ribosome. The antibiotic binding to the 70S ribosome and 1.15 M LiCl core reconstituted with S9 and L6 was considerably inhibited by unlabelled dibekacin or kanamycin, and partially inhibited by gentamicin or neomycin, but was not significantly affected by streptomycin or viomycin.

Aminoglycosides↗
PubMed1988

Mode of action of deoxypheganomycin D on Mycobacterium smegmatis ATCC 607.

Deoxypheganomycin D, a specific inhibitor of mycobacteria, inhibits the growth in vitro of Mycobacterium smegmatis ATCC 607 (M. 607) bacteriostatically at concentrations as high as 7 X 10(-5) M. It shows no cross-resistance to paromomycin, capreomycin, viomycin, streptothricin, kanamycin and streptomycin. Deoxypheganomycin D at 2.8 X 10(-7) M where the cell growth of M. 607 is only partially inhibited does not significantly inhibit DNA, RNA or protein synthesis but leads to marked decrease (13% of control) in [14C]glycerol-derived radioactivity in cell-walls. In the presence of 7 X 10(-6) M deoxypheganomycin D, the influx of leucine but not thymidine is affected while the reverse is true with efflux. The data suggest that the effect of deoxypheganomycin D on M. 607 may be related to both the cell membrane and specific mycobacterial lipid like components of the cell-wall.

Amino Acids↗
PubMed1989

Analysis of the promoter region of the cloned kanamycin resistance gene (kmr) from Streptomyces kanamyceticus.

The appropriate location and orientation of the kanamycin resistance gene (kmr) cloned on multicopy plasmids were determined by subcloning experiments. The transcription start site was identified by high-resolution S1 mapping and the kmr mRNA was shown to have a long leader of about 400 bp. An additional transcript upstream of the kmr gene was also detected, which ran in the opposite direction and overlapped 2 to 3 nucleotides with the kmr transcript. The presumptive promoter region of this physiologically unidentified RNA was similar to the Escherichia coli promoter consensus sequence both in the -10 and -35 regions, whereas the putative promoter region of the kmr gene exhibited sequence similarities in the -10 region to the promoters of the endoglycosidase H (endoH) and the viomycin phosphotransferase (vph) genes from Streptomyces.

Base Sequence↗
PubMed2002

Sequence analysis and structure prediction of 23S rRNA:m1G methyltransferases reveals a conserved core augmented with a putative Zn-binding domain in the N-terminus and family-specific elaborations in the C-terminus.

N1-methylation of G748 within 23S ribosomal RNA results in resistance to the macrolide tylosin in Streptomyces. In contrast, the Escherichia coli mutant lacking N1-methylation of G745 exhibits increased resistance to viomycin, in addition to severe defects of growth characteristics. Both methylated guanines are located in hairpin 35, in domain II of prokaryotic 23S rRNA. G748 and G745 are modified by related S-adenosylmethionine-dependent methyltransferases (MTases), TlrB and RrmA respectively. Earlier sequence comparisons allowed identification of the AdoMet-binding site, however the catalytic site and the target-recognition region of these enzymes could not be delineated unambiguously. In this work, we carried out sequence-to-structure threading of the rRNA:m1G MTase family against the database of known structures to Identify those "missing regions". Our analysis confirms the earlier prediction of the AdoMet-binding site, but suggests a different location of the putative catalytic center than was previously postulated. We predict that RrmA and TlrB possess two regions that may be responsible for specific interactions with their target nucleic acid sequences: a putative Zn-finger domain in the N-terminus and the variable domain close to the C-terminus, which indicates that 23S rRNA MTases exhibit the primary structural organization distinct from other nucleic acid MTases, despite sharing the common catalytic domain.

Amino Acid Sequence↗
PubMed1975

[Biosynthesis and the isolation of the new anthracyclin antibiotics, violamycins A, BI, BII and their aglycones].

