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Biomedical subjects

G H Miller

Publications and source records attributed to G H Miller.

At least 55 records · Page 3Linked to original sources
PubMed1992

Genetic analysis of bacterial acetyltransferases: identification of amino acids determining the specificities of the aminoglycoside 6'-N-acetyltransferase Ib and IIa proteins.

The aminoglycoside 6'-N-acetyltransferase [AAC(6')-I] and AAC(6')-II enzymes represent a class of bacterial proteins capable of acetylating tobramycin, netilmicin, and 2'-N-ethylnetilmicin. However, an important difference exists in their abilities to modify amikacin and gentamicin. The AAC(6')-I enzymes are capable of modifying amikacin. In contrast, the AAC(6')-II enzymes are capable of modifying gentamicin. Nucleotide sequence comparison of the aac(6')-Ib gene and the aac(6')-IIa gene showed 74% sequence identity (K. J. Shaw, C. A. Cramer, M. Rizzo, R. Mierzwa, K. Gewain, G. H. Miller, and R. S. Hare, Antimicrob. Agents Chemother. 33:2052-2062, 1989). Comparison of the deduced protein sequences showed 76% identity and 82% amino acid similarity. A genetic analysis of these two proteins was initiated to determine which amino acids were responsible for the differences in specificity. Results of domain exchanges, which created hybrid AAC(6') proteins, indicated that amino acids in the carboxy half of the proteins were largely responsible for determining specificity. Mutations shifting the specificity of the AAC(6')-Ib protein to that of the AAC(6')-IIa protein (i.e., gentamicin resistance and amikacin sensitivity) have been isolated. DNA sequence analysis of four independent isolates revealed base changes causing the same amino acid substitution, a leucine to serine, at position 119. Interestingly, this serine occurs naturally at the same position in the AAC(6')-IIa protein. Oligonucleotide-directed mutagenesis was used to construct the corresponding amino acid change, a serine to leucine, in the AAC(6')-IIa protein. This change resulted in the conversion of the AAC(6')-IIa substrate specificity to that of AAC(6')-Ib. Analysis of additional amino acid substitutions within this region of AAC(6')-Ib support the model that we have identified an aminoglycoside binding domain of these proteins.

Acetyltransferases↗
PubMed1992

Revision of standards for adjusting the cation content of Mueller-Hinton broth for testing susceptibility of Pseudomonas aeruginosa to aminoglycosides.

A multilaboratory study was undertaken to reassess the amount of calcium and magnesium that should be added to Mueller-Hinton broth when testing Pseudomonas aeruginosa against amikacin, gentamicin, isepamicin, netilmicin, and tobramycin. To achieve parity with agar dilution tests, cation-adjusted broth should contain 20 to 25 mg of calcium and 10 to 12.5 mg of magnesium per liter rather than the 50- and 25-mg/liter supplements recommended previously. For quality control of tests with contemporary media, MIC control limits should be adjusted by lowering the current MIC limits by at least 1 doubling-dilution interval.

Aminoglycosides↗
PubMed1992

[Mechanisms of resistance to dactimicin and isepamicin in clinical strains of gram-negative rods isolated in Czechoslovakia].

Dactamicin is a new member of the pseudo-disaccharide group of antibiotics. It is structurally close to astromicin. Dactimicin is active against a wide variety of bacteria, including resistant strains with aminoglycoside-inactivating enzymes. Isepamicin is a broad-spectrum aminoglycoside, a derivative of gentamicin B. It is also active against many aminoglycoside-resistant strains. In a series of gram-negative bacterial isolates from various Czecho-Slovak regions, in vitro investigation yielded a good activity of dactimicin and isepamicin against amikacin- and gentamicin-resistant strains producing the enzyme AAC/6'/ or a combination of AAC/6'/ + ANT/2"/ enzymes. Dactimicin was not effective against strains producing the enzyme AAC/3/-I, and isepamicin was not effective or only slightly effective against bacterial isolates producing a combination of AAC/6'/ + AAC/3/ enzymes. (Tab. 3, Fig. 2, Ref. 10.).

