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C Carbon

Publications and source records attributed to C Carbon.

At least 217 records · Page 12Linked to original sources
PubMed1990

Significance of tissue levels for prediction of antibiotic efficacy and determination of dosage.

Determination of tissue levels is widely thought to provide useful information in the investigation of a new antibiotic, however this assumption is not fully justified. In this paper the following questions are covered. Firstly, the methodological problems encountered in the measurement of antibiotic levels in solid tissues and extravascular fluids are described. Secondly, the difficulties encountered in interpreting tissue concentrations are discussed, given the heterogeneity of distribution of drugs, potential intracellular penetration, binding to tissue proteins and local factors reducing antibacterial activity. Thirdly, the respective importance of animal and human data on tissue levels for prediction of efficacy is analysed. In some animal models it is possible to study the conditions affecting antibacterial activity and to obtain data relevant to the clinical situation. However, the inoculum effect, the metabolism of bacteria, the mechanism of the bactericidal action of drugs and the type of infected tissue are important factors to be taken into account. In humans, data obtained from infected tissue is sparse and contributes little to knowledge. Knowledge of tissue levels may be important for establishing whether data obtained in animals can be applied to humans or not. Fourthly, the importance of tissue levels in determining antibiotic dosages is evaluated. In humans, tissue levels are of limited value in the determination of unitary dose and dosage intervals in relation to the clinical response. Trough serum levels of free drug, half-life at the beta-phase and rate of in vitro killing are the most important parameters to be considered. Their relative importance depends mainly on the mode of action of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

An experimental model for salpingitis due to Chlamydia trachomatis and residual tubal infertility in the mouse.

A mouse model of salpingitis and subsequent tubal infertility induced by a human strain of Chlamydia trachomatis has been studied. C3H/He female mice were inoculated into the ovarian bursa. Some of the mice (six infected, five controls) were killed on days 15 and 23 and the remaining animals (10 infected, 10 controls) were mated on day 15. On day 15, the infection was maximal with intratubal inflammation, elevated antichlamydial antibody titre and positive cultures in 12 cases out of 16. After 19 weeks of housing with the male, the proportion of fertilized females was significantly lower in the infected group (20% versus 100% in the control group P less than 0.01). In the killed mice, hydrosalpinx and or tubal occlusion were noted at this time in nine cases out of 10, despite an apparent bacteriological healing.

Animals↗
PubMed1990

Pharmacokinetics of lomefloxacin in healthy volunteers: comparison of 400 milligrams once daily and 200 milligrams twice daily given orally for 5 days.

We evaluated the effect of repeated oral doses (5 days of treatment) on the kinetics of lomefloxacin in volunteers and compared the kinetics after two different regimens, i.e., 400 mg once daily and 200 mg twice daily. After 400 mg of lomefloxacin was given once daily, no significant modification in the pharmacokinetic parameters was noted between the first and the fifth dose (maximum concentration of drug in serum, about 4 mg/liter; elimination half-life, about 6.3 h). After a dose of 200 mg every 12 h, a significant increase in the minimum concentration of drug in serum (0.49 +/- 0.1 and 0.72 +/- 0.2 mg/litter at days 1 and 5, respectively) and the area under the concentration-time curve (about 20%) was noted. The 400-mg regimen is probably adequate for therapeutic use.

4-Quinolones↗
PubMed1990

Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain of Klebsiella pneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase.

We studied the activity of the combination of sulbactam and ceftriaxone against a Klebsiella pneumoniae strain producing TEM-3, a new extended-broad-spectrum beta-lactamase, in an endocarditis model. In vitro, ceftriaxone was strongly inactivated in the presence of TEM-3 (MBC, 128 micrograms/ml with an inoculum of 5 x 10(5) CFU/ml). A marked inoculum effect was demonstrated with sulbactam: effective concentrations of inhibitor needed to reduce the MIC and MBC of ceftriaxone to similar levels increased from 1 microgram/ml in the presence of an inoculum of 5 x 10(5) CFU/ml to 20 micrograms/ml in the presence of an inoculum of 1 x 10(7) CFU/ml. In vivo, sulbactam given at 200 mg/kg of body weight every 12 h, a dosage higher than that previously reported to be effective against rabbit endocarditis caused by other microorganisms, was not sufficient to restore the complete activity of ceftriaxone given at 30 mg/kg once daily for 4 days. This insufficient activity may be correlated with the presence of a high level of beta-lactamase inside the vegetations, as indicated by a quantitative in vitro assay of beta-lactamase activity in the cardiac vegetation, suggesting an insufficient inactivation of the extended-broad-spectrum beta-lactamase in vivo.

