fosfomycin and Disease-Models--Animal

Topics: Acetamides; Aminoglycosides; Animals; Anti-Bacterial Agents; beta-Lactams; Clindamycin; Daptomycin; Disease Models, Animal; Fluoroquinolones; Fosfomycin; Guidelines as Topic; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Tetracyclines; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Alternative treatments are needed against NDM-1-producing Escherichia coli. Colistin (COL) and fosfomycin (FOS) often remain active in vitro but selection of resistant mutants is frequent if used separately. We determined whether the combination of colistin and fosfomycin may be useful to treat infections with NDM-1-producing E. coli with varying levels of resistance.. Isogenic derivatives of E. coli CFT073 with blaNDM-1 and variable levels of resistance to colistin and fosfomycin (CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively) were used. The combination (colistin + fosfomycin) was tested in vitro and in a fatal peritonitis murine model. Mortality and bacterial loads were determined and resistant mutants detected.. Colistin MICs were 0.5, 16 and 0.5 mg/L and fosfomycin MICs were 1, 1 and 32 mg/L against CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively. In time-kill curves, combining colistin with fosfomycin was synergistic and bactericidal against CFT073-NDM1 and CFT073-NDM1-FOS, with concentrations of 4× MIC (for both drugs), but not against CFT073-NDM1-COL (concentrations of colistin = 0.5× MIC), due to regrowth with fosfomycin-resistant mutants. Mice died less and bacterial counts were lower in spleen with the combination compared with monotherapy against all strains; the combination prevented selection of resistant mutants except for CFT073-NDM1-COL where fosfomycin-resistant mutants were found in all mice.. Combining colistin and fosfomycin was beneficial in vitro and in vivo against NDM-1-producing E. coli, even with strains less susceptible to colistin and fosfomycin. However, the combination failed to prevent the emergence of fosfomycin-resistant mutants against colistin-resistant strains. Combining colistin and fosfomycin constitutes an alternative for treatment of NDM-1 E. coli, except against colistin-resistant strains.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Colistin; Disease Models, Animal; Drug Synergism; Escherichia coli; Fosfomycin; Mice; Microbial Sensitivity Tests; Peritonitis

Vancomycin-resistant Enterococcus faecium (VREfm) infections are increasing. Current anti-VREfm options (linezolid and daptomycin) are suboptimal. Fosfomycin maintains good efficacy against VREfm and chloramphenicol is active against ≥ 90% of VREfm. We tested chloramphenicol + fosfomycin (CAF+FOS) against 10 VREfm isolated from blood. MICs were 64 to 512 µg/mL for fosfomycin and 8 to 16 µg/mL for chloramphenicol. The combination decreased both MICs, with a synergic effect in 50% of the isolates and an additive effect in the remaining 50%. Time-kill assays performed on fractional inhibitory concentration index ≤ 0.5 strains confirmed the synergism. The antibiotic combination at ¼ of minimum inhibitory concentrations (MICs) caused a ≥ 2 log

Topics: Animals; Anti-Bacterial Agents; Chloramphenicol; Disease Models, Animal; Drug Synergism; Enterococcus faecium; Fosfomycin; Gram-Positive Bacterial Infections; Humans; Kaplan-Meier Estimate; Microbial Sensitivity Tests; Moths; Sepsis; Vancomycin-Resistant Enterococci

Escherichia coli is the most common cause of Gram-negative prosthetic joint infections (PJIs) and ciprofloxacin is the first-line antibiofilm antibiotic. Due to the emergence of fluoroquinolone resistance, management of E. coli PJIs has become challenging and is associated with high treatment failure rates. We evaluated the efficacy of a newly isolated bacteriophage ɸWL-3 as a therapeutic agent in combination with ciprofloxacin, fosfomycin, gentamicin, meropenem or ceftriaxone against biofilm of a ciprofloxacin/ceftriaxone-resistant E. coli strain and the ATCC 25922 reference strain. ɸWL-3 was first characterised in terms of virion morphology, absorption rate, burst size and killing kinetics against both E. coli strains. The tested antibiotics presented high inhibitory concentrations (ranging from 16 to >1024 μg/mL) when tested alone against biofilms. Co-administration of ɸWL-3 with antibiotics improved the antibiotic efficacy against biofilm, especially after staggered exposure, reducing the minimum biofilm bactericidal concentration (MBBC) up to 512 times. The in vivo antimicrobial activity of ɸWL-3/fosfomycin combination against both E. coli strains was assessed in a Galleria mellonella invertebrate infection model. Treatment of infected larvae after lethal doses of E. coli resulted in enhanced survival rates when combinatorial therapy with ɸWL-3/fosfomycin was applied on E. coli ATCC 25922-infected larvae compared with monotherapy, but not for EC1-infected larvae, which we speculated could be due to higher release of endotoxins in a shorter period in EC1-infected larvae exposed to ɸWL-3. Our study provides new insights into the use of bacteriophages and antibiotics in the treatment of biofilm-associated infections caused by antibiotic-resistant bacteria.