Aminoglycosides↗
PubMed1992

A physician's guide to smoking cessation.

Claims of the effectiveness of smoking cessation services and products are often misleading. It is important that physicians be well informed in order to make appropriate recommendations to their patients who smoke. In this article smoking cessation products and programs are critically evaluated and issues such as cure rates and validation of self-reported abstinence are discussed. Many commercial products are available to aid in cessation, although none has been proven effective. With the exception of nicotine polacrilex gum and transdermal patches in conjunction with a multicomponent clinic, medications are generally ineffective. Smoking cessation programs range from the provision of self-help materials to multisession groups and clinics. Multicomponent, behavioral-based group programs have been the most successful. Physicians should raise the issue of smoking cessation as frequently as possible with smokers and should recommend the use of smoking cessation products and services as appropriate. Referrals should be made to programs that base their success rates on scientifically accepted standards, including a 1-year follow-up, inclusion of dropouts and nonrespondents in calculating outcome, and biochemical validation of self-reported abstinence. Reports of success rates of 80% to 95% at the end of a 1-year program should be viewed with skepticism. Ideally, whether working independently or through referral, the physician should actively promote smoking cessation for all patients who smoke.

Health Promotion↗
PubMed1991

Correlation between aminoglycoside resistance profiles and DNA hybridization of clinical isolates.

DNA hybridization data and aminoglycoside resistance profiles (AGRPs) were determined for 4,088 clinical isolates from three studies (United States, Belgium, and Argentina). The correlation between susceptibility profiles and hybridization results was determined with nine DNA probes. For each of the seven aminoglycoside resistance profiles which we were able to test, the data suggested at least two distinct genes could encode enzymes which lead to identical resistance profiles. Furthermore, the DNA hybridization data showed that individual strains carried up to six unique aminoglycoside resistance genes. DNA hybridization revealed interesting differences in the frequencies of these genes by organism and by country.

Acinetobacter↗
PubMed1990

Resistance to aminoglycoside antibiotics in gram-negative bacilli and staphylococci isolated from blood. Report from a European collaborative study. The ESGAR Study Group (European Study Group on Antibiotic Resistance).

The incidence of resistance to gentamicin, tobramycin, amikacin and netilmicin was determined by the microdilution method in Mueller-Hinton broth among blood culture isolates consecutively collected in 37 laboratories in 14 European countries. The distribution of bacteria was similar in each laboratory, Escherichia coli and staphylococci predominating. Resistance levels varied between laboratories but they were higher to all four antibiotics in Southern Europe than in Central and Northern Europe. Aminoglycoside resistance was usually associated with production of aminoglycoside-modifying enzymes, ANT(2"), AAC (3)-V, AAC (6')-I predominating in Gram-negative bacilli and APH (2") + AAC (6') and ANT (4')-I in staphylococci.

Aminoglycosides↗
PubMed1990

Appearance of amikacin and tobramycin resistance due to 4'-aminoglycoside nucleotidyltransferase [ANT(4')-II] in gram-negative pathogens.

Following the use of amikacin as the principal aminoglycoside at a Denver hospital, amikacin resistance appeared first in Pseudomonas aeruginosa and then in Escherichia coli, Klebsiella pneumoniae, and other enteric organisms from debilitated and compromised patients who had spent time in intensive care units and who had been treated with multiple antibiotics, usually including amikacin. In a P. aeruginosa isolate, resistance to amikacin and tobramycin was transferable by the IncP-2 plasmid pMG77, while in E. coli and K. pneumoniae resistance was carried by the transmissible plasmids pMG220, pMG221, and pMG222 belonging to the IncM group. Isolates and transconjugants produced an enzyme with adenyltransferase activity with substrates having a 4'-hydroxyl group, such as amikacin, kanamycin, neomycin, Sch 21768, isepamicin (Sch 21420), or tobramycin, but not with aminoglycosides lacking this target, such as dibekacin, netilmicin, sisomicin, or gentamicin C components. Genes encoding the 4'-aminoglycoside nucleotidyltransferase [ANT(4')] activity were cloned from pMG77, pMG221, and pMG222. A DNA probe prepared from the ANT(4') found in P. aeruginosa hybridized with the ANT(4') determinant found in E. coli. A probe for the ANT(4') from Staphylococcal spp., which differs in its modification of substrates, like dibekacin, that have a 4"- but not a 4'-hydroxyl group, failed to hybridize with the gram-negative ANT(4') determinant, which consequently has been termed ANT(4')-II.

