Antistaphylococcal and antistreptococcal killing kinetics of ciprofloxacin, ofloxacin, sparfloxacin, and trovafloxacin.
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Anti-Infective Agents↗
Biomedical subjects
S Ripa
Publications and source records attributed to S Ripa.
In vitro extracellular and intracellular activity of two newer and two earlier fluoroquinolones against Listeria monocytogenes.
Two new fluoroquinolones (trovafloxacin and sparfloxacin) with enhanced activity against gram-positive pathogens and two earlier compounds (ciprofloxacin and ofloxacin) were tested for their in vitro inhibitory and bactericidal activity against 80 strains of Listeria monocytogenes. All strains were uniformly highly susceptible to trovafloxacin, the MIC90 being 0.25 mg/l. Resistance to sparfloxacin was not detected, however the MIC90 of sparfloxacin was eight times that of trovafloxacin. A few strains were resistant to ciprofloxacin and ofloxacin (MIC90 4 mg/l for both drugs). MBCs usually exceeded MICs by 2 to 4 times. The MBC90 of trovafloxacin (1 mg/l) was lower than that of the other three drugs (8 mg/l). After checking their ability to enter and grow within human enterocyte-like Caco-2 cells, four strains were used to study the intracellular activity and eradicating power of the four quinolones. Trovafloxacin was more active than sparfloxacin and the earlier fluoroquinolones in terms of both intracellular killing and inhibition of a cytopathogenic effect. The uniform high-level activity of trovafloxacin against Listeria monocytogenes isolates in conventional in vitro assays and its extracellular and intracellular killing of invasive strains suggest that this and maybe other new fluoroquinolones should be further investigated as possible anti-listerial agents.
Anti-Infective Agents↗
Purpuromycin: an antibiotic inhibiting tRNA aminoacylation.
Purpuromycin, an antibiotic produced by Actinoplanes ianthinogenes, had been reported previously to inhibit protein synthesis. In the present report, we demonstrate that the mechanism of action of this antibiotic is quite novel in that it binds with fairly high affinity to all tRNAs, inhibiting their acceptor capacity. Although more than one molecule of purpuromycin is bound to each tRNA molecule, the inhibitory activity of this antibiotic was found to be selective for the tRNA acceptor function; in fact, after the aminoacylation step, purpuromycin was found to affect none of the other tested functions of tRNA (interaction with the ribosomal P- and A-sites and interaction with translation factors). Accordingly, purpuromycin was found to inhibit protein synthesis only when translation depended on the aminoacylation of tRNA and not when the system was supplemented with pre-formed aminoacyl-tRNAs. Because purpuromycin did not interfere with the ATP-PPi exchange reaction of the synthetase or with the initial interaction of the enzyme with its tRNA substrate, the basis for the inhibition of aminoacylation is presumably the formation of a nonproductive synthetase-tRNA complex in the presence of purpuromycin in which the tRNA is unable to be charged with the corresponding amino acid.
Anti-Bacterial Agents↗
[Italian clinical cardiology research at the international level. Statistical data from the period 1983-1993].
Recent studies show that, among advanced countries, the rank of cardiological research finds Italy last for number of scientific publications and for gross expenditure on research and development. To assess more thoroughly the characteristics of Italian clinical cardiological research we examined, over the period 1983-1993, all original articles published by five important international cardiology journals (Circulation, American Heart Journal, American Journal of Cardiology, Journal of the American College of Cardiology and European Heart Journal). During the mentioned period the Italian contribution (743 articles over a total of 16375, mean prevalence of 4.5%) has increased from 3% in 1983-1985 to 5.8% in 1991-1993 (p < 0.0001). Taking into account that research often results from the joint-work of different centers, the 743 articles derived from 1056 contributions from just over 120 centers. Of these contributions 57% were from universities, 23% from hospitals, 19% from research institutes, and 1% from private foundations. The cooperation with foreign countries has steadily increased, particularly with the USA (45%) and with the European nations (42%). Within the first three names, the contribution of female Authors has increased from 7% in 1983-1985 to 16% in 1991-1993 (p = 0.0001). The mean prevalence of female Authors as last name was 4% and did not change with time. As to geographic distribution, 57% of the scientific publications comes from the North, 28% from the Centre, and 15% from the South. After adjusting these data for population size, the percentages were respectively 40, 46, and 14%. An index of productivity (the ratio between the number of scientific contributions from universities and research institutes and their funding) was highest in the North. The Italian scientific contribution to international cardiological research is not satisfactory, although it is significantly increasing; yet, this trend might worsen due to the shortage of funding. The collected data outline that in the three main national geographic areas, the distribution of funds and scientific productivity are markedly unbalanced.
