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PubMed1986

[Transference of antibiotics into prostatic tissues: sampling method by transurethral resection for the measurement of the concentration of antibiotics in prostatic tissue].

The transeference of two antibiotics, i.e. cefmetazole (CMZ) and fosfomycin (FOM), into prostatic tissues was examined. Prostatic tissue samples were obtained from patients with benign prostatic hyperplasia while undergoing open prostatectomy or transurethral resection of the prostate (TUR-P). 2 g of CMZ or 4 g of FOM was intravenously administered within about 10 minutes starting 1 hour before the removal or resection of the prostate, and blood samples were collected at the end of the administration and during surgery. In TUR-P, resected prostatic tissues were washed with the TUR perfusate and the antibiotic in the tissue was presumed to be released into the perfusate. The following preliminary experiments were, therefore, carried out. The removed prostate was divided into three segments, i.e. urethral region, central region and capsular region, and the CMZ or FOM level in each tissue was measured. The remaining tissues were cut into small pieces for immersion in the TUR perfusate for 10-90 minutes. The tissue fragments were removed every 10 minutes to measure the tissue concentration of CMZ or FOM. The concentration of CMZ or FOM in the prostatic tissues did not vary among the three regions, however it markedly decreased with increase in the period of immersion. This suggested that the concentration of these agents into the prostatic tissues was represented by the concentration in the tissues near the urethra obtained immediately after the start of TUR-P.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed1987

Pharmacokinetic evaluation of fosmidomycin, a new phosphonic acid antibiotic.

The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single--and repeated--dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated even when given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after oral dosing of 500 mg is in general about 20-40%, which can be calculated to be on average about 30% (in comparison with fosfomycin which is on average only about 11%). Absorption seems to be slow and moderate. In the single-dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 mg p.o. and 7.5 mg/kg (ca. 500 mg) i.m. doses respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 micrograms/ml at 0.25 h. The serum half-lives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses respectively. In repeated-dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 micrograms/ml were recorded at steady state. The serum protein binding found in man was less than 1%. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMedDate not supplied

Antibiotic consumption and faecal bacterial susceptibility in surgical in-patients.

A one-day prevalence study of resistance of faecal bacteria to 19 antibacterial agents was performed in 144 surgical inpatients. Most of the drug-resistant isolates were of aerobic and anaerobic species commonly seen in infections, which indicates that surveys of faecal flora can yield rapid information on local patterns of drug resistance in pathogens relevant to abdominal infection. In faecal bacteria the drug resistance pattern only weakly reflected the local antibiotic consumption. The amount of administered aminoglycosides was relatively small, and no gentamicin-resistant aerobes were found. Absence of resistance was found also for some of the newer agents not yet in clinical use (aztreonam, latamoxef, norfloxacin), but not for others (ceftazidime, ceftriaxone). Despite heavy use of fosfomycin and metronidazole, resistance had not emerged among aerobic and anaerobic bacteria, respectively. Imipenem was unique in inhibiting growth of all aerobic and anaerobic faecal bacteria, in the studied patients with the single exception of a strain of Enterobacter.

Abdomen↗
PubMed1985

[Study on the drug sensitivity of multiple drug-resistant Staphylococcus aureus].

Of clinically isolated Staphylococcus aureus showing resistance to multiple drugs among penicillins (PCs), cephem antibiotics (CEPs), aminoglycosides (AGs), minocycline (MINO) and fosfomycin (FOM), 64 strains were selected for the determination of MIC. Twenty-one drugs were used for the determination of MIC, with ampicillin (ABPC), cloxacillin (MCIPC), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefuroxime (CXM), cefamandole (CMD), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), cefmetazole (CMZ), cefoxitin (CFX), latamoxef (LMOX), cefotetan (CTT), cefoperazone (CPZ), gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), MINO, and FOM. MIC80 of each drug at 10(6) CFU/ml were: ABPC, MCIPC, CEZ, CTM, CXM, CTX, CZX, CMX, CFX, LMOX, CTT, CPZ, GM, DKB and TOB greater than 100 micrograms/ml; CET 50 micrograms/ml; CMD and AMK 25 micrograms/ml; CMZ 12.5 micrograms/ml; FOM 6.25 micrograms/ml; and MINO 0.78 micrograms/ml. The ratio of highly resistant strains with MIC greater than 100 micrograms/ml at 10(6) CFU/ml varied according to drug, and a difference tended to be seen in the degree of influence by resistant factors reflected upon MIC, e.g. drugs for which a high resistance of more than 50% was confirmed were ABPC, CXM, CZX, LMOX and TOB, and 20 approximately 30% MCIPC, CTM, CTX, CMX and CFX. MIC on MCIPC which has a correlation of structural activity with methicillin correlated with cephems (CEPs) resistance to a high degree, but many of the so-called new CEPs showed resistance even to the strains with a low MIC on MCIPC. It was assumed that CEPs resistant strains have multiple drug resistant factors based on the fact that such strains showed multiple drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗
PubMed1985