Amikacin↗
PubMed1990

Microbiological and pharmacokinetic studies of acyl demycinosyltylosin and related tylosin derivatives.

A series of tylosins and acyl derivatives of 23-O-demycinosyltylosin (DMT) were initially tested for in vitro antibacterial activity and serum levels in squirrel monkeys (po) and mice (iv). Overall, the DMT compounds were more active in vitro than the tylosins. Two tetraacylated DMTs, Sch 37644 and Sch 38646, were selected from the initial studies for further evaluation and compared to erythromycin and A-56268 (6-O-methyl erythromycin). Sch 37644 and Sch 38646 were 2 to 8-fold less potent in vitro against Gram-positive bacteria than erythromycin and A-56268. In squirrel monkeys, Sch 37644 (AUC, 19.7 micrograms.hour ml) and A-56268 (21.6 micrograms.hour/ml) had similar serum levels following po administration of 20 mg/kg, while Sch 38646 (11.8 micrograms.hour/ml) and erythromycin (1.5 micrograms.hour/ml) had lower levels. In mice administered 200 mg/kg orally, Sch 37644 (AUC, 19.4 micrograms.hour/ml) and Sch 38646 (15.4 micrograms.hour/ml) had higher serum levels than erythromycin (5.7 micrograms.hour/ml). A-56268 was the most active po macrolide in mouse protection studies (PD50S) against Staphylococci and Streptococci, while Sch 37644 and Sch 38646 were similar to erythromycin.

Animals↗
PubMed1990

The impact of passive smoking: cancer deaths among nonsmoking women.

In order to obtain an estimate of the impact of passive smoking on cancer mortality, a retrospective study was conducted examining the cancer mortality of nonsmoking wives with no known or minimal exposure in contrast to nonsmoking wives with moderate to life-time exposure to tobacco smoke. The study was based on the data from 906 deceased nonsmoking women who resided in Erie County, Pennsylvania, who were divided into the following three categories: 1. No known exposure. 2. Exposed nonemployed. 3. Employed (assumed to be exposed to environmental tobacco smoke in the workplace). The data were analyzed by the retrospective case-control method using cancer deaths as the cases and non-cancer related deaths as the controls. Also, the data from 401 smoking women were used for comparative purposes of the total percentage of cancer deaths among three groups: 1. Nonsmoking, nonexposed women. 2. Combined nonsmoking unemployed and employed exposed women. 3. Smoking women. The major findings from the study are: 1. Only (2.2%) of the total deaths reported among the nonsmoking women with no known or minimal exposure to tobacco smoke were due to cancer of any site. 2. No cases of lung cancer deaths were reported for the nonexposed, nonsmoking women, and eight lung cancer deaths were reported among the nonsmoking women who were exposed to passive smoking. Also, for this small group of 170 nonsmoking nonexposed women, there were no reported cases of breast cancer, genitourinary or lymphatic cancer. 3. Employed nonsmoking women experienced proportionately more cancer deaths (34.3%) than both nonexposed (2.2%) and exposed nonemployed wives (18.9%). The combined groups of exposed nonsmoking wives (nonemployed and employed) contracted 25.5% cancer deaths. 4. Age-adjusted data showed similar trends. 5. Cancer death rates for women smokers was 35.5% of the total deaths of women smokers. Public health officials should consider requiring that the workplace be free from tobacco smoke since these data imply that passive smoking has a very detrimental effect upon nonsmokers. Also, smokers should be made aware of the potential damage they inflict on others in their home as well as the workplace.

Aged↗
PubMed1989

Netilmicin sulfate as single-agent therapy for Pseudomonas infections.

