Activity Of Fosfomycin Research Articles

Bactericidal activity of cefotaxime and fosfomycin in cerebrospinal fluid during the treatment of rabbit meningitis experimentally induced by methicillin-resistant Staphylococcus aureus.

The purpose of this study was to evaluate the therapeutic effect of cefotaxime (CTX) and fosfomycin (FOS), alone or in combination, in an experimental meningitis, with cerebrospinal fluid (CSF) concentrations of the two antibiotics reproducing those obtained in human CSF during bacterial meningitis. With a dose of 50 mg/kg of CTX and 100 mg/kg of FOS injected i.v. (CTX over 0.5 h and FOS over 3 h), CSF concentrations were comparable to those observed in man. In a series of five rabbits per treatment group, the bacterial population was counted before and after treatment (two doses with a six-hour interval) with CTX, FOS or CTX + FOS (CTX over 0.5 h before the end of FOS infusion). By the 12th hour of treatment, the percentage of bacteria surviving in CSF compared to the initial population was 4.35% for CTX, 0.20% for FOS and 0.19% for CTX + FOS. Thus, it seemed that CTX + FOS was not more active than FOS alone. In another series of four rabbits per group, the bactericidal effect was followed at T0, T6, T12, T24 and T48 after treatment (two doses with a six-hour with a six-hour interval). With CTX, a variable drop in bacterial count from one rabbit to the other occurred during the first 12 h, and then a bacteriostasis followed. With FOS, a quick bactericidal effect was observed during the first 12 h, becoming slower during the following 36 h (0.03% of bacteria surviving at the 48th hour). With CTX and FOS in combination, a quick bactericidal effect was achieved, remaining steady over a 48-hour period (0.001% of bacteria surviving at the 48th hour).

Inability of gentamicin and fosfomycin to eliminate intracellular Enterobacteriaceae

The ability of gentamicin and fosfomycin to kill Salmonella typhimurium and Escherichia coli in a HeLa cell culture system was investigated. Antibiotic activity against extracellular, cell membrane-attached and intracellular bacteria were determined. Both gentamicin and fosfomycin had the same low ability to kill intracellular bacteria. The efficacy of fosfomycin against extracellular bacteria was also low, whereas gentamicin rapidly killed such bacteria. These observations show that intracellular enterobacteria are protected from the bactericidal activity of gentamicin and fosfomycin.

The activity of rosoxacin, fosfomycin, cefotiam, and spectinomycin on beta-lactamase producing Neisseria gonorrhoeae.

We measured the activity of rosoxacin, fosfomycin, cefotiam, and spectinomycin against 51 isolates of beta-lactamase producing Neisseria gonorrhoeae, all of which were susceptible to each drug at sufficient concentrations. The development of strains of penicillinase producing N gonorrhoeae (PPNG) which are resistant to spectinomycin can therefore be avoided, as there are alternative drugs.

Comparative study of fosfomycin activity in Mueller–Hinton media and in tissues

Fosfomycin utilizes two uptake systems as ways of entry into microorganisms: the L-a-glycerophosphate and the hexose phosphate transport system. The latter is inducible by glucose-6-phosphate. The relationship between glucose-6-phosphate (concentration range 0-100 mg/l) and the susceptibility of Staphylococcus aureus was studied in Mueller-Hinton broth. An almost maximal enhancement of fosfomycin activity was found at 25 mg/l glucose-6-phosphate. Fosfomycin activity against Staph. aureus, Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Klebsiella spp., Serratia spp., and Pseudomonas aeruginosa was studied by use of the broth and the agar dilution method, in the presence and absence of glucose-6-phosphate (25 mg/l). The minimum inhibitory concentrations (MICs) of fosfomycin against Staph. aureus Streptococcus faecalis, E. coli, Ent. cloacae, Pr. mirabilis, and Ps. aeruginosa were estimated in particle free supernatants of 25% tissue homogenates (liver, kidney, lung, heart) and in parallel in Mueller-Hinton broth. With few exceptions the MICs in Mueller-Hinton broth (with glucose-6-phosphate) were similar to those found in tissues (no glucose-6-phosphate added).

Protective effect of fosfomycin on the experimental nephrotoxicity induced by dibekacin.

