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PubMedDate not supplied

Antibiotic susceptibility testing (agar disk diffusion and agar dilution) of clinical isolates of Enterococcus faecalis and E. faecium: comparison of Mueller-Hinton, Iso-Sensitest, and Wilkins-Chalgren agar media.

Forty-two isolates of Enterococcus faecalis and 56 isolates of Enterococcus faecium, including 8 vancomycin-resistant strains, were examined for comparative susceptibility to 27 antimicrobial drugs with the agar dilution method, employing Mueller-Hinton (MHA), Iso-Sensitest (ISTA), and Wilkins-Chalgren (WCA) agar. The Bauer-Kirby agar disk diffusion method was used to comparatively test 24 of the agents in parallel. The enterococci yielded better growth on ISTA and WCA. However, WCA completely antagonized co-trimoxazole and, though less, fosfomycin. Importantly, WCA slightly reduced the activities of teicoplanin (minimal inhibitory concentrations, MICs, raised up to twofold) and vancomycin (MICs raised two- to fourfold) against enterococci and staphylococcal quality control strains. Therefore, WCA was judged unsuitable for susceptibility testing of enterococci. For E. faecalis no discrepancies between agar dilution MICs and inhibition zone diameters were encountered with augmentin, ampicillin, ampicillin-sulbactam, chloramphenicol, mupirocin, oxacillin, teicoplanin, and co-trimoxazole. Overall, MHA yielded fewer very major (category I) and major (category II) discrepancies than ISTA. However, numerous minor (category III), slight (category IV), minimal (category V), and/or negligible (category VI) discrepancies were encountered with ciprofloxacin, doxycycline, erythromycin, fosfomycin, fusidic acid, meropenem, ofloxacin and rifampin. With respect to E. faecium, only cefotaxime, mupirocin, oxacillin, and teicoplanin yielded nondiscrepant results. Several very major (I) and major (II) discrepancies were observed with augmentin, ampicillin, ampicillin-sulbactam, doxycycline, fusidic acid, imipenem, and penicillin G. Minor discrepancies (categories III-VI) were particularly numerous with augmentin, chloramphenicol, ciprofloxacin, doxycycline, and piperacillin. The largest numbers of negligible (VI) discrepancies were noted with fosfomycin, fusidic acid, and ofloxacin. It is recommended to test one cephalosporin (cefuroxime or the like) in parallel for educational purposes and to exclude fosfomycin, fusidic acid, and rifampin from test batteries because of the wide scatter of test results. The large number of minimal (V) discrepancies of ciprofloxacin against E. faecalis, the numerous minor (III) and slight (IV) discrepancies of chloramphenicol against E. faecium, and the not insignificant number of very major (I) and minor (III) discrepancies observed with meropenem against isolates of E. faecalis necessitated proposals for new disk intermediate susceptibility criteria.

Agar↗
PubMedDate not supplied

Activity of fosmidomycin in an in vitro model of the treatment of bacterial cystitis.

The response to fosmidomycin of four strains of Escherichia coli was studied in an in vitro model of the treatment of bacterial cystitis. Three susceptible strains of E. coli responded well to relatively low concentrations of fosmidomycin: doses achieving peak concentrations of 50 or 250 mg/l suppressed bacterial growth for 13 h or more; however, when the surviving bacteria were challenged with a second dose, a reduced response was observed. When a fully resistant strain was exposed to fosmidomycin, bacterial growth was also suppressed for 13 h or more, even when the peak concentration achieved was below the conventionally determined minimum inhibitory concentration. Resistant variants which emerged after exposure to fosmidomycin were also resistant to fosfomycin in the absence of the potentiating agent, glucose-6-phosphate. In the presence of glucose-6-phosphate, complete (or partial) susceptibility to fosmidomycin and fosfomycin was retained by three of the four strains. These results suggest that fosmidomycin and fosfomycin are transported into E. coli by a similar mechanism, and that deletion of the hexose phosphate transport system does not occur following exposure to fosmidomycin in the absence of glucose-6-phosphate.

Cystitis↗
PubMed1993

Evaluation of agents for use in medium for selective isolation of Lyme disease and relapsing fever Borrelia species.

