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Biomedical subjects

H Mattie

Publications and source records attributed to H Mattie.

At least 55 records · Page 3Linked to original sources
PubMed1990

Antibacterial activity of four cephalosporins in an experimental infection in relation to in vitro effect and pharmacokinetics.

The in vitro activity of four cephalosporins was compared with their effects in an experimental thigh infection (cefuroxime and cefamandole against Escherichia coli and cefamandole, ceftriaxone, and ceftazidime against Klebsiella pneumoniae) in granulocytopenic mice. The effect in vitro (ER) was defined as the difference between the growth rate without antibiotic and the growth rate at the steepest part of a 3-h growth curve in the presence of an antibiotic. The relation between concentration and ER was described with the Hill equation. Using pharmacokinetic parameters of the plasma concentrations in vivo and those of the Hill equation the corresponding time course of ER was calculated and by integration with respect to time (0tERdt), an estimate was obtained of the effect on bacteria. For all four antibiotics this estimate was significantly correlated with the actual values of the effect in vivo (EN), defined as the difference in numbers of bacteria between controls and antibiotic-treated animals at 4 h.

Agranulocytosis↗
PubMed1990

Effect of amphotericin B, fluconazole and itraconazole on intracellular Candida albicans and germ tube development in macrophages.

Candida albicans may resist intracellular killing by macrophages through the formation of germ tubes. Antifungal drugs that inhibit intracellular germ tube formation could therefore facilitate host defence against C. albicans. We assessed the effects of amphotericin B and the new triazole drugs fluconazole and itraconazole on the multiplication and intracellular germ tube formation of C. albicans phagocytosed by murine peritoneal macrophages, and compared the findings with the effects of these drugs on C. albicans in the absence of macrophages. The fungicidal effect of amphotericin B against C. albicans in macrophages was less prominent than that found for extracellular candida. However, amphotericin B completely blocked germ tube formation of C. albicans both in macrophages and extracellularly. Fluconazole and itraconazole had little effect on the number of candida but significantly, although incompletely, inhibited germ tube formation both inside macrophages and extracellularly. The inhibition of intracellular germ tube formation by the triazoles may facilitate host defences against C. albicans and contribute to the efficacies of these drugs in vivo.

Amphotericin B↗
PubMed1990

Relation between the therapeutic efficacy of imipenem in an experimental infection in granulocytopenic mice and its effect on murine intestinal microbial ecology.

A study was performed to assess the effect of parenteral administration of imipenem on the intestinal microbial ecology of mice in relation to the therapeutic efficacy of the drug. The therapeutic effect of imipenem was assessed in a short-term experimental thigh muscle infection with Escherichia coli in irradiated mice. The maximum antibacterial effect of imipenem was approached at a single dose of 80 mg/kg. At this dose of imipenem the number of viable E. coli in the thigh muscle decreased from 9 x 10(6) to 4 x 10(5), whereas in untreated controls this number increased from 9 x 10(6) to 2 x 10(8). Daily administration of a dose of 80 mg/kg imipenem caused significant changes in the intestinal flora of conventional mice, despite the low concentrations of the drug (about 1 mg/kg) found in the caecum 30 min after infection of this dose. These changes consisted of an increase in the number of E. coli and enterococci and a decrease in the number of Staphylococcus aureus in the faeces. Furthermore, at this dose of imipenem, the number of Candida albicans recovered from the faeces after oral contamination with this organism was increased. We conclude from these animal experiments that the use of imipenem in high doses causes ecological changes in the intestinal bacterial flora with the potential to promote colonization by candida.

Animals↗
PubMed1990

Antistaphylococcal activities of teicoplanin and vancomycin in vitro and in an experimental infection.

The efficacies of vancomycin and teicoplanin in an experimental Staphylococcus aureus infection in granulocytopenic mice were related to their activities in vitro and their pharmacokinetic profiles. In vitro teicoplanin had a higher intrinsic activity than vancomycin did; and it also had a more favorable pharmacokinetic profile, resulting in higher peak concentrations in plasma, a longer elimination half-life, and a larger area under the concentration-time curve than those of vancomycin. To predict the antibacterial efficacies of the drugs in vivo on the basis of their activities in vitro and pharmacokinetics, a mathematical model was applied. In the model the in vitro effect was expressed as the difference in growth rate between control cultures and those in the presence of the antibiotic (ER), and the in vivo effect was expressed as the difference between numbers of CFU in control and antibiotic-treated animals (EN). The integral of ER against time, ERt, was calculated by using the concentrations found in vivo. A significant linear relationship was found between EN and ERt for different dosages at the same times (4 h) after drug administration as well as for the same doses at consecutive times, although at the lowest doses of teicoplanin the observed effect was less than the predicted effect.