Cardiology↗
[Cardiac pacemaker and radiotherapy: a growing association. Report of a clinical case].
Cardiac pacing is increasingly common. In 1986, in the USA there were more than 500,000 pacemaker-implanted patients and at least 100,000 new pacemaker implants were performed, for a total of 3,000 pacemakers for million inhabitants. The increment in cardiac pacing is due to: a fall in cardiovascular mortality; increased elderly population, in which bradyarrhythmias are frequent; and the introduction of implantable cardioverter defibrillators (ICD). In 1992, in Italy, there were 30,500 deaths due to lung tumours and 10,900 deaths for breast malignancies. Both malignancies are more common in patients older than 65. Lung and breast cancer therapy involves the use of surgery, radiation, or chemotherapy, and often a combination of two or all three. In particular 40% of cancers are managed with radiotherapy. It is therefore likely that cancer patients may require radiotherapy at sites (lung, breast) where a pacemaker is implanted. The authors describe the finding on a chest radiogram of a one centimeter nodular mass at the right superior lobe almost completely hidden by the pacemaker. The modalities to proceed to radiotherapy, without damaging the sensitive pacemaker, are discussed.
Aged↗
Antianginal and antiischemic efficacy of monotherapy extended-release nisoldipine (Coat Core) in chronic stable angina.
A double-blind, randomized, placebo-controlled study was conducted to test the peak and trough antianginal and antiischemic monotherapy efficacy and safety of a new extended-release formulation of nisoldipine (nisoldipine Coat Core [Bayer Corporation], 20 mg, 40 mg, and 60 mg once daily compared to placebo). Study patients had a history of chronic, stable angina pectoris, exercise-induced angina in association with ST segment depression, and exercise test reproducibility. Of the 483 patients enrolled in the study, results were valid for safety analysis for 312 and for efficacy analysis for 284. There was a statistically significant improvement in total exercise time at both peak and trough for patients taking 20 mg and 60 mg of nisoldipine compared with patients taking placebo, but the group taking 60 mg was not better than the group taking 20 mg (33.9 and 33.7 seconds, respectively, at trough). The results were similar for the secondary endpoints (time to onset of angina and time to 1 mm ST segment depression). No correlation was evident between plasma nisoldipine levels and total exercise duration. Headache and peripheral edema were the most frequently reported adverse events and were dose related. There were no discontinuations due to adverse events in patients randomized to the 20-mg nisoldipine group. No deaths occurred while patients were receiving active nisoldipine therapy. Therapy with this extended-release formulation of nisoldipine is an effective once-daily treatment for chronic stable angina pectoris. It represents one of the few dihydropyridine calcium channel antagonists that has shown efficacy when administered as monotherapy to patients with angina.
Adult↗
Zinc and the elderly.
It is frequent in the elderly a zinc deficit, for many causes, which frequently occur in old age. Mineral deficit cause humoral and cellular immunity depression, with large increase of susceptibility to infections and increase of morbidity and mortality; besides it increases the proteinic malnutrition so frequent in old people. This condition is particularly presented in surgical patients and in patients undergoing total parenteral nutrition, when not specifically zinc supplemented. The evaluation of plasmatic zinc for diagnostic aims is scarcely significant, because hypoproteinemia (above all, hypoalbuminemia) is constantly present in old people: more useful and important is the leucocytic mineral evaluation, particularly in polymorphonuclear neutrophils. The average of recommended daily allowance of zinc is 15 mg for elderly people.
Aged↗
[Zinc and diabetes mellitus].
In patients with type 1 and 2 diabetes was frequently found: low blood zinc levels, high zincuria, severe and ubiquitous cellular depletion of zinc, increased basal and after loading blood mineral clearance, and hyperglycaemia due to the reduction of pancreatic insulin secretion and to the reduced biological action of the hormone on liver, as a consequence of chronic zinc deficit. Strong endocellular zinc depletion in diabetics; low insulin secretion; insulin biological action decrease for zinc deficit; IG-I concentration decrease, that happens in this condition; insulin and IGF-I resistance; insulin and IGF-I receptors depletion in diabetics: are strong arguments for zinc pharmacological supplementation, in gastric protective formulation, to avoid gastroenteric problems.
