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Biomedical subjects

M N Swartz

Publications and source records attributed to M N Swartz.

At least 19 recordsLinked to original sources
PubMed1990

Mutants of Escherichia coli K-12 exhibiting reduced killing by both quinolone and beta-lactam antimicrobial agents.

Norfloxacin, ofloxacin, and other new quinolones, which are antagonists of the enzyme DNA gyrase, rapidly kill bacteria by largely unknown mechanisms. Earlier, we isolated, after mutagenesis, Escherichia coli DS1, which exhibited reduced killing by quinolones. We evaluated the killing of DS1 and several other strains by quinolones and beta-lactams. In time-killing studies with norfloxacin, DS1 was killed 1 to 2 log10 units compared to 4 to 5 log10 units for the wild-type parent strain KL16, thus revealing that DS1 is a high-persistence (hip) mutant. DS1 exhibited a similar high-persistence pattern for the beta-lactam ampicillin and reduced killing by drugs that differed in their affinities for penicillin-binding proteins, including cefoxitin, cefsulodin, imipenem, mecillinam, and piperacillin. Conjugation and P1 transduction studies identified a novel mutant locus (termed hipQ) in the 2-min region of the DS1 chromosome necessary for reduced killing by norfloxacin and ampicillin. E. coli KL500, which was isolated for reduced killing by norfloxacin without mutagenesis, exhibited reduced killing by ampicillin. E. coli HM23, a hipA (34 min) mutant that was isolated earlier for reduced killing by ampicillin, also exhibited high persistence to norfloxacin. DS1 differed from HM23, however, in the map location of its hip mutation, lack of cold sensitivity, and reduced killing by coumermycin. Results of these studies with strains DS1, KL500, and HM23 demonstrate overlap in the pathways of killing of E. coli by quinolones and beta-lactams and identify hipQ, a new mutant locus that is involved in a high-persistence pattern of reduced killing by norfloxacin and ampicillin.

Anti-Bacterial Agents↗
PubMed1989

Mechanisms of quinolone resistance in Escherichia coli: characterization of nfxB and cfxB, two mutant resistance loci decreasing norfloxacin accumulation.

Two genetic loci selected for norfloxacin (nfxB) and ciprofloxacin (cfxB) resistance were characterized. Both mutations have previously been shown to confer pleiotropic resistance to quinolones, chloramphenicol, and tetracycline and to decrease expression of porin outer-membrane protein OmpF. nfxB was shown to map at about 19 min and thus to be genetically distinct from ompF (21 min), and cfxB was shown to be very closely linked to marA (34 min). cfxB was dominant over cfxB+ in merodiploids, in contrast to other quinolone resistance mutations. The two loci appear to interact functionally, because nfxB was not expressed in the presence of marA::Tn5. Both nfxB and cfxB decreased the expression of ompF up to 50-fold at the posttranscriptional level as determined in strains containing ompF-lacZ operon and protein fusions. Both mutations also decreased norfloxacin accumulation in intact cells. This decrease in accumulation was abolished by energy inhibitors and by removal of the outer membrane. These findings, in conjunction with those of Cohen et al. (S. P. Cohen, D. C. Hooper, J. S. Wolfson, K. S. Souza, L. M. McMurry, and S. B. Levy, Antimicrob. Agents Chemother. 32:1187-1191, 1988), suggest a model for quinolone resistance by decreased permeation in which decreased diffusion through porin channels in the outer membrane interacts with a saturable drug efflux system at the inner membrane.

Anti-Infective Agents↗
PubMed1989

Isolation and characterization of an Escherichia coli strain exhibiting partial tolerance to quinolones.

