Showing papers in "Chemotherapy in 1977"

Pharmacokinetics of Fosfomycin

Abstract: Fosfomycin, an antibiotic discovered in Spain, has a unique chemical structure and pharmacologic features that are promising for clinical therapy. It is only partially absorbed orally, with relatively low blood levels. Intramuscularly, however, absorption is complete with peak blood levels 3-5 times as high as orally, and rapid intravenous injections give serum concentrations almost twice as high as intramuscularly. Some accumulation occurs with all three routes, and concentrations in excess of 1,000 mug/ml are consistently obtained in the urine with parenteral doses every 6 h. The serum half-life is 1.5-2 h, urinary excretion is by glomerular filtration, the antibiotic is not bound to serum proteins, and the volume of distribution is large. Diffusion into tissues and body fluids is good. Thus, the pharmacologic characteristics of fosfomycin along with its low toxicity make it comparable in these respects to other well-established antibiotics.

Fosfomycin: Laboratory studies.

Abstract: Fosfomycin, a nontoxic broad-spectrum antibiotic, different in structure from all previously described antibiotics, acts selectively by inhibiting cell wall formation. It was overlooked during many years of screening because of antagonism by culture medium ingredients and frequent occurrence of resistant mutants. It is effective in many because the neutralizing substances are not present and resistant mutants of most species are avirulent. Fosfomycin has favorable pharmacologic characteristics. It is not cross resistant, does not show antagonism, and has been used successfully in combinations. An insoluble calcium salt is used in oral formulation and a sodium salt for parenteral administration. Overall success rates of 86% were reported with 1,000 patients in Spain and 79% in Japan.

Pharmacokinetics of ampicillin, cephalothin and doxycycline in various tissues of the rat

Abstract: To study the behavior of antibiotics in the tissues, rats were sacrificed repeatedly in groups of six, after the injection of 25 mg/kg ampicillin, 100 mg/kg cephalothin or 10 mg/kg doxycycline. These

Concentrations of tinidazole in body fluids and tissues in gynaecological patients.

Abstract: The concentrations of tinidazole in various tissues and body fluids were studied in gynaecological patients after a single 2g oral dose. Tinidazole was determined by the agar-diffusion technique using a strain of Clostridium bifermentans. Reliable estimates of concentrations down to 0.5 microng/ml could be obtained. Dichloromethane extraction of tinidazole added to various tissues in known amounts gave a recovery of 100 +/- 10%. Peak serum values of 32-52 microng/ml were reached 3-6h after the administration. The concentrations in peritoneal fluid, obtained at operation 8.5-15h after the intake, varied between 16 and 40 microng/ml. Specimens from the Fallopian tubes yielded 15-26 microng tinidazole/g tissue; similar levels were obtained specimens from myometrium, endometrium, portio, vaginal secretions, omental fat, and cutis. It is concluded that, with the given dose, tinidazole concentrations are achieved in fluids and tissues of the female genital tract that are far in excess of those that should be therapeutical in infections caused by microorganisms know to respond to nitroimidazole treatment.

Bacteriological evaluation of fosfomycin in clinical studies.

Abstract: Since fosfomycin has behaved in vitro as a broad-spectrum antibiotic, an attempt has been made to evaluate this behaviour in controlled clinical study carried out at different Spani

Pharmacokinetic Study of Intravenous Rifampicin

Abstract: The time course of the serum and urine concentrations of rifampicin were evaluated during and after administration of an intravenous preparation of the antibiotic. 300, 450 and 600 mg dose levels of the antibiotic were evaluated, all being given as intravenous infusion after solution in 500 ml of glucose, the infusion lasting 3 h. The results have shown that the serum level curves and the kinetic parameters calculated on them do not differ to any major extent from those corresponding to the same doses given orally. No changes of relevance in the half-life values were observed between doses. Changes in serum bilirubin levels were observed with a pattern similar to that commonly seen with oral administration of rifampicin.

Fosfomycin, antimicrobial activity in vitro and in vivo.