Topics: Animals; Anti-Bacterial Agents; Bacteriophages; Biofilms; Ceftriaxone; Ciprofloxacin; Combined Modality Therapy; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Fluoroquinolones; Fosfomycin; Gentamicins; Meropenem; Microbial Sensitivity Tests; Moths; Phage Therapy; Prosthesis-Related Infections

Treatment of Staphylococcus aureus infections is challenging owing to widespread multidrug resistance. There is now considerable interest in the potential of combination therapies. Although linezolid/fosfomycin combination appears to be a promising treatment option based on in vitro data, further preclinical work is needed. In this study, the Galleria mellonella system was employed to study the in vivo efficacy of this combination in order to determine whether it should be explored further for the treatment of S. aureus infections.. The antimicrobial activity of linezolid and fosfomycin alone and in combination was assessed versus four S. aureus. Synergy studies were performed using the microtitre plate chequerboard assay and time-kill methodology. The in vivo activity of linezolid/fosfomycin combination was assessed using a G. mellonella larvae model.. The combination of linezolid and fosfomycin was synergistic and bacteriostatic against four tested strains. Treatment of G. mellonella larvae infected with lethal doses of S. aureus resulted in significantly enhanced survival rates when low-dose of combination has no significant differences with high-dose combination (P > 0.05), G. mellonella hemolymph burden of S. aureus suggest that combination therapy with rapid and sustained bacteriostatic activity compared monotherapy.. This work indicated that linezolid combination with fosfomycin has synergistic effect against S. aureus in vitro and in an experimental G. mellonella model, and it suggests that high-dose of linezolid and fosfomycin may not necessary.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Linezolid; Microbial Sensitivity Tests; Moths; Staphylococcal Infections; Staphylococcus aureus

Unfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Fosfomycin; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Minocycline; Pneumonia; Tigecycline

Osteomyelitis, or bone infection, is often induced by antibiotic resistant Staphylococcus aureus strains of bacteria. Although debridement and long-term administration of antibiotics are the gold standard for osteomyelitis treatment, the increase in prevalence of antibiotic resistant bacterial strains limits the ability of clinicians to effectively treat infection. Bacteriophages (phages), viruses that in a lytic state can effectively kill bacteria, have gained recent attention for their high specificity, abundance in nature, and minimal risk of host toxicity. Previously, we have shown that CRISPR-Cas9 genomic editing techniques could be utilized to expand temperate bacteriophage host range and enhance bactericidal activity through modification of the tail fiber protein. In a dermal infection study, these CRISPR-Cas9 phages reduced bacterial load relative to unmodified phage. Thus we hypothesized this temperate bacteriophage, equipped with the CRISPR-Cas9 bactericidal machinery, would be effective at mitigating infection from a biofilm forming S. aureus strain in vitro and in vivo. In vitro, qualitative fluorescent imaging demonstrated superiority of phage to conventional vancomycin and fosfomycin antibiotics against S. aureus biofilm. Quantitative antibiofilm effects increased over time, at least partially, for all fosfomycin, phage, and fosfomycin-phage (dual) therapeutics delivered via alginate hydrogel. We developed an in vivo rat model of osteomyelitis and soft tissue infection that was reproducible and challenging and enabled longitudinal monitoring of infection progression. Using this model, phage (with and without fosfomycin) delivered via alginate hydrogel were successful in reducing soft tissue infection but not bone infection, based on bacteriological, histological, and scanning electron microscopy analyses. Notably, the efficacy of phage at mitigating soft tissue infection was equal to that of high dose fosfomycin. Future research may utilize this model as a platform for evaluation of therapeutic type and dose, and alternate delivery vehicles for osteomyelitis mitigation.