Fosmidomycin: a new phosphonic acid antibiotic. Part I: Phase I tolerance studies.

The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single and repeated dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated even when given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after oral dosing of 500 mg is in general about 20-40% which can be calculated to be, in average, about 30% (in comparison with fosfomycin which is, in average, about 11% only). The absorption seems to be slow and moderate. In single dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 mg oral and 7.5 mg/kg (ca. 500 mg) i.m. doses, respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 micrograms/ml at 0.25 h. The serum halflives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses, respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses, respectively. In repeated dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 micrograms/ml were recorded at steady state. The serum protein binding could be found in man less than 1%. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Fosmidomycin, a new phosphonic acid antibiotic. Part II: 1. Human pharmacokinetics. 2. Preliminary early phase IIa clinical studies.

The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single and repeated dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated when even given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after the oral dosing of 500 mg is in general about 20-40% which can be calculated to be in average about 30% (in comparison with fosfomycin which is in average about 11% only). The absorption seems to be slow and moderate. In single dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 oral and 7.5 mg/kg (ca. 500 mg) i.m. doses respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 micrograms/ml at 0.25 h. The serum halflives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses respectively. In repeated dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 micrograms/ml were recorded at steady state. The serum protein binding could be found to be less than 1% in man. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1979

[Effect of fosmocyin-Na on reproductive performance of rats and rabbits. I. Teratogenicity test (author's transl)].

The teratogenicity study of fosfomycin-Na (FOM-Na) was undertaken in Wistar rats and New Zealand white rabbits. Rats were treated intraperitoneally at dose levels of 125, 250, 750 and 1,500 mg/kg/day from day 7 to day 17 of gestation, and rabbits were treated intravenously at dose levels of 80, 100, 200, 400 and 800 mg/kg/day from day 6 to day 18 of gestation. In the case of rats, two-thirds of pregnant mothers in each group was sacrificed on day 20 of gestation and then their fetuses were examined for external, visceral and skeletal observation. The remaining mothers were allowed to deliver naturally, and then their offsprings were examined for postnatal development. In the case of rabbits, all pregnant mothers were sacrificed on day 29 of gestation and their fetuses were examined. Body weight of rat mothers during gestation were decreased and 4 mothers were dead until day 20 of gestation in the maximum dose. In this dose, foetal toxicity was recognized too. However, external, visceral and skeletal anomalies related with FOM-Na treatment were not observed in all groups. No effect on development of offsprings was observed. No effect of treatment of FOM-Na to rabbits was found except foetal body weight was slightly decreased in the maximum dose.

Animals↗
PubMed1984

[In vitro study of strains of Staphylococcus: choice of an antibiotic].

The aim of this study is to determine the best antibiotic in presumptive staphylococcal infection and/or bacteriologically established staphylococcal infection before results of antibiotic sensitivity tests are available. 382 strains were analyzed. Only sensitivity or resistance to antibiotics were considered. Vancomycin is the best antistaphylococcal agent (3% resistance rate on the 382 strains), (11% resistance rate on Methicillin-resistant Staphylococcus aureus strains). Pristinamycin and Virginiamycin also yield excellent scores but are less efficient against Methicillin-resistant staphylococci (21%). Cefalotin is still an excellent antistaphylococcal agent (7%). Fosfomycin is especially valuable against polyresistant staphylococci, with a 26% resistance rate on Methicillin-resistant Staphylococcus aureus. Lastly, significant increases in resistance rates relative to 1966 staphylococci strains are found only for penicillin (68% versus 78%) and rifamycin (3.6% versus 8%).