The conditions of fermentation, isolation and some of the physico-chemical properties of the new anthracycline antibiotics, i. e. viomycin A, BI, BII and their aglycones, produced by a strain of Streptomyces violaceus IMET JA 6844 are described. Violamycin A is mainly a complex of aminoglycosides of epsilon- and dzeta-isorhodomycinone, beta-rhodomycinone and (alpha)2-rhodomycinone. The sugar component is rhodosamine. Violomycin BI is mainly a complex of trisaccharides of the same aglycones mentioned above. The sugar components are rhodosamine, 2-desoxy-L-fucose and rhodinose. Violomycin BII is mainly a rhodosaminyl-2-desoxy-L-fucosyl-derivative of epsilon- and dzeta-isorhodomycinone, beta- and epsilon-rhodomycinone and (alpha)2-rhodomycinone. Violamycin complexes A, BI, BII mainly consist of 6 aglycone components which are similar to the other members of anthracyline antibiotics but can be diferentiated from them by physico-chemical and biological properties. Epsilon- and dzeta-isorhodomycinone, epsilon- and (alpha)2-rhodomycinone and dzeta-rhodomycinone one of the 8 minor components contained in the mixture of the aglycones of the violomycin complex so far has been determined as constituents of an antibiotic.

Aerobiosis↗
PubMed1975

[Bacteriological investigations and animal experiments with Mycobacterium ulcerans (Tübingen 1971) (author's transl)].

In 1972 we reported the first isolation of M. ulcerans in Germany and in 1973 we reviewed the epidemiology, clinical features and therapy of Buruli ulcer (6, 7). Initial isolation was done from swabs of the edge of the ulcer on Loewenstein-Jensen medium at 30-33 degrees C. Subcultures showed poor growth at 37 degrees C, and none at 22 degrees C or 42 degrees C or on Loewenstein-Jensen medium without glycerine. No acylamidase or lipolytic activity was detectable and the organisms were catalase positive, triphenyltetrazolium chloride reduction positive, nitrate reduction negative and nicotinic acid production positive (Table 2). Possibly our strain is a nicotinic acid positive variant, as is the strain described by RUNYON et al. (16). (The bacteriological characteristics are summarized in Table 2). Our strain was sensitive to dihydrostreptomycin, cycloserine, viomycin, rifampicin and a riminophenacin derivate (Lampren), but was resistent to isoniazid, para-aminosalicyclic acid, ethionamid and ethambutol (Table 3). White mice and rats but no guinea pigs are susceptible to infection with M. ulcerans. Injection into the foot pad is preferable to intraperitoneal or subcutaneous injection (Table 4). After such an injection of material from our patient, signs of disease appeared in the following order: 1. foot pad swelling; 2. redness and oedema of the whole leg; 3. ulceration of the dorsum of foot (fig. 1) with fluctuant, gross oedema of the subcutaneous tissue and loss of hair; 4. atrophy and contraction of the infected extremity with the development of further ulceration on the abdomen and tail. In the two months following an injection of a standard suspension of M. ulcerans the animals developed such gross oedema of the subcutaneous tissues of the abdomen that its progression could be followed by regular weighing (fig. 2). By the end of the two months, the total body weight was double that of control uninfected animals.

Animals↗
PubMed2006

API TB Consensus Guidelines 2006: Management of pulmonary tuberculosis, extra-pulmonary tuberculosis and tuberculosis in special situations.