Abstract: Antibacterial activities of fosfomycin were investigated both in vitro and in vivo for the purpose of comparative evaluation on its fundamental properties with other antimicrobial agents. The MIC was determined with nutrient agar (Dif-co) inoculated with one loopful of 1,000-fold dilution (about 106 cells/ml) of bacterial suspension cultured overnight in nutrient broth. This substance showed antibacterial activity to most gram-positive and gram-negative bacteria, being strongest to Enterobacteriaceae with a peak of the MIC at 1.56 μg/ml in Salmonella. It was also active against P. aeruginosa with a peak of the MIC at 6.25 μg/ml in its sensitivity distribution. Intravenous and subcutaneous fosfomycin Na salt and oral fosfomycin Ca salt were given to 5-week-old ddN strain male mice challenged with clinical isolates of P. aeruginosa, E. coli and P. mirabilis. Therapeutic effect was observed in all these test organisms. In P. aeruginosa, it was more effective than car-benicillin.

Bactericidal Activity of Tinidazole

Abstract: The new antiprotozoal agent, tinidazole, was found to be bactericidal against all 52 isolates of obligate anaerobic bacteria tested, 42 Bacteroides fragilis, 4 clostridia and 6 pept

Comparative pharmacokinetics of cefazolin, cephalothin, cephacetril, and cephapirine after intravenous administration.

Abstract: The pharmacokinetics of cephazolin given in intravenous dosages of 0.5 and 1.0 g and cephapirine, cephacetril and cephalothin in 1.0 g doses have been compared. The cefazolin appears to have favourable pharmacokinetic properties.

The Influence of 5-FIuorocytosine on Nucleic Acid Synthesis in Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus

Abstract: 5-Fluorocytosine (5-FC) has a rapid inhibitory effect on the synthesis of RNA and DNA in the yeast and hyphal form of Candida albicans . 5-FC has a less marked effect on the

Treatment of Chronic Salmonella Carriers

Abstract: The present stage of our studies suggests that, provided a highly effective combined therapy is, and can be, carried out correctly, all excreters can be cured of their chronic carrier state by chemoth

Pharmacokinetic Study of Fosfomycin and its Bioavailability

Abstract: The pharmacokinetics of fosfomycin in humans was studied in six young healthy volunteers after intravenous administration of 500 mg fosfomycin and after the same dose in oral administration in three different formulations. It was proven that fosfomycin follows a bicompartmental pattern, for which the disposition constants, the biological half-lives for the fast and slow phases, and the distribution constants were calculated. The renal excretion constant was evaluated making determinations of fosfomycin in the urine, and this constant together with the elimination constant allowed us to determine the extrarenal elimination. The concentration and quantity of the drug in the central and peripheral compartments were calculated and tabulated for different periods of time. An analogous behavior was obtained with the three formulations that were orally administered, with an average bioavailability of 37% in relation to the intravenous bioavailability, as evaluated by means of the accumulative renal excretion.

Amoxycillin and Co-Trimoxazole in Acute Purulent Exacerbations of Chronic Bronchitis

Abstract: 100 hospital patients suffered from acute exacerbations of chronic bronchitis. 50 were treated with amoxycillin in a dose of 500 mg, three times a day for 10 days and the results compared with 50 patients treated with co-trimoxazole in a dose up to 480 mg trimethoprim and 2,400 mg of sulphamethoxazole daily in males, and two thirds of this dose in females. The trial was single-blind. During the acute phase of infection, both treatments were equally effective in clinical improvement, conversion of the sputum from purulent to mucoid, diminution of quantity and elimination of pathogenic bacteria. Amoxycillin was quicker in sputum conversion and gave less side effects, but the differences were not significant. During the 2-4 weeks following treatment, only a third of the patients who had received co-trimoxazole remained well and free from purulent relapse, as opposed to 72% who had received amoxycillin, a difference significant at the 2% level.

Susceptibility to fosfomycin of hospital strains isolated in Nantes (France). Frequency of mutation to resistance.

Abstract: Susceptibility of 760 bacterial isolates to fosfomycin has been determined by the agar dilution method. The MICs of 364 strains have been determined by comparison of agar alone and agar plus glucose-6-phosphate. This later enhances the activity of fosfomycin. Lastly, we studied frequency of mutation toward resistance for 109 susceptible strains. We obtained 88 stable mutants.