Anti-Bacterial Agents↗
PubMed1984

Other antibiotics.

This is a survey of the pharmacokinetics and mechanisms of action, orthopedic use, antimicrobial activity, and adverse reactions to erythromycin, lincomycin and clindamycin, tetracycline, chloramphenicol, polymyxins, vancomycin, and fosfomycin. Although these antibiotics are rarely preferred to more active drugs such as the beta-lactams or aminoglycosides in orthopedic sepsis, they are nevertheless highly beneficial and in some situations can be the first-choice drug.

Anti-Bacterial Agents↗
PubMed1983

[Comparative study, on healthy volunteers, of the bioavailability of 2 pharmaceutical formulations of oral cofosfolactamines. Trials between subjects].

The relative bioavailability of two drug-product formulations, aqueous suspension and tablets, of a fixed-dose combination of fosfomycin with amoxicillin (cophosfolactamine) has been comparatively studied in five healthy volunteers by means of a randomized within subjects experimental design. The plasmatic concentrations were consistent with the in vitro synergistic effects. The liquid formulation has a significantly higher bioavailability than that of the tablets.

Adult↗
PubMed1982

[Purulent meningitis in children. II. Treatment and prognosis].

In the years 1970 to 1979 312 patients with purulent meningitis were treated at the University of Innsbruck, Department of Pediatrics. The overall fatality rate was 16%, the majority of fatal cases were due to gram negative organisms before 1977. The mortality rate of meningococcal meningitis due to H. influenzae was 5.6 and 1.6%, respectively and compares very well to reports in the literature. 12% of children are severely handicapped. Hearing impairment is the most frequent cause of retardation with 6.8%. We compared therapeutic results of two different treatment regimen in our clinic with the therapeutic results in other centers reported in the literature. The combination of ampicillin and chloramphenicol was superior to other treatment modalities particularly ampicillin monotherapy in H. influenzae meningitis and meningitis due to unknown organisms. Theoretical reservations against this combination have been eliminated by the proof of the bactericidal action of chloramphenicol against the most common meningeal pathogens and the synergistic action with beta lactam antibiotics. In pneumococcal meningitis the administration of high doses of Na-Penicillin G as i. v. bolus proved to be connected with unexpected complications and fatalities. The administration of 25000-40000 E Na Penicillin G as an i. v. infusion over 1 hour 4--6 times daily was a less hazardous yet effective therapy. Unsatisfying results in the treatment of gram negative meningitis in neonates prompted the investigation of a new compound fosfomycin for this indication. In vitro investigation of the antimicrobial activity against 68 meningeal pathogens and investigation of this drug in a lapine model showed encouraging results. In the last years a limited clinical trial in severely affected newborn infants was done with promising therapeutic efficacy. A larger scale investigation of this drug is now proceeding in form of a National cooperative Study of gram negative meningitis in Austria. Besides an effective antimicrobial treatment particular attention has to be paid to an adequate fluid and electrolyte replacement. Symptomatic therapy of complications e. g. seizures as well as continuous close monitoring of all vital signs is mandatory for optimal therapeutic success. Subdural effusions have been observed infrequently and only diagnostic subdural punctures have been performed.

Ampicillin↗
PubMed1994

Forty years of screening programmes for antibiotics.

The article gathers the reflections on the experiences of forty years doing research on the screening of natural product in the pharmaceutical industry. Over those years new technologies have improved the methodology. However, the steps followed in such a research are the same: the isolation and cultivation of microorganisms; the definition of assays with well defined targets; the demonstration of their efficacy for the discovery and selection of active substances produced by microorganisms; the classification and structural determination of the new products; and the study of their therapeutical efficiency. Examples of the processes which led to the production of several antibiotics (fosfomycin, cefoxitin and thienamycin) are described. One important lesson that the author has learnt is that microorganisms have unique fingerprints and that generalization should be avoided in the planning of this work.

Anti-Bacterial Agents↗
PubMed1994

[A study on nephrotoxicity of arbekacin and vancomycin in rats].