INTRODUCTION: The World Health Organization (WHO) has declared Tuberculosis (TB) a global emergency in 1993. Prevalence of TB and Human Immunodeficiency Virus (HIV) co-infection worldwide is 0.18% and about 8% TB cases have HIV infection. Effective chemotherapy has been available for treatment of TB for over 50 years now. In World Health Organization (WHO)-International Union Against Tuberculosis and Lung Disease (IUATLD) Working Group Global Anti-Tuberculosis Drug Resistance Surveillance (1994-1997), the incidence of MDR TB in Delhi was found to be 14%, of which primary multi-drug resistance was only 1.4%, indicating that most of MDR TB is acquired as a result of poor chemotherapy. DIAGNOSIS OF TB: Since TB is an infectious disease caused by Mycobacterium (M) tuberculosis the diagnosis of TB should (as far as possible) be by demonstration of M. tuberculosis on culture or acid-fast bacilli (AFB) on smear examination. The World Health Organization (WHO) has strongly recommended sputum smear examination as the preferred screening test and suggests examination of 3 deeply coughed out sputum samples - spot sample on day 1, overnight sample and a spot sample in the morning on day 2. Recently it has been shown that sputum smear positivity is greater than 90% where greater than 5 ml of sputum is used for smear diagnosis of pulmonary TB. Culture of M. tuberculosis is the gold standard for diagnosis of TB. Culture of mycobacteria is a much more sensitive test than smear examination and has been estimated to detect 10-100 viable mycobacteria per ml of sample and in case of active disease they are found to be 81% sensitive and 98.5% specific. Culture methods are also required for further drug sensitivity testing in cases of suspected drug resistant cases. Isoniazid and rifampicin resistance can be reliably measured; resistance to pyrazinamide, ethambutol, and streptomycin is more difficult due to limitations of technique. The therapeutic index for a given drug is low for certain second-line drugs such as ethionamide, cycloserine, viomycin and para amino salicylic acid (PAS) and it leads to misinterpretation of results due to failure to distinguish between sensitive and resistant strains. Misdiagnosis of MDR-TB due to laboratory related errors has been reported recently. MANAGEMENT OF TB: Chemotherapy of TB consists of prevention of infection, also called primary chemoprophylaxis, when isoniazid 5 mg/kg is given to prevent infection in newborn infants of infectious mothers till mother is sputum smear positive (2-3months). Treatment of latent tuberculosis, also called secondary chemoprophylaxis, when isoniazid 5 mg/kg is given for 6 months to prevent disease in infected persons (asymptomatic MT positive individuals) and treatment of disease with Short Course Chemotherapy (SCC), as per WHO categories. Essential anti-tuberculosis (ATT) drugs Isoniazid (H), Rifampicin (R), Ethambutol (E), Pyrazinamide (Z) and Streptomycin (S) are the essential first line anti-tuberculosis drugs. Anti TB regimen consists of two phases: an initial intensive phase (IIP) and a continuation phase (CP). Best effective SCC for treatment of TB, for adults and children, for pregnant and lactating females, for cases associated with diabetes mellitus and HIV infection, for cases with pre-existing liver diseases (but normal liver functions) and mild renal failure is 2EHRZ, 4HR given daily or thrice weekly. Higher dose SCC intermittent therapy given in thrice weekly (2E3H3R3Z3, 4H3R3) has now been advocated by WHO and implemented by the Revised National TB Control Programme. DOTS, directly observed therapy short course, where the patient takes the drugs under the direct observation (DO) of a health worker to ensure regularity of consumption of drugs. Fixed dose combinations (FDCs) drugs consisting of two or three antituberculosis medications, provide a realistic and welcome alternative to DO that minimizes the opportunity for a patient to selectively take only a single medication. MANAGEMENT OF TB IN SPECIAL SITUATIONS: Pregnancy: All drugs, that is, rifampicin, isoniazid, ethambutol, and pyrazinamide can be used during pregnancy. Streptomycin is not given due to ototoxicity to the fetus. Prophylactic pyridoxine in the dose of 10mg/day is recommended along with ATT. Diabetes mellitus: The drug regimen is same as in nondiabetic. Strict control of blood glucose is mandatory. Also, doses of oral hypoglycemic agents may have to be increased due to interaction with Rifampicin. Prophylactic pyridoxine is indicated. Renal failure: Dosages may have to be adjusted according to the creatinine clearance especially for streptomycin, ethambutol and isoniazid. In acute renal failure, ethambutol should be given 8 hours before hemodialysis. In post renal transplant patients: Rifampicin-containing regimens are avoided as rifampicin causes increased clearance of cyclosporin. Pre-existing liver disease: In stable disease with normal liver enzymes, all anti-tuberculous drugs may be used but frequent monitoring of liver function tests is required. Treatment in unconscious patient (patients unable to swallow): If patients are fed by Ryle's tube or gastrostomy tube, usual doses and drugs may be powdered and administered avoiding feeds 2-3 hours before and after the dose. In cases where enterostomy has been performed or parenteral nutrition is being used, intramuscular streptomycin and isoniazid and intravenous quinolones may be used and switch to oral therapy once oral feed resume. Treatment of TB with HIV co-infection: In early stages the presentations of TB in TB-HIV co-infection is the same as HIV negative but in late stages extra-pulmonary and dissemination are common. The usual short course chemotherapy is indicated in HIV positive patients. The response is usually good but relapse is frequent. After initiating ATT or anti-retroviral therapy (ART) worsening of preexisting lesions or appearance of new lesions is seen, "paradoxical response" or "immune reconstitution phenomenon". Multidrug resistant TB can occur due to poor compliance to ATT due to behavioural pattern, increased incidence of side effects and malabsorption of drugs due to associated diarrhea. ART for HIV, containing protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) cannot be used along with R, as R induces metabolism of PI and reduces the efficacy. The various options are i) to postpone anti-retroviral therapy ii) to use no PI or NNRTI containing anti-retroviral combinations iii) to use certain PI/ and/or NNRTIs with modification in doses iv) Efavirenz (EFZ) or Saquinavir with Ritonavir, without the need to adjust the doses v) to use non R regimens e.g. 2SHEZ+10HE MANAGEMENT OF MDR TB: As far as possible treatment of MDR TB should be referred to specialized units with facilities for quality controlled DST and experienced in handling such cases. If such referrals are not possible, one must remember that while initiating or revising therapy for MDR-TB, drugs selection must rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence.