Protection by fosfomycin of the nephrotoxicity of dibekacin was studied using Fischer 344 rats and urinary parameters such as volume, osmolality, protein, N-acetyl-beta-D-glucosaminidase, leucine aminopeptidase, lactate dehydrogenase and nucleated cells were determined as markers of nephrotoxicity. The duration of treatment was 11 d. Fosfomycin reduced polyuria, proteinuria, enzymuria and cyturia induced by dibekacin best by the concomitant administration, followed by pre-treatment, but not by post-treatment. Protection was effective in the dose ratio of dibekacin: fosfomycin = 1:2 - 1:32, regardless of administration routes. As judged from urinalysis, protection by fosfomycin (320 mg/kg) was almost complete for the experimental nephrotoxicity induced by 10 mg/kg of dibekacin, and still significant for that by 40 mg/kg. This was supported by the histo-pathological and ultrastructural improvement of proximal tubules and by suppressed blood urea nitrogen and creatinine values. Protective activity of fosfomycin was more potent than that of cephalothin, when compared on the weight basis.

Transport of Antibiotics into Bacteria

Publisher Summary This chapter reviews that accumulation of antibiotics by bacteria has, in the past, appeared to be a paradox because it was believed that few drugs could use transport systems involved in uptake of essential solutes. Several examples of antibiotics, which behave in this manner have been described. The situation is not only confined to antibiotics, because various heavy metal ions are also accumulated by systems that usually function to transport essential ions. The potentiation of fosfomycin activity in infected mice by coadministration of glucose 6-phosphate is demonstrated in the chapter. This resulted in induction of uhpT in the bacteria within the animal and increased transport of drug into the microorganisms. Another promising approach involves transport of antibiotics linked to natural substrates, so that the transport system is misused by the adduct. Although some adducts may have chemotherapeutic potential, other hybrid molecules may prove ineffective because they will become too bulky for transport. This may be particularly critical for Gram-negative bacteria where the exclusion limit for passive diffusion through outer membrane porins is usually about 600 daltons.

Voraussetzungen für die Wirkungssteigerung von Fosfomycin durch Glukose-6-Phosphat in der Therapie von tierexperimentellen Infektionen

In chemotherapy of otherwise fatally infected mice (intraperitoneally) the effective dose50 (ED50) of fosfomycin (2 single doses, subcutaneous application 1 and 6 h post infect.) was decreased significantly by supplementing the antibiotic solution with 100 mg glucose-6-phosphate (G-6-P) per kg animal and per injection if also the MIC of the infecting strain (Klebsiella oxytoca and K. aerogenes II) was lowered by addition of G-6-P (25 mg/l) to the nutrient medium (Table 1 and 2). With strains not exhibiting any influence on the MIC no such effect was observed (Table 1). From this it is concluded that the enhancement of antimicrobial activity of fosfomycin in vivo is based on the same mechanism as in vitro. This mechanism is the initiation of a second route of transportation into the bacterial cell (7), the hexose-6-phosphate transport system that apparently is inducible not only in vitro but also in vivo. Blood levels of G-6-P sufficient or above to induce this system in vitro (5 mg/l) were being held with doses of 100 mg/kg body weight in dogs during 70 to 120 min (Fig. 3) and 45 to 70 min (Fig. 4) when applicated subcutaneously or intravenously respectively. These periods of contact are adequate to induce a considerable decrease of the MIC. With the strain used (K. oxytoca) the MIC of 128 mg/l was lowered by contact with G-6-P during 60 or 120 min to 16 or 8 mg/l respectively (Fig. 5). For full induction of the hexose-6-phosphate system resulting in a MIC of 2 mg/l however, 8 h were necessary. From the above findings it is concluded that clinical studies are necessary. As G-6-P is a (short-lived) physiological product of cell metabolism and nontoxic such studies are justifiable in cases where therapeutic use of fosfomycin can be regarded as an indication.

Wirkungssteigerung von Fosfomycin durch Zusatz von Glukose-6-Phosphat bei intraperitoneal infizierten Mäusen

The increase of antimicrobial activity of Fosfomycin by glucose-6-phosphate (G-6-P) has often been demonstrated by in vitro studies. However, this effect was never sufficiently established in vivo. Our study was carried out in order to investigate the effects of the addition of G-6-P to Fosfomycin in white mice (strain G.P. of N.I.H.), which were intraperitoneally infected with a strain of S. typhimurium (10(3) c.f.u/0.5 ml i.p.). One and six hours after the infection, 0.1 ml consisting of increasing doses of G-6-P (0, 5, 25, 50, 250 and 500 micrograms/g) and decreasing doses of Fosfomycin (15.6, 7.8, 3.9, 1.95, 0.98 and 0.49 micrograms/g) were applied i.m., using 10 animals for each combination. Tables 1 and 2 show the results of this therapy with regard to the reduction of the ED50 of Fosfomycin. It can be seen that the addition of 25 micrograms G-6-P/g body-weight significantly reduces the ED50 within the first days (Tab. 1), while doses of 50 and more micrograms G-6-P/g significantly reduce the ED50 during the whole investigation period (Tab. 2). These results justify the proposal to use a combination of Fosfomycin and G-6-P in clinical studies for the treatment of human infections.