Nephrotoxicities of arbekacin (ABK) and/or vancomycin (VCM) were examined by administrating rats intravenously with single doses or 10 times repeated daily doses. ABK was found less toxic to kidney than VCM, and the toxicity was strengthened by combined treatment with VCM and ABK. Fosfomycin decreased the nephrotoxicity when added to the single or combined treatment with ABK and VCM.

Aminoglycosides↗
PubMed1994

[Antibiotic efficacies of combined uses of arbekacin and various antibiotics against methicillin-resistant Staphylococcus aureus].

Efficacies of combined uses of arbekacin(ABK) with other antibiotics against between 57 and 76 clinically isolated methicillin-resistant Staphylococcus aureus(MRSA) were examined. Other antibiotics tested were fosfomycin(FOM), 5 cephems(CEPs), 2 penicillins(PCs) and imipenem. Percentages of strains that grew at various combination of serially diluted drugs in a microdilution method were scored, and for each pair of drugs > or = MIC50 or > or = MIC90 was determined. FIC-indices were calculated at > or = MIC50. Bacterial growth was inhibited by low concentrations of ABK dose-dependently, while most of the strains tested were resistant to 9 other drugs. FIC-indices with ABK were lowest when used together with ampicillin (ABPC) (0.516) followed by combinations with cefotiam (CTM) and cefuzonam (CZON) (each, 0.53), and FOM (0.625). When combined with 0.5 microgram/ml of ABK, 0.5 microgram/ml of ABPC inhibited more than 50% of MRSA strains. CTM or CZON in combination with the same amount of ABK to 2 micrograms/ml inhibited more than 50% of MRSA. Thus ABPC was found to be the most efficient in combined use with ABK to inhibit clinical MRSA strains.

Aminoglycosides↗
PubMed1994

[Efficacy of combination therapy against MRSA in Ibaraki Prefecture].

Clinical efficacies of fosfomycin (FOM) or arbekacin (ABK) plus beta-lactam combination therapies against methicillin-resistant Staphylococcus aureus (MRSA) infections were examined in 15 major hospitals in Ibaraki Prefecture. The subjects were 54 inpatients from January 1991 to April 1993, and most of them showed moderate to severe infections with underlying diseases. MRSA alone was isolated from 23 patients and the other 31 patients had polymicobes including MRSA. Pseudomonas aeruginosa was the most frequent among the co-isolated strains. The number of patients treated with FOM and cefmetazole (CMZ) was 22 (Group C) and that with FOM and flomoxef (FMOX) was 25 (Group F). CMZ or FMOX was administrated 60 minutes after FOM administration. To 8 nonresponding patients in Groups C and F and 7 nonresponders to the other therapies, ABK and ceftazidime (CAZ) or ABK and piperacillin (PIPC) were treated simultaneously (Group A). The clinical efficacies of Groups C and F were 63.6% and 64%, respectively. The bacteriological efficacies (eradication rates) of both groups including microbial substitutions were 42.9% in the former and 56.5% in the latter. No statistical differences were observed in the clinical and the bacteriological efficacies between Groups C and F. The clinical and bacteriological efficacies in Group A were 66.7% and 46.2%, respectively. No side effects were observed in any cases. Mild disturbances of hepatic functions were observed in 2 cases of Groups C and F, and there were no abnormal laboratory test results in Group A.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

[Treatment with arbekacin of surgical infections by resistant strains of Staphylococcus aureus. Arbekacin Study Group].