Algorithms↗
PubMed1988

[Interactions of antitubercular drugs].

Antituberculous drugs are never used alone but are often given concomitantly with drugs prescribed for other diseases. We have therefore reviewed the potential interactions of antituberculous drugs between themselves and with other drugs. Rifampicin being a potent enzyme inducer will decrease the plasma levels of a wide range of drugs. This in turn will decrease the effectiveness of these drugs if they are unmetabolized and active, or increase drug toxicity if the metabolites are toxic. Within the first category are the oral contraceptives, steroids, oral antidiabetics, oral anticoagulants and digitalis. Within the second category is thought to be isoniazid on account of its hepatotoxicity. In contrast, isoniazid (INH) is an enzyme inhibitor. Drugs with hepatic metabolism will tend to accumulate, although this seems clinically relevant only with antiepileptic drugs, diazepam, triazolam and oral anticoagulants (with high INH doses). Many other cases of drug interaction have been described, but they seem to be rare and may not be clinically relevant. INH and rifampicin do not seem to modify each other's metabolism consistently, but it may be wise to check the serum INH levels during coadministration. As said above, rifampicin does increase the hepatotoxicity of INH. INH also inhibits monoamine oxidase and will interact with other MAOI, as well as with fish, cheese or wine with high histamine or tyramine contents. The only interaction found with ethambutol is with diazepam: it increases its clearance and free fraction. Obviously, streptomycin potentiates the ototoxicity of other amino-glycosides, such as capreomycin, kanamycin or viomycin, so that combining them is strictly contra-indicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitubercular Agents↗
PubMed1985

[Genetic control of Actinomycetes resistance to antibiotics].