Animals↗
PubMed1990

Comparative study of the effects of four cephalosporins against Escherichia coli in vitro and in vivo.

A thigh muscle infection induced with Escherichia coli in irradiated mice was used as a model to compare the in vivo pharmacodynamics of the antibacterial effect of four cephalosporins (i.e., cefepime, ceftriaxone, ceftazidime, and cefoperazone) with the in vitro antibacterial pharmacodynamics of these drugs. The following in vitro pharmacodynamic parameters were determined: the maximum effect as a measure for efficacy, the 50% effective concentration as a parameter for potency, and the slope of the concentration-effect relationship. For analysis of the in vivo antibacterial pharmacodynamics, the same parameters were applied for the dose instead of the concentration. For the detection of a relationship between concentration and antibacterial effect in vivo, we determined the pharmacokinetics of the four cephalosporins in the plasma of mice. The results showed that, in general, there is a direct relationship between the in vivo and in vitro pharmacodynamics of these cephalosporins. The maximum effects of cefepime, ceftazidime, and cefoperazone were approximately similar in vivo and in vitro. The sequence of potency of these drugs was, in descending order, cefepime, ceftazidime, and cefoperazone. Ceftriaxone differed from the other three cephalosporins in that it displayed unexpected in vivo pharmacodynamics. Ceftriaxone was just as efficacious as the other three in vitro, but its maximum effect in vivo was much lower. This relatively low maximum effect of ceftriaxone in vivo was not explained by the pharmacokinetic characteristics of the drug. From the present results it can be concluded that the in vitro efficacy of cephalosporins does not necessarily have a predictive value for the in vivo efficacy.

Animals↗
PubMed1990

Influence of cytostatic treatment on the efficacy of erythromycin and roxithromycin in a staphylococcal infection in mice.

Mice made monocytopenic with etoposide or both granulocytopenic and monocytopenic with cyclophosphamide were infected in a thigh muscle with 3 x 10(6) CFU of Staphylococcus aureus; 1 h later erythromycin or roxithromycin was administered, and 4 h after that the number of CFU per thigh was determined. In vitro as well as in vivo, the maximal effect of both antibiotics was only bacteriostatic. Monocytopenia did not diminish the efficacy of either erythromycin or roxithromycin in vivo, whereas the combination of granulocytopenia and monocytopenia markedly decreased the efficacy of both drugs: a 4-fold dose increase was necessary to obtain the same final number of CFU at the site of infection as in the controls. It is concluded that granulocytes contributed substantially to antibiotic efficacy against S. aureus in this short-term infection model.

Animals↗
PubMed1990

A predictive parameter of antibacterial efficacy in vivo, based on efficacy in vitro and pharmacokinetics.

A method is described to predict the efficacy of antibiotics at changing concentrations in vitro or in an experimental thigh infection in granulocytopenic mice from the activity at constant concentrations in vitro, using pharmacokinetic parameters. The combinations studied were erythromycin against Staphylococcus aureus (in vitro and in vivo), four cephalosporins against two Gram-negative rods (in vivo), netilmicin against Pseudomonas aeruginosa (in vitro) and vancomycin against S. aureus (in vivo). The effect in vitro (ER) was defined as the difference between the growth rate without antibiotic and the growth rate in the presence of an antibiotic. The relationship between concentration and ER was described with the Hill equation. Using pharmacokinetic parameters of exponentially declining concentrations in vitro or of a bi-exponential concentration course in vivo together with the parameters of the Hill equation, the corresponding time course of ER was calculated. By integration with respect to time, an estimate, called ERt, was obtained of the effect on bacterial numbers, called EN, defined as the difference between the number of bacteria in the controls and the number in the presence of the antibiotics. For all antibiotics studied the value of ERt was significantly correlated with the actual values of EN.

Animals↗
PubMed1990

Minocycline treatment for rheumatoid arthritis: an open dose finding study.

Ten patients with active definite or classical rheumatoid arthritis (RA) were treated with oral minocycline (maximal daily dose 400 mg) during 16 weeks in an open study. Seven patients reported side effects (in most cases vestibular) leading to premature discontinuation in one. Half of the efficacy variables improved significantly after 4 weeks of therapy. At the end of the study all variables were significantly changed compared with their pretreatment values. We conclude that minocycline may be beneficial in RA. This effect needs to be confirmed in controlled studies.

Administration, Oral↗
PubMed1989

Decontaminating efficacy of ciprofloxacin in an animal model.