Barbour-Stoenner-Kelly (BSK) II medium containing fosfomycin, 5-fluorouracil, trimethoprim and sulfamethoxazole was evaluated for the selective isolation of the Borrelia species responsible for Lyme disease and relapsing fever. The maximum non-inhibitory concentrations of fosfomycin, 5-fluorouracil, trimethoprim and sulfamethoxazole for six strains of borreliae were 500 to > 1000 micrograms/ml, 250 to > 500 micrograms/ml, 125 to 500 micrograms/ml and 125 to 500 micrograms/ml, respectively. The combination of four agents (fosfomycin 400 micrograms/ml, 5-fluorouracil 100 micrograms/ml, trimethoprim 10 micrograms/ml, sulfamethoxazole 50 micrograms/ml) did not inhibit the growth of borreliae, allowing growth in cultures inoculated with a few organisms (theoretically a single organism). In contrast, the four-agent combination completely inhibited the growth of 12 of 13 other bacterial strains tested as possible contaminants. This combination also allowed the selective growth of borreliae in experimentally contaminated specimens. The four-agent combination in BSK II medium may be useful for selective isolation of Borrelia species responsible for Lyme disease and relapsing fever from clinical and environmental samples.

Bacteriological Techniques↗
PubMed2002

Empirical treatment of adult postsurgical nosocomial meningitis.

BACKGROUND: The combination of cefotaxime and fosfomycin (CTX-FOS) has been proposed in France for the empirical treatment of postoperative nosocomial meningitis since the late 1980s. The purpose of this work was to evaluate this strategy today, as well as other possible treatments. METHODS: Each patient undergoing a neurosurgical procedure was prospectively included in a database designed for the surveillance of surgical site infection (SSI). For each meningitis detected, we analysed the in vitro susceptibility of the causative micro-organisms to cefotaxime alone (CTX), cefotaxime-fosfomycin (CTX-FOS), vancomycin (VAN) and cefotaxime-vancomycin (CTX-VAN) combinations. The patient population was divided into two groups according to the presence or absence of CSF shunting material. FINDINGS: 116 patients had had a postoperative meningitis/ventriculitis during the last 36 months, among 6447 patients undergoing neurosurgery in our department (1.8%). Ten patients had aseptic meningitis (8.6%). Overall sensitivity to CTX was 69.8%, as compared to 77.3% with CTX-FOS combination (NS). This result was due to a large proportion of fosfomycin resistant cocci in our population. The CTX-VAN combination increased the overall in vitro susceptibility up to 91.5%, but the benefit of this combination was only significant in CSF shunting material patients. In these latter patients, VAN was as effective as CTX-FOS combination. INTERPRETATION: CTX-FOS combination is no longer the best choice for empirical treatment of post neurosurgical meningitis. CTX alone can be safely used in patients without a CSF shunt; in those with either a ventriculostomy or a CSF shunt associated ventriculitis, a CTX-VAN combination could improve treatment efficacy, provided that high doses of vancomycin are used to ensure correct CSF diffusion.

Adult↗
PubMed2006

Restricted use of glycopeptides in paediatric cancer patients with fever and neutropenia.

Until now, studies confirming the safety of glycopeptide restriction in the empirical treatment of prolonged fever and neutropenia included only nine children. In an open-label observational study, the use of teicoplanin in paediatric oncology patients was investigated. A period of unrestricted use (2001-2003) was compared with a second period (2004) following implementation of a restrictive treatment guideline. Empirical first-line treatment consisted of piperacillin/tazobactam; in 2004, fosfomycin was added after 72 h as the second-line combination instead of teicoplanin. In total, 213 episodes (n=163 in 2001-2003; n=50 in 2004) managed with teicoplanin or fosfomycin (only 2004) were eligible. Empirical treatment of fever of unknown origin with teicoplanin was reduced by 97%. In 2004, the mean length of stay was 0.4 days shorter, no infection-related death occurred and no vancomycin-resistant enterococci were detected. Restriction of empirical glycopeptides is safe in paediatric cancer patients after first-line treatment with piperacillin/tazobactam. Fosfomycin appears to offer a feasible and cost-saving alternative in second-line combination therapy.

Adolescent↗
PubMed2001

Treatment of lower urinary tract infection in pregnancy.