Quinolone antimicrobial agents rapidly kill bacteria by largely unknown mechanisms. To study this phenomenon, a strain of Escherichia coli inhibited but inefficiently killed by (i.e., partially tolerant to) norfloxacin was isolated and characterized. E. coli KL16 (norfloxacin MIC, 0.10 microgram/ml; MBC, 0.20 microgram/ml) was mutagenized with nitrosoguanidine and cyclically exposed to 3 micrograms of norfloxacin per ml. After five cycles, a bacterial strain (DS1) which was killed 1,000-fold less than KL16 during 3 h of drug exposure was isolated. The MIC and MBC of norfloxacin for DS1 were 0.20 and 1.5 micrograms/ml, respectively. Over a range of norfloxacin concentrations, DS1 was killed 2 to 4 orders of magnitude less than KL16. DS1 grew more slowly than KL16 but after normalization for growth rate was killed four times less rapidly than KL16 at drug concentrations 10-fold higher than respective MICs. DS1 and KL16 cells filamented similarly upon exposure to norfloxacin. DS1 exhibited tolerance to other DNA gyrase A subunit antagonists (ofloxacin and ciprofloxacin) and DNA gyrase B subunit antagonists (novobiocin and coumermycin) but not to the aminoglycoside gentamicin, suggesting involvement of DNA gyrase. DS1 also appeared to be minimally tolerant to the beta-lactam cefoxitin. DS1 exhibited increased susceptibility to the mutagen methyl methanesulfonate, implying a defect in DNA repair. This report describes the first use of quinolone enrichment for isolation of a bacterial strain partially tolerant to quinolones. The study of defects in such tolerant strains offers an approach to an increased understanding of the mechanisms of bacterial killing by quinolones.

Anti-Infective Agents↗
PubMed1989

Effects of inhibition of the B subunit of DNA gyrase on conjugation in Escherichia coli.

Antagonism of the DNA gyrase B subunit in the donor bacterium by coumermycin or thermal inactivation inhibited transfer of plasmid R64drd-11. Coumermycin also inhibited Hfr transfer, with kinetics after drug removal suggesting that transfer resumed from the point of inhibition, in contrast to inhibition with nalidixic acid, after which transfer reinitiated from the origin of transfer.

Aminocoumarins↗
PubMed1987

Antagonism of wild-type and resistant Escherichia coli and its DNA gyrase by the tricyclic 4-quinolone analogs ofloxacin and S-25930 stereoisomers.

The mechanism of action of the quinolone analogs ofloxacin and S-25930, which are unusual because of the presence of a third ring with an asymmetric carbon, was studied. Drug-resistant strains of Escherichia coli were selected by serial passage in the presence of ofloxacin, and a mutation was mapped near the gyrA gene of DNA gyrase. DNA gyrase containing the A subunit purified from this strain as compared with the isogenic wild-type strain exhibited increased resistance to ofloxacin, proving that the mutation was located in the gyrA gene. For S-25930, the S stereoisomer was more potent than the R isomer in inhibiting wild-type E. coli and DNA gyrase containing an A subunit isolated from this strain. Both isomers had decreased potency against the isogenic ofloxacin-resistant (gyrA) strain and its purified enzyme, but the S isomer remained more potent than the R isomer. These studies, using a combined genetic and biochemical approach, demonstrate (i) that DNA gyrase is a target of the tricyclics ofloxacin and S-25930, (ii) that serial exposure to ofloxacin can select resistance to tricyclic quinolone agents by mutation in the gyrA gene, and (iii) that the more potent antibacterial activity of S relative to R S-25930 correlates with increased activity against DNA gyrase for both wild-type and ofloxacin-resistant (gyrA) isogenic strains.

Anti-Bacterial Agents↗
PubMed1979

Single-antibiotic therapy for streptococcal endocarditis.

Ninety-nine patients treated with penicillin G potassium, cephalothin sodium, or vancomycin hydrochloride were studied to evaluate single-drug therapy for nonenterococcal streptococcal endocarditis. Eighty-six patients survived; of these, 66 received penicillin alone. The maximum serum bactericidal titer obtained at the expected nadir of serum antibiotic concentration was 1:8 or greater in 70 (95%) of the 74 patients studied. No relapse occurred among the 66 patients treated wih penicillin. Only one patient experienced a relapse that occurred following therapy with suboptimal doses of vancomycin. Distinct second episodes of endocarditis occurred in five patients. While 13 patients died, none died of intractable infection. The treatment of endocarditis due to penicillin-susceptible streptococci with high-dose parenteral penicillin or a bactericidal penicillin substitute for four weeks or longer results in bacteriologic cure rates comparable with those achieved with combined penicillin-streptomycin regimens.

Administration, Oral↗
PubMed1979

Clinical aspects of Legionnaires' disease.