Diabetes Mellitus, Type 1↗
[Zinc and atherosclerosis].
The relationship between zinc and atherosclerosis is reviewed. Administration of strong doses of the mineral can turn out atherogenic through three mechanisms: 1. Through the alterations of the lipidic arrangement: decrease of HDL, increase of total cholesterol and LDL cholesterol (action promoted by the induced hypocupremia). 2. Through the alterations of the vasal wall, in consequence of the biochemical modifications of the basic substance (again, through secondary hypocupremia). 3. Through the increased platelet aggregation which seems to be produced by strong doses of zinc. In addition to these harmful actions, the antioxidative action, typical of zinc, must be stressed, which prevents oxidation of LDL and consequently stops the main mechanism of atherogenesis. Besides, the mineral restricts and nullifies the loss of metallothionein in zinc, produced by free radicals and subsequent functional alterations. Moreover, the calcium antagonist action of zinc must be considered: it blocks calcium and its several favorable actions on atherogenesis. In consideration of these last aspects, the rule of zinc, in suitable doses, could be considered as basic in the context of a strategy of prophylaxis and therapy of the atherosclerosis process.
Adult↗
[Zinc and arterial pressure].
There are complex relations between zinc and arterial pressure. The mineral, which enters in the composition of zinc-enzyme "angiotensin-converting-enzyme" (ACE), takes part in arterial pressure regulation also through influences on others hormonal systems, which carry on many complex actions on circulation (glucocorticoids, catecholamines). It is frequent to find in hypertensive subjects low levels of plasmatic zinc (and high of cadmium): in "essential" hypertensive patients, particularly, it would be present a primary genetic defect leading, through transmembrane desregulation of ionic pumps, to high intracellular zinc and, secondarily, to high intracellular calcium. On the other hand, the same hypertensive process causes zinc and copper metabolism modifications, with an increase in zinc tissue concentration (opposite behaviour of copper). Moreover the plasmatic zinc reduction causes a proportional decrease of plasmatic and tissue ACE activity and arterial hypotension: zinc administration, in vitro and in vivo, clearly increases ACE action, with normalization of altered parameters due to zinc deficit.
Blood Pressure↗
Survey of clinical isolates of Staphylococcus aureus for borderline susceptibility to antistaphylococcal penicillins.
On the basis of the MICs of methicillin and oxacillin, 975 clinical isolates of Staphylococcus aureus were categorized as having resistance, borderline susceptibility or full susceptibility to penicillinase-resistant penicillins (PRPs). The borderline phenotype accounted for 122 isolates (12.5%), whereas 562 isolates were fully susceptible and 290 resistant; one remaining isolate had resistance to methicillin and borderline susceptibility to oxacillin. Reductions in the MICs of methicillin and oxacillin in the presence of sulbactam were greater in strains with borderline PRP susceptibility than in fully susceptible or resistant isolates. Over 99% of fully PRP-susceptible strains, 93% with borderline susceptibility and 71% of resistant strains were susceptible to ampicillin/sulbactam. The production of beta-lactamase, assayed in all strains using nitrocefin as substrate, could be detected without prior induction in 729 strains and after induction only in another 156 strains. With only two exceptions, the beta-lactamase negative strains were part of the fully PRP-susceptible group of organisms (88 of 562 isolates). Among the borderline isolates, strong beta-lactamase reactions were encountered with particular frequency, but not in all strains and not exclusively in borderline strains. Although associated with the majority of borderline strains, beta-lactamase hyperproduction thus did not appear to be an essential feature of the borderline phenotype. The results obtained may have implications for laboratory and clinical medicine, also in the light of recent findings suggesting that other mechanisms besides beta-lactamase hyperproduction may account for borderline susceptibility to PRPs.
Ampicillin↗
Pharmacokinetics of fluconazole in normal volunteers.