Urinary tract infection (UTI) is a common complication of pregnancy. Approximately 20--40% of women with asymptomatic bacteriuria will develop pyelonephritis during pregnancy. All pregnant women, therefore, should have their urine cultured at their first visit to the clinic. In a clinical study comparing single-dose treatment with 3 g fosfomycin trometamol versus a 3-day course of 400 mg ceftibuten orally, the inclusion criteria were acute symptomatic lower UTI (acute cystitis), significant bacteriuria (> or =10(3) CFU/ml), pyuria and confirmed pregnancy. Excluded were patients with asymptomatic bacteriuria or acute pyelonephritis. Predisposing factors comprised a history of recurrent UTI, diabetes mellitus, analgesic nephropathy, hyperuricaemia or Fanconi's syndrome. Escherichia coli was the most frequently isolated pathogen in both groups. Therapeutic success (clinical cure and bacteriological eradication of uropathogens) was achieved in 95.2% of the patients treated with fosfomycin-trometamol versus 90.0% of those treated with ceftibuten (P, non-significant). The treatment of acute cystitis in pregnant women using a single-dose of fosfomycin trometamol was equally effective as the 3-day course of oral ceftibuten. Both regimens were well tolerated with only minor adverse effects. Long-term chemoprophylaxis should be suggested in patients with recurrent UTI or following acute pyelonephritis during pregnancy.

Adult↗
PubMed2002

EPR study of substrate binding to the Mn(II) active site of the bacterial antibiotic resistance enzyme FosA: a better way to examine Mn(II).

FosA is a manganese metalloglutathione transferase that confers resistance to the broad-spectrum antibiotic fosfomycin, (1R,2S)-epoxypropylphosphonic acid. The reaction catalyzed by FosA involves the attack by glutathione on fosfomycin to yield the product 1-(S-glutathionyl)-2-hydroxypropylphosphonic acid. The enzyme is a dimer of 16 kDa subunits, each of which harbors one mononuclear Mn(II) site. The coordination environment of the Mn(II) in the FosA x Mn(2+) complex is composed of a glutamate and two histidine ligands and three water molecules. Here we report EPR spectroscopic studies on FosA, in which EPR spectra were obtained at 35 GHz and 2 K using dispersion-detection rapid-passage techniques. This approach provides an absorption envelope line shape, in contrast to the conventional (slow-passage) derivative line shape, and is a more reliable way to collect spectra from Mn(II) centers with large zero-field splitting. We obtain excellent spectra of FosA bound with substrate, substrate analogue phosphate ion, and product, whereas these states cannot be studied by X-band, slow-passage methods. Simulation of the EPR spectra shows that binding of substrate or analogue causes a profound change in the electronic parameters of the Mn(II) ion. The axial zero-field splitting changes from [D] = 0.06 cm(-1) for substrate-free enzyme to 0.23 cm(-1) for fosfomycin-bound enzyme, 0.28 (1) cm(-1) for FosA with phosphate, and 0.27 (1) cm(-1) with product. Such a large zero-field splitting is uncommon for Mn(II). A simple ligand field analysis of this change indicates that binding of the phosphonate/phosphate group of substrate or analogue changes the electronic energy levels of the Mn(II) 3d orbitals by several thousand cm(-1), indicative of a significant change in the Mn(II) coordination sphere. Comparison with related enzymes (glyoxalase I and MnSOD) suggests that the change in the coordination environment on substrate binding may correspond to loss of the glutamate ligand.

Anti-Bacterial Agents↗
PubMed2005

A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA).

MurA (UDP-N-acetylglucosamine enolpyruvyl transferase, EC 2.5.1.7) catalyzes the first committed step in the synthesis of the bacterial cell wall. It is the target of the naturally occurring, broad-spectrum antibiotic fosfomycin. Fosfomycin, an epoxide, is a relatively poor drug because an ever-increasing number of bacteria have developed resistance to fosfomycin. Thus, there is a critical need for the development of novel drugs that target MurA by a different molecular mode of action. We have identified a new scaffold of potent MurA inhibitors, derivatives of 5-sulfonoxy-anthranilic acid, using high-throughput screening. T6361 and T6362 are competitive inhibitors of MurA with respect to the first substrate, UDP-N-acetylglucosamine (UNAG), with a K(i) of 16 microM. The crystal structure of the MurA.T6361 complex at 2.6 angstrom resolution, together with fluorescence data, revealed that the inhibitor targets a loop, Pro112 to Pro121, that is crucial for the structural changes of the enzyme during catalysis. Thus, this new class of MurA inhibitors is not active site-directed but instead obstructs the transition from the open (unliganded) to the closed (UNAG-liganded) enzyme form. The results provide evidence for the existence of a MurA.UNAG collision complex that may be specifically targeted by small molecules different from ground-state analogs of the enzymatic reaction.