The frequency of infection by methicillin-resistant Staphylococcus aureus (MRSA) is high in Japan and control of such strains is urgently needed. Arbekacin (ABK), a semisynthetic aminoglycoside, has potent activity against S. aureus, including resistant strains, and against Gram-negative bacteria as well. For this reason, in surgical infections (which are often caused by more than one bacterium), this drug might be particularly effective. We calculated the MIC and the decrease in the MIC when cultures of 59 resistant strains of S. aureus isolated in our wards at Osaka City University Hospital, contained arbekacin in the medium. We also used the drug to treat 12 infections caused by resistant strains of S. aureus. The MICs of vancomycin had a single peak at 0.5 microgram/ml, and those for ABK had double peaks at 0.5 and 4.0 micrograms/ml. The effect of arbekacin in lowering the MIC of minocycline (MINO) was slight because of the low MIC of MINO. Effects on fosfomycin (FOM), ampicillin, clavulanic acid/ticarcillin, cefotiam, cefuzonam, flomoxef, and imipenem/cilastatin were strong; the peaks were lowered by 1/2(7)-1/2(11). When 1.0 micrograms/ml ABK was present in the medium, the efficacy of FOM was increased enough that, by prediction from the pharmacokinetics of FOM (blood level when given at the usual dose), all but one (2%) of the 47 resistant strains would be eradicated clinically. If 2.0 micrograms/ml ABK were in the medium, all strain would be eradicated, by our calculations. We treated 11 infections and one colonization by resistant strains of S. aureus with ABK and evaluated the response in these cases of infection. Four infections were treated with FOM as well. The clinical efficacy was good in four infections (three patients), fair in four, and poor in three, for an efficacy rate of 36%. All presumed causative bacteria were eradicated in two (18%) of the 11 infections and S. aureus strains were eradicated in three (27%) of the 11 infections. No symptoms of side effects were reported, but blood urea nitrogen and creatinine rose in a 72-year-old woman with duodenal perforation and peritonitis. The MIC levels of ABK were satisfactory, but clinical efficacy for staphylococcal infections caused by resistant strains was unsatisfactory.

Adult↗
PubMed1993

Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents.

Cis-diamminedichloroplatinum II (cisplatin), a divalent platinum compound and potent cell-cycle nonspecific chemotherapeutic agent, produces a dose-limiting, permanent, high-frequency sensori-neural hearing loss and peripheral neuropathy, and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. The exact mechanism(s) of ototoxicity and/or nephrotoxicity are still unknown. Continued aggressive high-dose cisplatin chemotherapy necessitates the investigation of ways to decrease the dose-limiting side effects that inhibit the administration of cisplatin at therapeutic and tumoricidal doses. This multifaceted project investigates two categories of potential inhibitors of cisplatin toxicity that, when coadministered with a known tumoricidal and ototoxic dose of cisplatin, will decrease or inhibit the ototoxicity: 1. phosphonic acid antibiotics (fosfomycin; 1,2 epoxypropylphosphonic acid); 2. nonglucocorticoid 21-aminosteroids, which are free oxygen radical scavengers (LAZAROIDS: U74006F and U78517F). This project also investigates the role of pigmentation as a variable affecting the evaluation of platinum-induced ototoxicity in the guinea pig animal model. Identification of an optimal animal model for future cisplatin toxicity research should be based on previously established species-specific differences in total drug dose, systemic toxicity, and morphological and functional evidence of cochlear toxicity, as affected by differences in pigmentation and drug tolerance. Cytocochleography, brainstem auditory evoked response (BSER), scanning and transmission electron microscopy of organ of Corti and the stria vascularis, double-blind light microscopy of renal, small intestine, and peripheral nerve tissue, and gamma-emission analysis of 195Mplatinum localization in inner ear neuroepithelium and the stria vascularis are used in the global evaluation of the ototoxic effects of cisplatin in both the adult albino and pigmented guinea pig.

Albinism↗
PubMed1995

[A case report of pyomyositis--early diagnosis and follow-up by MRI].

We report a rare case of pyomyositis in a 28-year-old Japanese woman who was not immunocompromised. She was admitted because of high fever, sore throat, and severe tenderness and swelling of the right calf. Redness, swelling, and tenderness indicated presence of acute inflammation in the calf. CT of the lower extremities demonstrated low density areas in the right soleus muscle and surrounding fascia with marked swelling, which were of high signal on T2 weighted images of MRI. There was no finding of abscess formation. A tentative clinical diagnosis of acute pyomyositis was made, and antibiotics therapy with a combination of fosfomycin and sulbactam/cefoperazone was started although the arterial blood culture was negative for bacteria. Associated acute tonsilitis was the most probable focus of pyomyositis. Antibiotics relieved her symptoms, and the inflammation subsided in several weeks. No surgical procedure was necessary. MRI taken tree weeks after the onset demonstrated abscess formation between the soleus and gastrocnemius muscles. Slight high intensity indicating scar formation remained in the area of the former abscess six weeks after the onset. MRI was very useful not only in making the early diagnosis but also in the follow-up of pyomyositis.

Adult↗