Fosfomycin: Absorption and excretion.

Abstract: Summarized results of absorption and excretion of fosfomycin after oral and intravenous administration obtained from hospitals and institutions in Japan are reported. Fosfomycin was rapidly absorbed and excreted from the urine once it was distributed, the 6-hour urinary recovery reaching about 20% in the case of oral administration and 90% in the case of intravenous injection. These phenomena are almost the same as those previously published. Higher concentration was noticed in the kidney, which gradually decreased according to the fall of the blood level. The blood level reached its maximum of about 3 mug/ml after oral administration to adults at a dose of 500 mg.

Comparative studies on the evaluation of the effect of new anthelminthics on various intestinal helminthiasis in Iran. Effects of anthelminthics on intestinal helminthiasis

Abstract: The effect of pyrantel pamoate, levamisole, mebendazole, thiabendazole and bephenium hydroxynaphthoate on various intestinal helminths were evaluated among the inhabitants of four villages in the Dezful area southwest of Iran. A total number of 328 persons, all infected simultaneously with Ascaris and hookworm (Ancylostoma duodenale) and 49.2% with Trichostrongylus spp., were randomly divided into six groups. One group was kept as the control and the other five were each treated with one compound. Follow-up examinations showed that all of the drugs used were highly effective on Ascaris, and the differences in the cure rate were not statistically significant except for bephenium hydroxynaphthoate which showed a lower cure rate. For hookworm, cure rates of 100, 90, and 85% were observed with levamisole, pyrantel pamoate and bephenium hydroxynaphthoate, respectively. Cure rates observed with mebendazole and thiabendazole were 35 and 51%, respectively. For Trichostrongylus, the highest cure rate was achieved with levamisole, followed by thiabendazole and mebendazole. While the percentage of people showing side-effects was rather low for all drugs, thiabendazole and bephenium hydroxynaphthoate produced a higher, and levamisole a lower, percentage of side effects.

Selected and spontaneous variants of Serratia marcescens with combined resistance against chloramphenicol, nalidixic acid, and trimethoprim.

Abstract: Combined resistance against chloramphenicol (CHLOR), nalidixic acid (NA), and trimethoprim (TMP) was demonstrated in isolates and variants of a nosocomially significant, multiple-drug-resistant, nonconjugative strain of Serratia marcescens (bacteriocin type 18), either as a spontaneous event or after exposure of isolates and variants derived therefrom to increasing concentrations of CHLOR, NA, and TMP, respectively. This phenomenon was also noted among several selected mutants of two control strains of S. marcescens. The level of resistance was not absolute; the combined resistant mutants and variants were inhibited by 100–200 μg/ ml of CHLOR, 25–50 μg/ml of NA, and 12.5–25 μg/ml of TMP. However, the phenomenon of combined triple-resistance occurred irregularly with respect to the strain or variant of S. marcescens employed, and with regard to the selective drug utilized. Selection of mutants with CHLOR yielded a larger number of combined CHLOR-NA-TMP resistant mutants than selection with NA or TMP. Preliminary data obtained with spontaneously ‘cured’ variants of the multiple-drug-resistant strain of S. marcescens that had lost resistance against CHLOR, NA, TMP, penicillins, and aminoglycoside antibiotics, and which subsequently were shown to yield spontaneous mutants with combined triple-resistance against CHLOR, NA, and TMP, seem to indicate that this resistance phenomenon is not mediated extra-chromosomally, but rather chromosomally, and subject to phenotypic variation. The precise nature of this novel, unusual resistance mechanism against these three unrelated antimicrobial drugs remains to be elucidated.