Animals↗
PubMed1990

Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis.

The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However, the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin, alone or in combination with various dosing regimens of netilmicin, for the treatment of experimental left-sided Enterococcus faecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h), netilmicin at a high dose (4 mg/kg every 8 h), or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 micrograms/ml and 8 and 8 micrograms/ml for penicillin and netilmicin, respectively. A netilmicin concentration of 4 micrograms/ml was the lowest concentration that achieved synergism with penicillin, as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg), 9.8 (netilmicin at 4 mg/kg), and 20.6 (netilmicin at 12 mg/kg) micrograms/ml. Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P less than 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin. Our data suggest that prolonged levels of aminoglycoside in serum might be important to exhibit the greatest in vivo efficacy of the combination against E. faecalis. They also indicate that use of a reduced total daily dose of aminoglycoside or an increase in the interval between each dose might reduce the efficacy of therapy in animals with this type of infection.

Animals↗
PubMed1990

Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase.

We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.

Animals↗
PubMed1990

Impact of the antibiotic dosage schedule on efficacy in experimental endocarditis.

The animal model of endocarditis provides a reliable and reproducible model of acute infection and appears appropriate for studying the parameters involved in the in vivo efficacy of antibiotic therapy. The following points are discussed: (i) beta-lactam antibiotics exhibit a time-dependent bactericidal effect which explains the importance of t1/2 beta in the determination of dosing intervals and the need for large unitary doses for increasing efficacy through extending the period of serum levels greater than MIC (ii). The impact of unitary doses and dosing intervals of aminoglycosides on their in vivo synergism with beta-lactams has been investigated in Escherichia coli and streptococcal infections. Once- daily dosing of netilmicin appears very synergistic with ceftriaxone on E. coli, and the aminoglycoside has a significant dose effect. Conversely, divided doses are necessary to exhibit full synergistic effect with penicillin G on E. faecalis. Different patterns of in vivo synergism can therefore be individualized (iii). The rapid bactericidal effect of quinolones and their in vivo post-antibiotic effect allowing large intervals between doses have been investigated with ciprofloxacin (iv). The importance of t1/2 beta on the in vivo effect of glycopeptides is illustrated by data comparing teicoplanin and vancomycin. It is concluded that in vitro killing rate within 3 h is the major factor interfering with the dose interval, followed by t1/2 beta which is of major importance for those drugs whose bactericidal effect is time-dependent. These parameters appear to have a similar importance in experimental endocarditis to that in other experimental models. However, infected vegetations represent a particular focus of infection incorporating heterogeneity of antibiotic distribution, high density of bacteria and reduced metabolic activity of microorganisms. These factors may explain the lack of in vivo postantibiotic effect observed with some antibiotics, correspondingly shorter dosage intervals in endocarditis than in other types of infections and a need for high unitary doses.

Animals↗
PubMed1990

[Therapeutic potential of ofloxacin in hospital medicine. A French multicenter study].

Bacteriological studies were carried out on samples taken from 1,824 patients in 12 departments of internal medicine (6 University Hospital Departments and 6 Regional Hospital Departments), over a period of six weeks. Four hundred and twenty-two samples were positive on culture. These included 189 urine samples, 81 samples from the respiratory tract and 71 blood samples for culture. Four hundred and forty-four bacterial strains were isolated (including 290 Gram- organisms, 146 Gram+ organisms, 6 intracellular and 2 anaerobic organisms) 427 of which were tested vis a vis ofloxacin. Seventy-five per cent of identified bacteria were susceptible to ofloxacin including 88% Gram- bacteria, 79% staphylococci and 17.5% streptococci. Bacteria resistant to ofloxacin were responsible for 16 out of 183 of infections originating in the community and 29 out of 116 of infections of nosocomial origin. Enterobacterial strains were tested vis a vis nalidixic acid and staphylococcal strains vis a vis oxacillin: 9 of the 30 strains resistant to nalidixic acid were susceptible to ofloxacin, 4 of the 18 strains resistant to oxacillin were susceptible to ofloxacin. These data confirm the therapeutic potential of ofloxacin in the treatment of common infections encountered in hospital medicine.