A study was performed to assess the suppressive effect of ciprofloxacin on the aerobic gram-negative flora of the gastrointestinal tract in mice in relation to its effect on colonization resistance. Ciprofloxacin exhibited a potent decontaminating effect, with the maximum effect being reached at a dose of 8 mg/kg/day. At this dose aerobic gram-negative rods were eliminated from the gastrointestinal tract within 24h without any adverse influence on the parameters of colonization resistance measured.

Animals↗
PubMed1989

Effect of etoposide and cyclophosphamide on an experimental pulmonary infection in mice.

The effects of monocytopenia and granulocytopenia on the proliferation of Klebsiella pneumoniae and the efficacy of treatment with ceftriaxone were studied in an experimental lung infection in mice. Treatment with etoposide led to monocytopenia, and cyclophosphamide to granulocytopenia and monocytopenia. Both drugs gave a decrease in the number of alveolar macrophages during the infection and a diminished influx of granulocytes into the alveolar space. The mice treated with etoposide did not differ from controls with respect to either the proliferation of Kl. pneumoniae during the infection or the antibiotic efficacy of ceftriaxone. In cyclophosphamide-treated mice the proliferation rate of Kl. pneumoniae was higher than that in the control mice and a higher dose of ceftriaxone was needed to reduce the number of bacteria to the level in the controls. From these findings it is concluded that granulocytes play an important role in the numerical reduction of Kl. pneumoniae and that monocytes make no contribution to infection control in this model.

Agranulocytosis↗
PubMed1989

Piperacillin for prophylaxis in gynecological surgery.

The effectiveness of perioperative Piperacillin for prevention of operative-site infection after gynaecological surgery was studied in a total of 100 patients. In an open randomized clinical trial of 52 women undergoing abdominal or vaginal hysterectomy Piperacillin was compared to the combination Gentamicin/Metronidazole. Piperacillin was well-tolerated. Surgical-site infection was diagnosed in the Piperacillin group in two patients and in the Gentamicin/Metronidazole group in one patient. The occurrence of postoperative febrile morbidity was also similar between the two group. In 48 patients undergoing complicated gynecological surgery of long duration, only Piperacillin was administered perioperatively. Thirty-five of these 48 women underwent oncological operations and the mean operative length was 3.3 h. One patient developed a transient rash after the administration of Piperacillin. No other adverse side-effects were observed. Nine of these 48 patients developed a surgical-site infection postoperatively, and this was found to be significantly more often than in the first group of 52 patients. It was concluded that Piperacillin seems to be a valuable alternative for perioperative prophylaxis in gynecological surgery. Its effectiveness in vaginal and abdominal hysterectomy is similar to the combination of Gentamicin/Metronidazole, but after complicated surgery of long duration a decreased effectiveness should be reckoned with.

Bacterial Infections↗
PubMed1989

Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models.

Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects of pharmacokinetic profiles. We compared the relative efficacy and potency of three beta-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals. For beta-lactams, Emaxs were similar, whereas P50s increased 10- to 50-fold with longer intervals in both models. Aminoglycosides were significantly more bactericidal in the lung than in the thigh, and dosing interval had little impact on P50s in either model. Recognizing the variable impact of dosing interval on efficacy for different classes of antibiotics is mandatory for the proper design and interpretation of comparative trials.

Animals↗
PubMed1989

Determinants of efficacy and toxicity of aminoglycosides.

The relative efficacy of different aminoglycosides or of different dosage schedules of the same aminoglycoside should be quantitated and related to relative toxicity. Quantitative experimental indicators of efficacy should not only include MIC and MBC, but also the postantibiotic effect in vitro and in vivo, the emergence of resistance in in-vitro and in-vivo models, and the relationship between plasma concentration profiles and efficacy. Parameters of clinical efficacy are to be related to pharmacokinetic parameters such as the ratio between the peak serum concentration and the MIC. Toxicity in clinical trials should be assessed by the most sensitive methods available. Experimental and clinical studies have shown cortical uptake to be a sensitive indicator of renal toxicity. As far as ototoxicity is concerned endolymph and perilymph pharmacokinetics are not clearly related. Clinical ototoxicity should be assessed by sensitive methods, such as high frequency tone audiometry. Finally, risk factors for nephrotoxicity and ototoxicity (e.g., duration of treatment, associated nephrotoxic drugs, dehydration) should be assessed in the evaluation of clinical trials.

Aminoglycosides↗
PubMed1989

The tubular excretion of benzylpenicillin in patients with cystic fibrosis.