Leprosy Eradication Project of Malta

Abstract: This is the first publication of the initial 5-year-period of the eradication programme since its introduction in the Maltese Islands in the second half of 1972. All patients were treated with a combi

Antiviral Activity of N-Phenyl-N′-arylthiourea Derivatives against some Rhinoviruses

Abstract: The effect of 12 derivatives of N-phenyl-N′-aryl- or alkylthiourea, inhibitors of human enteroviruses and foot-and-mouth disease virus, on reproduction of some rhinoviruses (H-17, B-632) in HeLa Brist

Homocysteine Compounds which Influence the Growth of a Malignant Neoplasm

Abstract: Since homocysteine metabolism is important in the control of normal and abnormal growth, three homocysteine derivatives were synthesized and tested for effects on the growth of transplanted murine adenocarcinoma. Arachidonoyl homocysteine thiolactone (HCT) amide decreased growth, and oleoyl HCT amide increased growth of the neoplasm. Pyridoxal HCT enamine decreased the growth of the neoplasm when given for 2 weeks prior to transplantation, but the compound had no effect when given after transplantation. The two inhibitory substances were tolerated well by normal mice except in high doses. These findings suggest an approach to prevention and therapy of human malignancy which utilizes homocysteine derivatives of normal biochemical constituents.

Combined Action of Fosfomycin with β-Lactam and Aminoglycoside Antibiotics

Abstract: The combined action of fosfomycin with penicillin G, ampicillin and streptomycin was investigated. A total of 11 S. aureus and 10 E. coli were included in these studies. It has been shown that a combination of fosfomycin with penicillin G and streptomycin resulted in a synergistic effect. When S. aureus strains were tested, the combination of fosfomycin with penicillin G was more frequently effective than the combination of fosfomycin with streptomycin. The combination of fosfomycin with ampicillin and streptomycin showed a similar synergistic effect on 7 of 10 E. coli strains. The antagonistic effect never resulted when the above-mentioned combination of antibiotics were used. The authors postulate that a combination of fosfomycin with β-lactam or aminoglycoside antibiotics may be used in clinical practice and such a procedure should prevent an emergence of fosfomycin-resistant strains.

A study of the levels of fosfomycin in the cerebrospinal fluid in adult meningitis.

Abstract: In order to determine the liquor concentration of fosfomycin, we chose 27 patients who were suffering from meningitis with different etiology. According to route, type of administration and doses employed, we classified the patients into five groups. Blood samples were taken from the patients 1 h after concluding the administration of the antibiotic and 2 h after the CSF sample. The concentration of fosfomycin in the serum and the CSF were then determined in the laboratory. In order to evaluate the results we divided our cases into three groups according to the state of their meningeal inflammation. In the first group of patients with active meningitis, we obtained an average concentration of fosfomycin in the serum of 65.20 mug/ml and in the CSF of 10.88 mug/ml. In the second group of patients with meningitis in the remission stage, the concentration of fosfomycin in the serum was 83.58 mug/ml and in the CSF it was 9.63 mug/ml. In the third group of patients with their meningitis cured, the concentration of fosfomycin in the serum was 66.45 mug/ml and in the CSF it was 4.95 mug/ml. On the basis of the concentrations obtained and with regard to the sensitivity in vitro, we concluded that fosfomycin can be useful in the treatment of meningitis caused by Pneumococcus, Staphylococcus, E. coli and other gram-negative bacilli.

Antibiotherapy of Serratia marcescens Septicemia in Children

Abstract: The clinical and bacteriological response of 38 treatments performed on 24 children (11 of them neonates) carrying out separate treatments with carbenicillin (2 treatments), gentamicin [4], fosfomycin [6], and associated treatments with gentamicin plus carbenicillin [6], fosfomycin plus gentamicin [18] and fosfomycin plus carbenicillin [2] are considered. The clinical cure was obtained in 21 children (87.5%). The most effective treatment was fosfomycin plus gentamicin; both antibiotics showed synergism in vitro on isolated Serratia strains. A dosage of 75 mg/kg fosfomycin enables serum levels of about 32 mug/ml during 4-5 h, being this level higher to the MIC of all isolated strains of S. marcescens.

The activity of four antimicrobial agents. Including three nitroimidazole compounds, against Bacteroides sp.

Abstract: Forty strains of Bacteroides sp. were tested against three nitroimidazole compounds, metronidazole, tinidazole and nimorazole and the aminoglycosidic antibiotic spectinomycin. The effect of altering the inoculum and the presence of serum upon the minimum inhibitory concentration (MIC) was also noted. The three nitroimidazole compounds were all very active (average MIC = circa 0.25 mg/l. Tinidazole was twofold more active. The MIC of spectinomycin was 32 mg/l

Long-term treatment with sulphamethoxazole/trimethoprim (Bactrim) and nitrofurantoin in chronic urinary tract infections. A controlled clinical trial.