Alkyl and Aryl Transferases↗
PubMed1991

In-vitro activity of imipenem combined with beta-lactam antibiotics for methicillin-resistant Staphylococcus aureus.

The in-vitro activity of imipenem combined with beta-lactam antibiotics was studied for 25 strains of methicillin and imipenem-resistant Staphylococcus aureus (MRSA) in comparison with that of fosfomycin combined with cefmetazole. Using the chequerboard agar dilution method, strong synergy was seen for all strains for imipenem with cefoperazone, cefotiam, cefpiramide or piperacillin. All fractional inhibitory concentration indices (FIC indices) of these combinations were less than or equal to 0.12. For the combination of imipenem with cefotiam the synergy was found to be bactericidal, but was not affected by the temperature of incubation, the concentration of sodium chloride in the medium or beta-lactamase production. However, for the combination of fosfomycin with cefmetazole only 44% of the strains with a mean FIC index of 0.55, showed synergy. The remaining 56% of strains showed either partial synergy (44%) or additive activity (12%). The combinations of imipenem with the beta-lactam antibiotics were more effective than that of fosfomycin with cefmetazole.

Anti-Bacterial Agents↗
PubMed1981

Experimental endocarditis caused by Streptococcus sanguis: single and combined antibiotic therapy.

The effectiveness of penicillin G, fosfomycin, and cefoxitin alone and in combination was studied in vitro and in the treatment of left-sided Streptococcus sanguis endocarditis in rabbits. In vitro, the combinations penicillin G plus fosfomycin, penicillin G plus cefoxitin, and fosfomycin plus cefoxitin were synergistic or partially synergistic for S sanguis. Therapy with the combinations was more effective in eradicating the species from cardiac vegetations that was that with each antibiotic used alone.

Animals↗
PubMed1989

Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats.

The protective effect of piperacillin against the nephrotoxicity of cisplatin was compared with that of fosfomycin in Fischer 344 rats. Blood urea nitrogen, serum creatinine, and morphological changes were evaluated as the renal toxicological parameters. Rats receiving 2 mg of cisplatin per kg of body weight for 5 days showed significant (P less than 0.01 by multiple-comparison test) elevation of blood urea nitrogen and serum creatinine concentrations compared with rats receiving saline alone and also exhibited development of cell lesions in the pars recta of the tubules in the outer stripe of the outer medulla. However, piperacillin (250 and 1,000 mg/kg) significantly (P less than 0.01 by multiple-comparison test) reduced these toxicological parameters in comparison with results for cisplatin alone. The protective effect of piperacillin was superior to that of fosfomycin, although platinum levels in the kidney were higher with the combination of cisplatin and piperacillin than with cisplatin plus fosfomycin. Although the nephrotoxicity of cisplatin was also reduced when cisplatin was administered concomitantly with sodium chloride in mole-equivalents to 250 and 1,000 mg of piperacillin per kg, its protective effect was less than that of the corresponding piperacillin dose. These results suggest that piperacillin may have a role as a protective agent against the nephrotoxicity of cisplatin.

Animals↗
PubMed1987

Characterization of mutant histidine-containing proteins of the phosphoenolpyruvate:sugar phosphotransferase system of Escherichia coli and Salmonella typhimurium.