1. The tubular excretion of benzylpenicillin (BP) was investigated in six volunteers with cystic fibrosis. 2. The volunteers received a continuous infusion of BP at increasing infusion rates in order to maintain constant plasma concentrations at three different levels. Blood and urine samples were taken every 30 min. Sufficient urinary flow was ensured by a saline infusion (500 ml h-1). 3. The renal clearance of BP was calculated for the non-protein bound fraction of the drug. 4. Tubular clearance and tubular excretion rate were estimated from the renal clearance of the antibiotic minus the glomerular filtration rate; the latter was considered to be equal to creatinine clearance. 5. The data were analysed according to a Scatchard plot and values for ECu50 and maximal tubular excretion rate were calculated. The mean value of ECu50 was 89 +/- 24 (mg l-1 +/- s.d.) and that for the maximal tubular excretion rate was 2603 +/- 714 (mg h-1 +/- s.d.). The latter value was significantly less than that found in a previous study of healthy volunteers, but the ECu50 was similar. 6. It is concluded that the tubular excretory capacity for BP is decreased in patients with cystic fibrosis in direct relation to their low body weight.

Adolescent↗
PubMed1989

Comparison of the efficacies of amphotericin B, fluconazole, and itraconazole against a systemic Candida albicans infection in normal and neutropenic mice.

We compared the efficacies of the new triazole antifungal drugs fluconazole and itraconazole with that of amphotericin B in vitro and in an animal model of systemic candidiasis in normal and neutropenic mice. Antifungal treatment with fluconazole (2.5 to 20 mg/kg orally twice daily), itraconazole (10 to 40 mg/kg orally twice daily), or amphotericin B (0.1 to 4 mg/kg intraperitoneally once daily) was started 1 day after intravenous injection of 10(4) Candida albicans into normal mice or 10(3) C. albicans into neutropenic mice; the drugs were administered for 2 days. In normal mice the efficacy of treatment, which was assessed on the basis of the number of C. albicans cultured from the kidney, was greater for amphotericin B than for the triazoles. Fluconazole was more potent than itraconazole on the basis of equivalent doses, although itraconazole was more potent on the basis of the amount of free drug that was available. In neutropenic mice amphotericin B was less effective than it was in normal mice, whereas the triazoles were equally effective in normal and neutropenic mice. This was not expected, since in vitro data showed that amphotericin B was highly fungicidal, whereas both fluconazole and itraconazole had only a minimal effect on the growth of C. albicans in vitro.

Agranulocytosis↗
PubMed1989

Influence of etoposide and cyclophosphamide on the efficacy of cloxacillin and erythromycin in an experimental staphylococcal infection.

The effect of monocytopenia and granulocytopenia on the outgrowth of Staphylococcus aureus as well as on antibiotic efficacy was studied in an experimental thigh infection in mice. Pretreatment with etoposide reduced monocyte numbers in blood to 14% and those of granulocytes to 54% at the time of infection. Monocytopenia did not affect the proliferation of bacteria in the infected thigh or the reduction of bacterial numbers after treatment with cloxacillin or erythromycin. Pretreatment with cyclophosphamide reduced monocyte numbers to 15% and granulocyte numbers to 3%. This resulted in a marked increase in the number of bacteria at the site of infection and a decrease in the efficacy of antibiotic treatment.

Animals↗
PubMed1989

Comparison of in vivo and in vitro activities of antibiotics with different modes of action against a tolerant and a non-tolerant Staphylococcus aureus strain.

The antibacterial efficacies of 4 antibiotics with different modes of action against a penicillin-tolerant and a non-tolerant strain of Staphylococcus aureus were investigated. For the in vitro studies the minimum inhibitory concentration (MIC) and the minimum bacterial concentration (MBC) were determined and short-term growth experiments at different antibiotic concentrations were performed. For the in vivo studies, antibacterial efficacy in an experimental infection in normal and granulocytopenic mice was evaluated. For erythromycin, rifampicin and ciprofloxacin, there was no difference in the MIC and MBC values for the 2 strains. Benzylpenicillin had an MBC value for the tolerant strains which was 256 times higher than the MIC; with the non-tolerant strain there was no difference. EC50 values, calculated from the in vitro short-term growth curves, gave similar results. Only benzylpenicillin exhibited a difference in activity against the tolerant strain, as reflected by the EC50 that was 290 times the EC50 for the non-tolerant strain. Studies in normal and granulocytopenic mice gave similar results: benzylpenicillin was 268 times less active against the tolerant strain than against the non-tolerant strain. Erythromycin, rifampicin and ciprofloxacin were 2-3 times less active against the tolerant strain than against the non-tolerant strain. The presence of granulocytes is important for the antibacterial effect of all antibiotics studied, since in the absence of granulocytes higher doses of the antibiotics are needed in order to obtain the same antibacterial effect as when granulocytes are present.

Agranulocytosis↗