Bacteria, Anaerobic↗
PubMed1990

[Antibiotics and anti-inflammatory agents: drug interactions].

Antibiotics (AB) are sometimes used in patients taking anti-inflammatory drugs (AID) (steroidal and non steroidal anti-inflammatory drugs). At the present time, the usefulness of AID in bacterial infections has been established in a limited number of clinical situations. AID are able to modify the kinetics of AB through different mechanisms which are illustrated by results obtained with cephalosporins and phenylbutazone or diclofenac. In some conditions, these modifications might have consequences on in vivo effect of AB. Conversely, some AB are able to alter metabolism and/or kinetics of some steroids. Interactions of AI on AB toxicity have also been investigated on kidney and central nervous system. AB/AI kinetic interactions have to be investigated for a better understanding of the mechanisms through which AI improve the evolution of an infectious process.

Animals↗
PubMed1990

Interactions of free and liposomal amphotericin B with renal proximal tubular cells in primary culture.

We studied in vitro the renal toxicity of amphotericin B (AMB) and liposomal AMB using primary cultures of rabbit proximal tubular cells grown to confluence in serum-free medium. Toxicity was assessed by changes 1) in the Na(+)-dependent uptakes of P1 and alpha-methylglucopyranoside (MGP), characteristic functions of proximal tubular cells; 2) K+ release into the supernatant, dependent upon membrane permeability; and 3) lactic dehydrogenase release as a marker for cellular death. Cells were exposed for 1 hr to AMB, alone or intercalated in small unilamellar vesicles prepared with one of the following phospholipids: dipalmitoylphosphatidyl choline, distearoylphosphatidyl choline or dimyristoylphosphatidyl choline. Although AMB concentrations of 20 microM or less did not increase lactic dehydrogenase release, P1 and MGP uptakes were significantly reduced (50% inhibition) by 2.5 and 5 microM AMB, respectively. AMB toxicity was dose-dependent, up to 20 microM. Analysis of P1 and MGP uptake kinetics, after treatment of the cells with 10 microM AMB, showed that inhibition occurred through a decrease in Vmax (66 and 57% inhibition for P1 and MGP, respectively) without affecting Km value. K+ release appeared for 2.5 microM AMB and increased with higher concentrations. Alteration of Na(+)-dependent uptakes by AMB, which parallels K+ release, may result from an alteration of the sodium gradient. Na(+)-dependent uptakes and K+ release were unaffected by liposomal AMB, even at the highest concentration tested (80 microM). The protective effect of liposomes was the same regardless of the phospholipid used.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗
PubMed1990

Nifedipine enhances amoxicillin absorption kinetics and bioavailability in humans.

Intestinal absorption of aminopenicillins in vitro uses the dipeptide carrier system. Recent experiments have reported calcium ion to be a cellular mediator of the regulation of electrolyte transport through the enterocyte membrane, especially the Na/H exchange which is partly responsible for the proton gradient energizing the carrier system. In order to assess the in vivo relevance of these data, we studied, in healthy volunteers, the influence of nifedipine, a calcium channel blocking agent, on the intestinal uptake of amoxicillin, a commonly prescribed and well-absorbed aminopenicillin. Results obtained show that 1) intestinal absorption kinetics of amoxicillin follows a zero-order process, which further substantiates the existence of a saturable carrier-mediated process for this antibiotic in humans and 2) calcium channel blockade significantly enhances both absorption rate (by 70%) and bioavailability of amoxicillin (by 21.4%) without modifying its distribution or elimination. These findings might suggest that nifedipine could enhance amoxicillin intestinal uptake by stimulating its active transport.

Adult↗
PubMed1989

[Efficacy and tolerability of cefixime in international and French studies].