Histidine-containing phosphocarrier protein (HPr) is common to all of the phosphoenolpyruvate:sugar phosphotransferase systems (PTS) in Escherichia coli and Salmonella typhimurium, except the fructose-specific PTS. Strains which lack HPr activity (ptsH) have been characterized in the past, and it has proved difficult to delineate between tight and leaky mutants. In this study four different parameters of ptsH strains were measured: in vitro sugar phosphorylation activity of the mutant HPr; detection of 32P-labeled P-HPr; ability of monoclonal antibodies to bind mutant HPr; and sensitivity of ptsH strains to fosfomycin. Tight ptsH strains could be defined; they were fosfomycin resistant and produced no HPr protein or completely inactive mutant HPr. All leaky ptsH strains were fosfomycin sensitive, usually produced normal amounts of mutant HPr protein, and had low but measurable activity, and HPr was detectable as a phosphoprotein. This indicates that the regulatory functions of the PTS require a very low level of HPr activity (about 1%). The antibodies used to detect mutant HPr in crude extracts were two monoclonal immunoglobulin G antibodies Jel42 and Jel44. Both antibodies, which have different pIs, inhibited PTS sugar phosphorylation assays, but the antibody-HPr complex could still be phosphorylated by enzyme I. Preliminary evidence suggests that the antibodies bind to two different epitopes which are in part located in a beta-sheet structure.

Antibodies, Monoclonal↗
PubMed1987

Monuril in lower uncomplicated urinary tract infections in adults.

Fosfomycin trometamol is a new fosfomycin salt with much improved intestinal absorbtion, thus providing high levels of the drug both in serum and urine. The range of activity and the pharmacokinetic characteristics of this new salt emphasize its usefulness in therapy of urinary tract infections (UTIs), either as a single dose or in short courses. In a multicentric, open, non-controlled trial, fosfomycin trometamol was employed in the treatment of 365 UTIs (84 males and 281 females, of whom 13 were pregnant). 144 UTIs were community acquired, while 221 were hospital acquired; 48 were diagnosed as asymptomatic bacteriurias, 201 as lower uncomplicated symptomatic UTIs, 49 as lower complicated UTIs, 59 as recurrent lower symptomatic UTIs, and 8 as cystopyelitis. The drug was administered as a single dose, i.e. 3 g at once, in 198 cases and in short courses, i.e. 3 g daily for 2-3 days (in a few patients, though, for 11 days) in 167 cases. High success rates were attained using the single dose in asymptomatic bacteriurias (78.1%), in lower uncomplicated symptomatic UTIs (89.5%), as well as in UTIs of the female (85.3%) and community-acquired UTIs (97.4%). In all these cases, the single-dose regimen seems to be the most rational form of clinical use, since the multiple-dose regimen did not add any further advantage. In infections of the male, or in hospital-acquired or complicated UTIs, short therapy courses gave better results. The drug was well tolerated, even by pregnant women, and clinically irrelevant side effects were recorded in a small number of patients.

Clinical Trials as Topic↗
PubMed2001

Time-kill evaluation of antimicrobial regimens against clinical isolates of penicillin-resistant Streptococcus pneumoniae.

The rate of penicillin-resistant Streptococcus pneumoniae isolates in Spain is high. At present, penicillin and ceftriaxone are two drugs chosen for treating serious infections. In this study the bactericidal activity of four antimicrobial regimens against ten clinical isolates of S. pneumoniae (five with an intermediate resistance to penicillin and five highly resistant ones), was determined by means of kill kinetics studies using either penicillin, or ceftriaxone, in combination with vancomycin, or fosfomycin. The concentrations of the antimicrobial regimens (MICs 4x, 1x and 1/4x) were within possible physiological levels. While the combinations of penicillin, or ceftriaxone, plus vancomycin showed a significant increase in bactericidal activity, the bacterial reductions obtained in combination with fosfomycin were greater, achieving synergistic effects. These results suggest that in vivo trials with a regimen composed of ceftriaxone and fosfomycin would be worthwhile.

Anti-Bacterial Agents↗
PubMed2000

Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.

Vancomycin and certain fungicides may cause anaphylactoid reactions. We investigated the effects of vancomycin, miconazole and fluconazole on histamine release in rat peritoneal mast cells. Vancomycin and miconazole provoked histamine release in a dose-dependent manner. In contrast, fluconazole did not provoke histamine release at concentrations of 3 x 10(-6)-3 x 10(-3) M. Vancomycin is efficacious in the treatment of gram-positive bacterial infections; patients presenting themselves with mixed infections require concomitant therapy with a second antimicrobial agent. We investigated the effect of fosfomycin sodium, cilastatin sodium or fluconazole on vancomycin-induced histamine release. Fosfomycin sodium inhibited vancomycin-induced histamine release but neither cilastatin sodium nor fluconazole inhibited it in the mole ratios of daily doses used in humans. These results suggest that vancomycin and miconazole provoke histamine release in rat mast cells, but that fluconazole probably does not, while fosfomycin sodium may inhibit vancomycin-induced histamine release.