The results of studies on genetic control of resistance to antibiotics in Streptomyces strains are discussed. Cloning and sequence analysis of resistance genes yield information concerning their expression in homo- and heterologous systems, allow analysis of signal sequences responsible for initiation of transcription and translation. Cloning of genes coding for resistance to neomycin,viomycin, thiostrepton in Streptomyces and Bac. licheniformis ermD gene made them convenient selective markers for constructing vector molecules, useful for identification of homology regions in S. fradiae aph gene and TnS of E. coli; the site homologous to ermD gene has been thus revealed in S. erythreus chromosome. Possibilities of the studies aimed at elucidation of instability of many actinomycete characters using determinants of natural multiple resistance to antibiotics as a model are demonstrated. It has been shown that genetic instability is not related to the loss of plasmids and is associated with genes having chromosomal location. Simultaneous high frequency loss of a number of resistance characters determined by non-linked genes suggests the participation in gene activity regulation of actinomycete genome rearrangements. This is confirmed by evidence for such rearrangements found in strains with mutant phenotypes, including deletions in tyrosinase and streptomycin phosphotransferase genes in Mel- and StrS strains of S. reticuli and S. glaucescens.

Actinomycetaceae↗
PubMedDate not supplied

[Skin ulcer caused by Mycobacterium ulcerans in Cameroon. II. Bacteriological study].

Nine stains of Mycobacterium ulcerans isolated in Kamerun, in Congo and in France, were compared with six reference strains found in Zaïre, Australia and Mexico and M. intracellulare, M. simiae, M. paratuberculosis. These fiveteen strains constitutets an species whose typical features were: the difficult and slow growth at the optimum temperature of 30 degrees C, the biochemical tests and the sensitivity to rifampin, streptomycin, kanamycin, viomycin, cycloserin and probably capreomycin. In mice inoculated by the intravenous route, M. ulcerans gives ulcerations of external teguments and sometimes, internal lesions.

Anti-Bacterial Agents↗
PubMed1975

[Sensitivity of m. kansasii strains to various antibiotics and chemotherapeutics in vitro and in vivo (author's transl)].

Sensitivity of 40 strains of M. kansasii (var. luciflava) to various antibiotics and chemotherapeutics in vitro and in vivo was examined. The strains showed considerable individual variability in their susceptibility in vitro, most were more resistant to isoniazid and PAS and about one half of the investigated strains to streptomycin, too, if correlated to "wild" strains of M. tuberculosis. Susceptibility to ethionamide, thiosemicarbazone (Conteben), viomycin, kanamycin and cycloserine appears to be the same as in the case of M. tuberculosis strains, but the resistance to pyrazinamide is higher. Good effect has been observed in vitro with rifampicin, ethambutol, capreomycin and phenazine derivative B 663. Oleandomycin and gentamycin are ineffectual in the dosages of drugs we used. The activity of most of these drugs was observed in experimental infections of white mice--in mono-therapy and in various combinations-provoked by different strains of M. kansasii. The main criterion of the effectivity of the treatment was the enumeration of viable mycobacterial units in the lungs of the mice in ten-days intervals; in one part of the experiments the histological examination of the various organs of the mice was performed. The drugs of the I. and II. line of antituberculotics were ineffective or showed only a slight effect. A very good effect of rifampicin, ethambutol and phenazine derivative B 663 in monotherapy and in multiply drug therapy was observed.

Animals↗
PubMed1981

[Recommendations to otolaryngologists for patients with antituberculotic chemotherapy (author's transl)].

With long-time antituberculotic chemotherapy aminoglycosid-antibiotics (Streptomycin, Neomycin, Kanamycin, Gentamycin) and polypeptid-antibiotics (Polymyxin B, Viomycin, Capreomycin) will endanger the nervus statoacusticus. After discussing manner and frequency of possible troubles recommendations are given to the ENT-physician, how to minimize the damage for the cochleovestibular system.

Antitubercular Agents↗
PubMed1980

[Presence of histidine-degrading enzymes in mycobacteria and nocardia and reaction-kinetic studies on Mycobacterium smegmatis SN 2 (author's transl)].