The pharmacokinetic profile of fluconazole, after 100 mg i.v. infusion or oral administration of a single 50 mg or 150 mg dose, was investigated in 18 healthy volunteers. At a dose of 100 mg i.v., the half-life (t1/2 beta) was 29.73 +/- 8.05h. The mean residence time in the plasma was 27.56 +/- 5.98 h. The post-distributive volume V beta = 52.16 +/- 9.83 l, approximating that of total body water. Renal excretion accounted for 61.64 +/- 8.80% of the drug elimination after 48 h, with renal clearance Clr = 12.91 +/- 2.83 ml/min. Plasma clearance (Clp) was 21.03 +/- 5.07 ml/min. At oral doses of 50 and 150 mg the distribution and elimination of fluconazole resembled that following i.v. infusion. The peak levels in plasma at 2.5 h were 0.93 +/- 0.13 and 2.69 +/- 0.43 micrograms/ml, respectively. The large distribution volume, the long half-life and mean residence times, combined with a rapid absorption after oral administration, suggest that fluconazole will be effective at a wide range of body sites.
Administration, Oral↗
Bacteriolytic effect of teicoplanin.
The glycopeptide antibiotic teicoplanin belongs to the same group as vancomycin and ristocetin and is a valuable tool for studying the autolytic system of sensitive Gram-positive bacteria. Teicoplanin, at a concentration of 1 microgram ml-1, caused rapid lysis of exponential phase cells of Streptococcus faecalis. Bacillus spp. were most sensitive to the antibiotic; effective lysis occurred at 0.1 microgram teicoplanin ml-1. The bacteriolytic effect depended on the antibiotic concentration, the growth phase and growth rate of the target organism. Antibiotic added to overnight cultures did not cause lysis. Mg2+ (50 mM) was unable to prevent lysis. Mutants with decreased autolytic activity were more resistant to teicoplanin and lysed more slowly than the wild-type. Growth of bacteria in slightly acidic medium protected the cells against the lytic effect of teicoplanin typically observed at pH 7 or 8. This pH-dependent antibiotic tolerance was demonstrated with both bacilli and streptococci. Bacterial lysis was prevented by the presence of Ac-L-Lys(Ac)-D-Ala-D-Ala and normal growth was observed when this peptide was added simultaneously with teicoplanin. Bacteria pretreated with teicoplanin, washed and transferred to fresh medium or buffers behaved as if the antibiotic was still present; in neutral or slightly alkaline conditions strong lysis occurred, whereas in acidic buffer only bacteriostasis was observed. In contrast to vancomycin, teicoplanin induced some lysis of bacteria in hypertonic media, presumably by affecting the integrity of the cell membrane.
Amino Acid Sequence↗
In vitro activity of sulbactam/ampicillin against ampicillin-resistant, beta-lactamase-producing bacteria isolated in Italian hospitals.
A multicenter study aimed at assessing the in vitro activity of sulbactam/ampicillin against a wide range of bacterial pathogens was performed using 2,209 clinical strains, all recently collected from inpatients in seven Italian centers and preliminarily screened as being ampicillin-resistant and beta-lactamase producers. In comparative disk diffusion trials using 8 large-spectrum antimicrobials, the percentage of resistance to sulbactam/ampicillin in staphylococci was similar to the percentage of resistance to netilmicin and lower than to the other antibiotics; with gram-negative bacteria, only netilmicin, ofloxacin, and, less consistently, cefotetan showed lower incidences of resistance. The minimal inhibitory concentrations (MICs) of ampicillin alone and sulbactam/ampicillin together were determined using the agar dilution method. The Enterobacteriaceae strains which shifted to ampicillin susceptibility in the presence of sulbactam averaged 68%, but values significantly above or below average were observed in some genera of this family. The percentage of strains which the presence of sulbactam rendered ampicillin-susceptible in vitro reached 97% in Haemophilus strains and 100% in branhamellae and gonococci. High percentages were also recorded in staphylococci, with a peak of 100% in oxacillin-susceptible Staphylococcus aureus strains. In general, center-to-center differences were relatively limited.
Ampicillin↗
Pharmacokinetics of sulbactam/ampicillin in humans after intravenous and intramuscular injection.