In a prospective multicenter clinical trial, 69 patients with Pseudomonas infections were treated with netilmicin sulfate as the only antipseudomonal antibiotic. Clinical resolution or improvement was observed for 81% of the infections, whereas 19% were considered treatment failures. The bacteriologic response, based on follow-up culture results, showed elimination of Pseudomonas from 62% of the infection sites, with persistence in 30%. All isolates were susceptible by disk susceptibility testing (zone greater than or equal to 15 mm), and by microdilution testing in unsupplemented broth. The majority of isolates, however, were resistant in cation supplemented media. The clinical failures could be accounted for by factors other than netilmicin failure. In conclusion, netilmicin appeared effective as treatment for netilmicin-susceptible Pseudomonas infections in nonneutropenic adults. A low incidence of nephrotoxicity (12%) occurred despite careful monitoring of serum levels.

Adult↗
PubMed1989

Isolation, characterization, and DNA sequence analysis of an AAC(6')-II gene from Pseudomonas aeruginosa.

The gene encoding a 6'-N-acetyltransferase, AAC(6')-II, was cloned from Pseudomonas aeruginosa plasmid pSCH884. This gene mediates resistance to gentamicin, tobramycin, and netilmicin but not amikacin or isepamicin. The DNA sequence of the gene and flanking regions was determined. The 5'- and 3'-flanking sequences showed near identity to sequences found abutting a variety of different genes encoding resistance determinants. It is likely that the current structure arose by the integration of the 572-base-pair sequence containing the AAC(6')-II gene into a Tn21-related sequence at the recombinational hot spot, AAAGTT. We have compared the sequence of the AAC(6')-II gene to genes of other 6'-N-acetyltransferases. An AAC(6')-Ib protein (encoded by the aacA4 gene; G. Tran Van Nhieu and E. Collatz, J. Bacteriol. 169:5708-5714, 1987) that results in resistance to amikacin but not gentamicin was found to share 82% sequence similarity with the AAC(6')-II protein. We speculate that these two genes arose from a common ancestor and that the processes of selection and dissemination have led to the observed differences in the spectrum of aminoglycoside resistance.

Acetyltransferases↗
PubMed1987

Netilmicin disk susceptibility tests: effect of cations on the MIC correlates.

When testing Pseudomonas aeruginosa against netilmicin, MICs were markedly affected by the concentration of cations added to the test medium. A susceptible disk test result (zone greater than or equal to 15 mm) corresponded to MIC less than or equal to 4.0 micrograms/ml in unsupplemented broth, less than or equal to 12 micrograms/ml in broth with half the usual amount of cations and less than or equal to 32 micrograms/ml in broth with the recommended concentration of cations. Tests with 30 micrograms netilmicin disks best predicted susceptibility as determined by MICs in broth without added cations. When the MICs were determined in cation supplemented broth, the number of interpretive discrepancies increased to an unacceptably high level.

Cations↗
PubMed1987

Activity of (+)-cyclaradine (Sch 31172) against herpes simplex virus in vitro and in vivo.

(+)-Cyclaradine (Sch 31172) is the carbocyclic derivative of adenosine arabinoside (9-beta-D-arabinofuranosyladenine). Because it is not deaminated by deaminase in serum, as is adenosine arabinoside, (+)-cyclaradine is about 2 to 5 times more active in vitro against herpes simplex virus. (+)-Cyclaradine has in vitro activity nearly equivalent to that of phosphonoformate but is significantly less active than acycloguanosine (acyclovir; ACV), trifluorothymidine, or 9-(1,3-dihydroxy-2-propoxymethyl)guanine. The absolute ratios of in vitro activities are difficult to determine because of variability among virus strains, inoculum size, and dependence on the tissue culture cell line in which the comparative test is carried out. (+)-Cyclaradine is active against TK-, ACV-resistant mutants. In the guinea pig model of vaginal herpes simplex virus infection, (+)-cyclaradine is only slightly less active than ACV when both molecules are nearly equivalently bioavailable; thus, the large difference in activity seen in vitro is not reflected in this in vivo model system.