Since the initial description of Legionnaires' disease 2 years ago, a clearer picture of its clinical manifestations has emerged as a result of investigations of further epidemics and studies of laboratory-confirmed sporadic cases. Although individual clinical features are not sufficiently distinctive to distinguish Legionnaires' disease from other types of acute pneumonia, a composite can provide a sufficiently characteristic clinical profile to indicate the likelihood of this diagnosis. Such a profile includes high fever (above 39.4 degrees C); recurrent chills; relative bradycardia; early gastrointestinal symptoms (particularly diarrhea); prominent myalgias; microscopic hematuria; liver function abnormalities; toxic encephalopathy; nonproductive cough; absence of bacterial pathogens on Gram stain and culture of transtracheal aspirate; progression from patchy bronchopneumonia to lobar and multilobar consolidation; and frequently prompt and sometimes dramatic response to treatment with erythromycin.

Cough↗
PubMed1978

Plasmid-mediated resistance to antibiotic synergism in enterococci.

Mating experiments have shown that high-level resistance (minimal inhibitory concentration greater than 2,000 microgram/ml) to streptomycin and kanamycin, and resistance to penicillin-streptomycin and penicillin-kanamycin synergism are transferable by conjugation from resistant clinical isolates of enterococci to a sensitive recipient strain. Cesium chloride-ethidium bromide ultracentrifugation revealed a satellite (plasmid) band in resistant clinical isolates and the transconjugant strains but not in the sensitive recipient. Examination of these satellite bands by agarose gel electrophoresis and electron microscopy demonstrated a common plasmid with a weight of 45 megadaltons. Novobiocin treatment of a resistant clinical isolate produced simultaneous loss of high-level resistance to streptomycin and kanamycin, and of resistance to penicillin-aminoglycoside synergism. These results suggest that (a) high-level resistance to streptomycin and kanamycin among some clinical isolates of enterococci is associated with a 45 megadalton plasmid, and (b) the same plasmid is also responsible for the resistance to penicillin-aminoglycoside synergism observed in these strains.

Aminoglycosides↗
PubMed1978

Aminoglycoside-inactivating enzymes in clinical isolates of Streptococcus faecalis. An explanation for resistance to antibiotic synergism.

Clinical isolates of enterococci (Streptococcus faecalis) with high-level resistance to both streptomycin and kanamycin (minimal inhibitory concentration >2,000 mug/ml), and resistant to synergism with penicillin and streptomycin or kanamycin were examined for aminoglycoside-inactivating enzymes. All of the 10 strains studied had streptomycin adenylyltransferase and neomycin phosphotransferase activities; the latter enzyme phosphorylated amikacin as well as its normal substrates, such as kanamycin. Substrate profiles of the neomycin phosphotransferase activity suggested that phosphorylation occurred at the 3'-hydroxyl position, i.e., aminoglycoside 3'-phosphotransferase. A transconjugant strain, which acquired high-level aminoglycoside resistance and resistance to antibiotic synergism after mating with a resistant clinical isolate, also acquired both enzyme activities. Quantitative phosphorylation of amikacin in vitro by a sonicate of the transconjugant strain inactivated the antibiotic, as measured by bioassay, and the phosphorylated drug failed to produce synergism when combined with penicillin against a strain sensitive to penicillin-amikacin synergism.No differences were found in the sensitivity of ribosomes from a sensitive and resistant strain when examined in vitro using polyuridylic acid directed [(14)C]-phenylalanine incorporation in the presence of streptomycin, kanamycin, or amikacin. Therefore, we conclude that aminoglycoside-inactivating enzymes are responsible for the aminoglycoside resistance, and resistance to antibiotic synergism observed in these strains.

Aminoglycosides↗
PubMed1975

Spinal epidural abscess.

Thirty-nine patients with spinal epidural abscess were evaluated at the Massachusetts General Hospital between 1947 and 1974. Twenty had acute symptoms, and purulent epidural collections were present; 19 had prolonged courses, and epidural granulation tissue was observed at operation. Staphylococcus aureus was the most common etiologic agent (57 per cent), followed by streptococci (18 per cent) and gram-negative bacilli (13 per cent). The source of infection was osteomyelitis in 38 per cent of cases and bacteremia in 26 per cent. In 16 per cent epidural abscess was due to postoperative infection. The progression from spinal ache to root pain to weakness followed by paralysis continues to be characteristic of spinal epidural abscess. Although the disease is uncommon, the complications are so serious that prompt diagnosis and treatment are of paramount importance. The combination of back pain with fewer and local tenderness is an indication for cerebrospinal-fluid examination and, depending on the results, immediate performance of myelography.

Abscess↗