We investigated the pharmacokinetic properties of sulbactam/ampicillin (S/A), after intravenous (0.5/1.0 and 1.0/2.0 g) and intramuscular (0.5/1.0 g) coadministration in 10 male subjects. After 1.0/2.0 g intravenous doses of S/A the half-lives (t1/2 beta) were 1.14 +/- 0.14/1.09 +/- 0.16 h. The values for plasma clearance (CLp) were 198.83 +/- 26.27/250.33 +/- 39.28 ml/min and the renal clearance (Clr) 173.50 +/- 19.66/208.80 +/- 26.43 ml/min. The post distributive volumes (V beta) were 19.67 +/- 3.24/23.56 +/- 5.76 liters. Similar values were obtained after 0.5/1.0 g of S/A intravenous coinjection. After 0.5/1.0 g intramuscular coadministration the t1/2 beta values were 1.26 +/- 0.18/1.20 +/- 0.15 h. The values for Clp were 208.00 +/- 28.73/243.17 +/- 33.24 ml/min, for Clr 179.50 +/- 20.26/202.67 +/- 27.61 ml/min and for V beta 22.27 +/- 4.12/25.30 +/- 4.87 liters. The renal clearance of sulbactam is comparable to that of ampicillin and both clearances are greater than the glomerular filtration rate, suggesting active renal tubular secretion of the two drugs. The large volumes of distribution, and the ratio K12/K21 = 0.5 show the extensive distribution of the two drugs into extracellular fluids. The very similar values of the pharmacokinetic parameters of sulbactam and ampicillin confirm that the kinetics of the two drugs closely resemble one another.
Adult↗
Pharmacokinetics of bacampicillin using a compartment model with zero-order absorption.
The pharmacokinetics of bacampicillin, a prodrug of ampicillin which is absorbed from the gastrointestinal tract, were studied in 10 healthy male volunteers after administration of 1,200 mg in a single oral dose. The pharmacokinetic analysis was carried out by applying a single-compartment kinetic model with zero-order absorption. The apparent duration of absorption (T) was about 1 h for all subjects. The peak plasma concentrations (Cmax) were 17.89 +/- 1.82 micrograms/ml, and the mean plasma half-life during beta-phase was 1.17 +/- 0.14 h. The area under the curve was 41.22 +/- 5.29 micrograms.h/ml. The mean urinary recovery during 24 h amounted to 76.4 +/- 3.65% of the dose.
Adult↗
Pharmacokinetics of teicoplanin.
We investigated the pharmacokinetic properties of teicoplanin, after 200 mg i.v. and i.m. administration in 10 healthy male subjects by assuming a three-compartment open model with elimination from the central compartment. The mean peak plasma level was 7.16 micrograms/ml reached after 2.26 h. The half-life, the plasma and renal clearances, evaluated from i.v. data were 44.49 h, 15.31 and 9.08 ml/min, respectively. The same parameters after i.m. administration were 45.62 h, 15.31 and 9.46 ml/min. The estimates of creatinine clearance (Clcr greater than 80 ml/min), renal clearance and the low free fraction (fB approximately equal to 0.1) suggested a tubular reabsorption, FR, of the drug. The distribution volume at steady state after i.v. and i.m. administration (Vss = 41.29 and 44.76 litres) were nearly total body water. Bioavailability of the drug (F = 92.4%) showed an almost completely absorption of teicoplanin after i.m. administration. Urinary recovery was 49.6 and 47.9% of the dose after i.v. and i.m. administration, respectively.
Adult↗
Comparative activity in different media of ketoconazole, miconazole and amphotericin B against Candida lusitaniae and sucrose-negative Candida tropicalis.
This study evaluates the susceptibility of sucrose-negative Candida tropicalis and Candida lusitaniae strains to amphotericin B (AMB), miconazole (MCZ) and ketoconazole (KTZ). The susceptibility tests were carried out in different media: Antibiotic Medium 3 (AM-3m) and Earle Minimum Essential Medium (E-MEM) for AMB: Yeast Nitrogen Base (YNB) and E-MEM for imidazole compounds. The minimal fungicidal concentrations (MFCs) of AMB were slightly higher than minimal inhibitory concentration (MICs) except against Candida lusitaniae strains; whereas the MFCs of MCZ and KTZ were higher than the MICs by almost two-fold for all strains tested. AMB was more efficacious against sucrose-negative Candida tropicalis and the MICs were very definite; on the contrary, the MICs with KTZ were difficult to read. The MICs of AMB in E-MEM were essentially the same as those in AM-3m; whereas for KTZ and MCZ determined in YNB the MICs were generally higher than those obtained in E-MEM.
Amphotericin B↗