Acyclovir↗
PubMed1987

Influence of cation supplements on activity of netilmicin against Pseudomonas aeruginosa in vitro and in vivo.

In vitro studies were performed with 74 Pseudomonas aeruginosa isolates which were collected during a multicenter trial. The isolates were obtained from 70 patients who had been treated with netilmicin as the only antipseudomonal antibiotic. Clinically, 83% of the patients were cured or improved, and 64% of the Pseudomonas isolates were eliminated by chemotherapy. The 74 clinical isolates and 38 additional isolates with known mechanisms of aminoglycoside resistance were tested in three separate laboratories by disk diffusion methods and by microdilution tests with three broth media (Mueller-Hinton broth with full, half, and no cation supplements). Isolates that responded to netilmicin therapy and those that failed to respond were all susceptible by the disk test, and most were susceptible by microdilution tests with unsupplemented broth. However, over half of the clinical isolates appeared to be resistant when cations were added to the broth medium. Strains capable of producing enzymes that inactivate netilmicin were resistant by all methods tested. Broth dilution and agar dilution results were most comparable when half of the recommended cation supplements was added to Mueller-Hinton broth. Further consideration should be given to reducing the concentration of cations that are added to Mueller-Hinton broth when netilmicin susceptibility tests are being performed. However, additional studies with other aminoglycosides are needed before appropriate testing conditions can be standardized.

Adult↗
PubMed1987

Comparative in vitro and in vivo evaluation of N-D-ornithyl amphotericin B methyl ester, amphotericin B methyl ester, and amphotericin B.

N-D-Ornithyl amphotericin B methyl ester (O-AME), a semisynthetic derivative of amphotericin B methyl ester (AME), was compared with amphotericin B (AMB) and AME. In vitro, O-AME was more active than the other two against Candida spp. and other fungi and was only slightly affected by inoculum size, addition of serum, or changes in pH. In vivo, the dose of O-AME required to produce a 10,000-fold reduction of Candida albicans in a mouse kidney infection was similar to that of AMB and 1/10 that of AME. After intravenous treatment of infected mice and rats and subcutaneous treatment of mice, average 50% protective doses for O-AME and AMB were similar. Acute intravenous 50% lethal doses in mice indicated that O-AME was one-ninth as toxic as AMB but twice as toxic as AME. Acute renal function tests in rats indicated that Sch 28191 was less than 1/10 as toxic as AMB and slightly more toxic than AME. On this basis, the calculated advantage relative to AMB (with AMB equal to 1) was 8 for O-AME and 1.5 for AME.

Amphotericin B↗
PubMed1987

Evaluation of (+)-cyclaradine-5'-esters as prodrugs for (+)-cyclaradine in animals.

Both (+)-cyclaradine-5'-methoxyacetate (CM) and (+)-cyclaradine-5'-ethoxypropionate (CE) were converted to (+)-cyclaradine (C) in squirrel monkey and human sera at 37 degrees C. CE was more stable than CM. After oral administration (20 mg base equivalent per kg) of either CM or CE, no unchanged esters were observed in serum of squirrel monkeys, rabbits, or rats. Instead, C was detected, indicating conversions of CM and CE to C in vivo. In squirrel monkeys, the areas under the curve (AUCs) of C obtained from oral dosing with CM were 61% higher than those obtained from dosing with C, indicating that CM may be a good prodrug for C. In squirrel monkeys, rabbits, and rats, CE resulted in a 20 to 90% higher AUC of C than did CM, indicating that CE was better absorbed than CM.

Administration, Oral↗
PubMed1987

A novel tetracycline from Actinomadura brunnea. Fermentation, isolation and structure elucidation.

A novel tetracycline antibiotic, Sch 33256, was isolated from a culture broth of a new species of Actinomadura. The antibiotic was isolated by solvent extraction, Sephadex G-25 column chromatography and crystallization. The structure was determined by comparison of the spectra with that of chlortetracycline. Spectroscopic analysis of the compound yielded 2'-N-methyl-8-methoxychlortetracycline as the proposed structure.

Bacteria↗