Abstract: In a controlled clinical trial based on 30 geriatric patients with recurrent urinary tract infection, 12 out of 17 patients fulfilled a 12-month treatment with sulphamethoxazole/trimethoprim (Bactrim®

Interactions of fosfomycin with other antibiotics.

Abstract: We selected 100 strains of organisms that were isolated in our hospital, which came from pathological products and which had an MIC of fosfomycin of 256 mug/ml or more and belonged to the genera Klebsiella, Pseudomonas, Escherichia coli, Serratia, Enterobacter, Proteus, Acinetobacter, Levinea and Staphylococcus. We have studied the effect of the association of fosfomycin with 15 antibiotics (beta-lactamins, cephalosporins, aminoglycosides, etc.) and 5 chemotherapeutics. The 11 selected strains were studied by the 'chess board' technique in agar. A study was also carried out on the action of fosfomycin on E. coli K12 E711 in the phase of logarithmic growth. The 11 selected strains were studied by the 'chess board' technique in agar. Synergic effect with fosfomycin associated to other antimicrobials was found in 9 strains.

Elimination of Para-Aminosalicylic Acid in Patients with Liver Disease and Renal Insufficiency

Abstract: The elimination of para-aminosalicylic acid (PAS) after the intravenous injection of 20 mg PAS sodium/kg was estimated in patients with liver disease, in uremic patients and in volunteers without dama

Fosfomycin in the treatment of bacterial infections: summary of clinical trials in Japan.

Abstract: The Japan Research Committee of Fosfomycin was organized in the fall of 1972 to promote the basic and clinical studies on fosfomycin. First of all, a subcommittee of fosfomycin consisting of a limited number of members was organized to establish the methods of determination on its antibacterial activity and its concentration in the biological fluid, and the most applicable methods were devised. The clinical trials on its oral form in a small scale were commenced from spring in 1973, and then gradually expanded to almost all of Japan. The clinical trials on its parenteral intravenous form were also undertaken from the latter half of 1973. The basic and clinical results obtained from hospitals and institutes almost all over Japan, to which members of the above Committee belong, were presented by speakers under a hot discussion in two symposia which were held by the Japan Society of Chemotherapy; one on its oral form in June 1974, and another on its parenteral form in December 1974. I served as chairman in both of the symposia. The clinical results of fosfomycin in Japan which were mainly collected in both symposia are described below. Its antibacterial activity, and absorption and exretion will be presented elsewhere in this volume. Clinical results of its oral form: Dosage forms of fosfomycin-Ca salt, capsule and granules, were prepared for its clinical trials. It resulted effective in about 76% of 1,200 patients with infection due to gram-positive or gram-negative (Pseudomonas, Salmonella, Escherichia coli, etc.) bacteria in several fields. As far as rates of efficacy were concerned, it was more effective in surgical, urological, ophthalmic and some other fields than in internal and pediatric ones. Fosfomycin was given in a dose of 2-3 g/day for adults or 100-130 mg/kg for infants and children in most cases. Furthermore, it can be favorably mentioned that fosfomycin was proved to be effective in salmonellosis and resistant shigellosis by a certain research group specialized in the therapy of infectious enteritis. Clinical results of its parenteral form: Sterlized bulk material of fosfomycin-Na salt was prepared in a vial for clinical use. Similarly as in the case of oral form, it was applied to about 500 patients with several infections. It resulted effective in about 68% of them. This percentage was not as high because of the higher frequency of application to severe patients or patients with underlying disease. Fosfomycin was intravenously administered by one shot or drip infusion in a dose of 2-4 g/day for adults, or 100-250 mg/kg for infants and children in most cases. Adverse reactions: In oral form, the incidence of adverse reactions was about 10% but most of them were slight gastrointestinal disorders. In an extremely small number of patients a rise of SGOT and/or SGPT was observed. In parenteral form, the incidence of adverse reactions was a little higher, being about 17% including a rise of SGOT and/or SGPT, vascular pain, nausea, and vomiting, etc...