The occurrence of histidine degrading enzymes in whole cells of mycobacteria and nocardia was investigated. Out of 25 Mycobacterium strains, only M. smegmatis showed "histidase" activity, i.e. an uptake of histidine and a simultaneous release of ammonia. Consequently, the presence of "histidase" is a characteristic feature for M. smegmatis. In contrast to "histidase", single mycobacteria strains were able to take up histidine from the reaction mixture without liberation of ammonia or detectable oxidation of the substrate. This property was not species-specific. Therefore the determination of the released ammonia is decisive for the determination of the species-specific "histidase". Strains of the genus Nocardia proved to be more active concerning "histidase". Out of 18 species we found activity in all 4 N. erythropolis strains and in 7 out of 10 N. asteroides strains; the only strains of the species N. restrictus, N. opaca, N. blackwellii, N. paraffinae and R. terrae also showed "histidase" activity. Under the experimental conditions whereby 1 mmol/l of histidine and 10 mg/ml of bacteria were used, histidine was degraded by M. smegmatis within 6--8 hours; during which reaction 1,7--1,8 mmole/l of ammonia was released and 5/2--6/2 mmol of oxygen consumed. Other metabolites, such as urocanic acid or glutamic acid were not released in the reaction mixture. The kinetics of the degradation by whole cells was investigated in detail; the Michaelis constant was 0,53 . 10(-3)M, the optimal temperature found at 43,2 degree C, below and above which temperature the activation energies were 5177 and 11806 cal, respectively. "Histidase" is inducible in M. smegmatis. After cultivation of the bacteria on media containing histidine or urocanic acid, the enzymatic activity strongly increased. The same effect could be obtained by preincubating washed cells in buffer containing histidine or urocanic acif for 4 hours. "Histidase" was inhibited by streptomycin, viomycin and p-chlormercuribenzoate. The degeneration pathway is supposed to start from histidine via urocanic acid and glutamic acid; thus the proposed pathway is different from that one suggested by Bönicke (1964). Details of the degradation pathway using partially purified enzyme preparations will be described latter.

Ammonia↗
PubMedDate not supplied

Effects of antibiotic-diuretic interactions in the guinea pig model of ototoxicity.

The guinea pig model has been useful for estimating quantitatively the ototoxic effects of many different drugs. Our model utilizes measures of the Preyer pinna reflex, the alternating current cochlear potential and sensory hair-cell morphology to access drug effects. The principle pathophysiologic lesion of aminoglycoside-induced permanent ototoxicity appears to be sensory hair-cell loss in the organ of Corti. Aminoglycoside antibiotics were found to interact with loop-inhibiting diuretics, and the augmented ototoxic effects were attributed to hair-cell destruction. The interaction is specific for loop-inhibiting diuretics but not for the aminoglycosides since nonaminoglycoside antibiotics, such as viomycin and polymixin B, interacted similarly. Noninteractive antibiotics include amphotericin B and vancomycin. The absence of ototoxic effects with vancomycin is of interest in view of its broadening clinical utility.

Aminoglycosides↗
PubMedDate not supplied

[Strategy for choosing antibiotics for treating bacterial infections associated with chronic tick-borne encephalitis].

The capacity of wide-spectrum antibiotics kefzol and ristomycin to activate the persisting tick-borne encephalitis (TBE) virus and cause an exacerbation of chronic process was investigated in Syrian hamsters in whom a prolonged (77 to 270 days) persistent TBE infection was induced by three TBE strains: Vasilchenko, V-383, and 205. The degree of antibiotic-induced activation was assessed using the criteria characterizing the reproduction and peculiarities of persisting TBE virus, immunodepression, and morphologic changes in the central nervous system. Effects of kefzol and ristomycin were compared with those of 8 antibiotics studied previously. Ristomycin, levomycetin (chloramphycin), penicillin, ampicillin (ampital), and levoridan were referred to drugs devoid of evident provoking effect. Kefzol (cefamezin), florimycin (viomycin), and kanamycin (kanamytrex) were characterized as weak activators and streptomycin and tetracycline as potent activators of the persisting TBE virus. These data may be used when selecting alternative agents for therapy of secondary bacterial infections concomitant with TBE.

Animals↗