Activity of fosfomycin in the treatment of bacterial infections.

30 patients with different infections were treated with fosfomycin: 13 had urinary infections, 14 had pneumonial infections, 2 had staphylococcus osteomyelitis and 1 had staphylococcus septicemia. The antibiotic was administered in doses ranging from 100 to 230 mg/kg/day, with periods of treatment that lasted from 5 to 58 days. The doses were administered every 6 h by the oral or intramuscular route. A total of 35 organisms were isolated: 7 E. coli, 7beta-hemolitic Streptococcus, 6 Proteus sp., 6 S. aureus, 6 S. viridans, 2 Klebsiella sp. and 1 negative coagulase S. aureus. All were sensitive to fosfomycin in vitro, as was revealed by the diffusion in discs method. The therapeutic results were good in 29 of the 30 cases (96.7%). There were no important side effects. A patient complained of a local pain in the area of the injection. The transaminases increased temporarily in 2 patients. One patient had a moderate eosinophilia while under treatment.

Sensitivity of Vibrio spp. to fosfomycin.

The behavior of 15 strains of Vibrio eltor, halophilic Vibrios and NAG vibrios with respect to 14 antibiotics was studied by means of the single disc method in Mueller-Hinton agar. In the case of fosfomycin, the MIC for all of them was determined as well by the technique of progressive dilutions in solid medium. No conclusions were made because of the small number of strains studied. Nevertheless, it can be asserted that there is a marked difference in the activity of fosfomycin, since it was minimal against V. eltor, moderate against the NAGs and maximal against the halophilic Vibrio.

Fosfomycin in the bacteriuria of paraplegic patients.

A study was made of the activity of fosfomycin in vitro and in vivo against different bacterial strains localized in the urinary tract of paraplegic patients hospitalized for their rehabilitation in our Hospital. A total of 22 patients were studied and 24 treatments were carried out. A total of 33 organisms were isolated in the initial cultures. In all patients, the pattern of administration of the antibiotic was 4 g/day intramuscularly during 8 days. From the bacteriological standpoint, the results were excellent, although there was no question of clinical results due to the special circumstances of these patients. A sterilization of the urocultures was achieved in 20 of the 24 cases treated. No signs of intolerance or toxicity were observed in any of the patients upon administering the antibiotic.

Fosfomycin, Antimicrobial Activity <i>in vitro </i>and <i>in vivo</i>

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 (Difco) inoculated with one loopful of 1,000-fold dilution (about 10(6) 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 mug/ml in Salmonella. It was also active against P. aeruginosa with a peak of the MIC at 6.25 mug/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 carbenicillin.

Evolution of sensitivity to fosfomycin in bacteria isolated in 1973, 1974 and 1975 in the Servicio de Microbiologia y Epidemiologia of the 'Clinica Puerta de Hierro', Madrid.

The bacteriostatic activity of fosfomycin was studied in vitro against 1,243 clinical isolations of gram-positive cocci and 4,086 isolations of gram-negative bacilli that were obtained in 1973, 1974 and in the period from January to May of 1975. MIC was determined by the agar diffusion method, quantifying it by means of the standard curve that was worked out with the strain of E. coli NCTC 10,418. A slight increase in resistance was observed in the gram-positive cocci: 64 mug/ml were inhibitory for 63% of the 249 isolations obtained in 1973, 59.1% of the 716 isolations obtained in 1974, and 57.5% of the 278 isolations from 1975. A slight loss of sensitivity was also observed in the gram-negative bacilli: the aforementioned concentration of fosfomycin inhibited 36% of the 742 isolations from 1973, 33.6% of the 2,387 isolations from 1974 and 32.6% of the 957 isolations from 1975. 933 g of this antibiotic were consumed in our hospital in 1973, 4,203 g in 1974 and 957 g in 1975. The consumption rate per patient per year was 0.15, 0.72 and 0.20 g, respectively. In conclusion, although no change was observed in the sensitivity of some bacterial strains to fosfomycin, the overall study indicates a slight decrease in the sensitivity, although it does not apparently have any relationship to the consumption of fosfomycin in our hospital.

Susceptibility to Fosfomycin of Hospital Strains Isolated in Nantes (France). Frequency of Mutation to Resistance

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.