Animals↗
PubMed2004

Effect of antimicrobial agents on the production and release of shiga toxin by enterotoxaemic Escherichia coli isolates from pigs.

Edema disease (ED) of pigs is an enterotoxaemic disease caused by enterotoxaemic Escherichia coli (ETEEC) infection. Antimicrobial therapy for pigs with ED is controversial because it may induce death of sickish piglets. In this study, we investigated the effects in vitro of 7 antimicrobial agents, ampicillin, gentamicin, colistin, bicozamycin, fosfomycin, sulfamethoxazole-trimethoprim and enrofloxacin, on the release and production of shiga toxin (Stx) 2e by ETEEC strains. We found that more Stx 2e accumulated in the bacterial cells than was released into supernatant. Associated with inhibition of cell wall synthesis, the exposure to ampicillin or fosfomycin increased the release of Stx 2e. The production levels of Stx 2e in all antimicrobial-treated cultures were equal to the level in the control or less than in the control. These results suggest that cell wall synthesis inhibitors, such as ampicillin and fosfomycin, may change for the worse in the signs in ETEEC infectious pigs. On the other hand, gentamicin, colistin, bicozamycin and enrofloxacin may be useful for the treatment of pigs with ED.

Ampicillin↗
PubMed1980

In vitro and in vivo antibacterial activities of FR-31564, a new phosphonic acid antibiotic.

FR-31564, a new phosphonic acid antibiotic, was active against most Gram-negative bacteria except Serratia marcescens and glucose-nonfermenting Gram-negative rods excluding Pseudomonas aeruginosa. The antibacterial activity in vitro of FR-31564 was stronger than that of fosfomycin especially against Escherichia coli, Klebsiella pneumoniae, Enterobacter species and P. aeruginosa. FR-31564 also was active against Gram-negative bacteria resistant to beta-lactam antibiotics and against gentamicin-resistant strains of P. aeruginosa. The antibacterial activity in vitro of FR-31564, like that of fosfomycin, was enhanced when 10% rabbit blood was added to the nutrient agar. The therapeutic efficacy of FR-31564 in experimental infections in mice was superior to that of fosfomycin in infections due to most Gram-negative bacteria used, and was similar to that of gentamicin in infections due to Citrobacter freundii, Proteus rettgeri and Proteus inconstans B. The protective effect of FR-31564, particularly in the P. aeruginosa infection, was superior to that of other control drugs including gentamicin.

Animals↗
PubMed1999

[Choice of antibiotics in uncomplicated cystitis; application of 'system of objectified judgement analysis' (SOJA) method].

OBJECTIVE: To determine the drug of choice for the treatment of uncomplicated cystitis. METHOD: Drug selection was performed by means of the so-called 'system of objectified judgement analysis' (SOJA) method by a working group of 11 persons. The following selection criteria were used: pharmacokinetics, interactions, probability of hitting (the probability that the microorganism is sensitive to the antibiotic), development of resistance, specific use in urinary tract infections, efficacy, side effects, dosage-frequency, duration of treatment, cost and documentation. The following drugs were included in the study: amoxicillin (with or without clavulanic acid), nitrofurantoin, sulfamethizole, trimethoprim, co-trimoxazole, ciprofloxacin, norfloxacin, ofloxacin and fosfomycin trometamol. RESULTS: Fosfomycin and nitrofurantoin slow release showed the highest scores. The main selection criteria that determined the selection of a drug were especially specific use in urinary tract infections, development of resistance, probability of hitting and cost. CONCLUSION: Fosfomycin and nitrofurantoin slow release best fulfill the requirements for drugs in the treatment of uncomplicated cystitis. No comparative studies have been performed with the 3-day treatment of uncomplicated cystitis with nitrofurantoin slow release or with trimethoprim. Fluoroquinolones play no important part in the treatment of uncomplicated cystitis, mainly because of the risk of development of resistance.

Anti-Infective Agents↗