Cefixime, the first oral third generation cephalosporin, was administered to 2,832 patients in the USA, UK, FRG and France. 478/1063 patients were treated for urinary tract infections (upper or lower UTI) with 200 mg cefixime bid; clinical cure was obtained in 92 and 96 per cent of upper and lower UTI respectively, and bacteriological cure in 97.5 and 89 per cent of the cases; among 142 patients with a 1 month follow-up, no relapse or reinfection was observed in 78 per cent of cases. Of 521 patients treated for lower respiratory tract infection, 355 received 200 mg cefixime bid and 166 received a single daily dose of 400 mg. Clinical cure was obtained in 88 per cent and 93 per cent patients with pneumonia or bronchitis respectively, with bacteriological cure in 93.2 and 93.8 per cent. Among ENT infections, the most interesting study was in the treatment of sinusitis and otitis. Good clinical results were shown in nearly 95 per cent of cases, with bacteriological cure in more than 90 per cent. The safety studies demonstrated a global 6.6 per cent incidence of undesirable effect. These manifestations were mild and reversible, consisting of abdominal discomfort and minor diarrhea in most cases. The overall effectiveness of cefixime appears to be similar to that of established compounds as far as susceptible pathogens are concerned. However, in clinical trials, cefixime seemed to be effective on isolated bacteria unresponsive to conventional antibiotics.

Cefixime↗
PubMed1989

Serum bactericidal activity against Enterobacteriaceae producing broad-spectrum beta-lactamases in volunteers administered ofloxacin and cefotaxime, alone or combined.

The activity of ofloxacin and cefotaxime, alone or combined, against four strains of Enterobacteriaceae was evaluated both in vitro and in sera from volunteers given a single infusion over 30 min of 200 mg ofloxacin or 1 g cefotaxime. The strains showed resistance or decreased susceptibility to third-generation cephalosporins. The combination was not found to be synergistic in vitro. Analysis of the bactericidal titres and killing kinetics of sera taken at the time of the peak concentration and 6 h after the infusion, respectively, confirmed the absence of synergy between the drugs against these strains.

Cefotaxime↗
PubMed1989

Evaluation of antibiotic diffusion into cardiac vegetations by quantitative autoradiography.

The reason bacterial endocarditis is difficult to cure has been controversial for many years. One explanation could be that antibiotic diffusion inside the vegetations is heterogeneous. This hypothesis was investigated by means of an autoradiographic study of diffusion of labeled antibiotics into large infected cardiac vegetations of nutritionally variant Streptococcus endocarditis in rabbits. Ten days after infection, 653 microCi of [3H]penicillin, 410 microCi of [3H]tobramycin, or 174 microCi of [14C]teicoplanin were injected iv over 30 min. Thirty minutes after the end of infusion (T30), vegetation/blood radioactivity ratios were 2.48 +/- 1.27, 2.49 +/- 0.67, and 3.94 +/- 1.19 for penicillin, tobramycin, and teicoplanin, respectively. Autoradiography clearly showed that distribution of the three drugs was different: Tobramycin was homogeneously distributed; penicillin was more concentrated at the periphery but still reached the center of vegetations; teicoplanin was concentrated only at the periphery. The same distribution pattern was observed with teicoplanin at T120 (i.e., one t1/2 beta later) and also after simultaneous infusion of a therapeutic dose (15 mg/kg) of cold teicoplanin. The diffusion gradient exhibited by some antibiotics could explain the difficulty in sterilizing vegetations despite high local concentrations, and the deleterious effect of the size of the vegetations on the therapeutic response.

Animals↗
PubMed1989

Efficacy and safety of low dose aztreonam in the treatment of moderate to severe gram-negative bacterial infections.

One hundred and fifty-three patients with moderate to severe infections due to Gram-negative bacteria, including septicaemia (60 cases), lower respiratory tract infection (32 cases), intra-abdominal infection (40 cases) and urinary tract infection (21 cases), were treated with aztreonam 1 g every 12 h. This dosage is lower than usual. Criteria for inclusion included documented Gram-negative bacterial infections, and assessment of the severity of the disease by a scoring system for both community and hospital acquired infections. No other antibiotic active against Gram-negative bacteria was allowed. In 71 patients, in whom Gram-positive or anaerobic organisms were detected or suspected, additional agents effective against these organisms were administered. One hundred and forty-one patients (92.2%) were cured with a mean duration of treatment of 10.9 +/- 4.0 days. None of the Gram-negative bacteria initially isolated became resistant to aztreonam. Colonization, generally by a Gram-positive organism, was observed in 27 patients and superinfection in five. Aztreonam was well tolerated. This study suggests that a daily dosage of 2 g of aztreonam should be sufficient in the treatment of moderate to severe Gram-negative bacillary infections due to sensitive organisms.

Adolescent↗