Topics: Animals; Anti-Bacterial Agents; Bacteriophages; Biofilms; CRISPR-Cas Systems; Disease Models, Animal; Female; Fosfomycin; Gene Editing; Longitudinal Studies; Osteomyelitis; Rats; Rats, Sprague-Dawley; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem.. Prospective randomized animal study.. Animal Research, University of Barcelona, Spain.. Thirty female pigs.. The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance.. We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004).. Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Topics: Administration, Inhalation; Administration, Intravenous; Amikacin; Animals; Anti-Bacterial Agents; Bacterial Load; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Lung; Meropenem; Nebulizers and Vaporizers; Pneumonia; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Random Allocation; Swine; Trachea

A major developing problem in the treatment of Staphylococcus aureus infections is the emergence of resistance during treatment with daptomycin. Previous metabolomic analyses of isogenic S. aureus strains prior to and after evolution into a daptomycin non-susceptible (DapNS) state provided important metabolic information about this transition (e.g. perturbations of the tricarboxylic acid cycle).. To assess the significance of these metabolic changes, in vitro susceptibility to daptomycin was determined in daptomycin-susceptible (DapS) and DapNSS. aureus strains cultivated with metabolic inhibitors targeting these changes.. Only inhibitors that are approved for use in humans were chosen (i.e. fosfomycin, valproate, trimetazidine and 6-mercaptopurine) to assess the importance of metabolic pathways for daptomycin non-susceptibility. The ability of these inhibitors to forestall the emergence of DapNS strains was also assessed.. The combination of daptomycin and fosfomycin synergistically killed both DapS and DapNS strains in vitro and enhanced the in vivo outcome against a DapNS strain in experimental endocarditis. Interestingly, fosfomycin acts on the peptidoglycan biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA); however, it also had a significant effect on the enzymatic activity of enolase, an essential enzyme in S. aureus. While fosfomycin acted synergistically with daptomycin, it failed to prevent the in vitro evolution of daptomycin non-susceptibility. In contrast, trimetazidine, an anti-angina drug that stimulates glucose oxidation, abolished the ability of DapSS. aureus strains to transition to a DapNS state.. These data reveal that metabolic adaptations associated with DapNS strains can be targeted to prevent the emergence of and/or reverse pre-existing resistance to daptomycin.

Topics: Animals; Anti-Bacterial Agents; Daptomycin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Synergism; Endocarditis; Fosfomycin; Metabolism; Metabolomics; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance is a major limitation. Our aim was to determine whether the association of temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections.. Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected.. Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P < 0.001) and inhibited growth of resistant mutants in all cases.. The combination of fosfomycin and temocillin demonstrated a benefit in vitro and in vivo against E. coli strains producing KPC-3 or OXA-48-type carbapenemases. This combination prevented the emergence of fosfomycin resistance and proved to be more bactericidal than fosfomycin alone.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bacterial Proteins; beta-Lactamases; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Female; Fosfomycin; Mice; Microbial Sensitivity Tests; Penicillins; Peritonitis

Prevalence of fosfomycin resistance in E. coli clinical isolates from UTIs remains very low. Our hypothesis was that fosfomycin resistance may be associated with a biological cost. Three groups of strains of E. coli belonging to the B2 phylogenetic group were used: clinical wild-type (WT) isolates, clinical multidrug-resistant isolates and in vitro fosfomycin-resistant derivatives from the uropathogen clinical strain E. coli CFT073. In each group fosfomycin-susceptible and -resistant isolates were compared. In vitro, we found a significantly decreased growth rate for fosfomycin-resistant strains as compared with susceptible strains in the WT group. In a murine model of ascending UTI, there was a significant reduction in infection rates with fosfomycin-resistant isolates as compared with susceptible ones, in all 3 study groups, ranging from 28 to 39% (P<0.03). All fosfomycin-susceptible clinical strains were virulent in vivo (13/13), while fosfomycin-resistant clinical strains were either virulent (2/7) or non-virulent (5/7) (P<0.002). This difference was not explained by the number of virulence factors or pathogenicity-associated islands. In conclusion, fosfomycin resistance appears to carry some biological cost in E. coli, which may explain in part the apparent paradox of the low prevalence of fosfomycin resistance despite a high rate of spontaneous mutants.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Fosfomycin; Genetic Fitness; Mice, Inbred CBA; Urinary Tract Infections; Virulence

Gentamicin is the preferred antimicrobial agent used in implant coating for the prevention of implant-related infections (IRI). However, the present heavy local and systemic administration of gentamicin can lead to increased resistance, which has made its future use uncertain, together with related preventive technologies. Fosfomycin is an alternative antimicrobial agent that lacks the cross-resistance presented by other classes of antibiotics. We evaluated the efficacy of prophylaxis of 10% fosfomycin-containing poly(D,L-lactide) (PDL) coated K-wires in a rat IRI model and compared it with uncoated (Control 1), PDL-coated (Control 2), and 10% gentamicin-containing PDL-coated groups with a single layer of coating. Stainless steel K-wires were implanted and methicillin-resistant Staphylococcus aureus (ATCC 43300) suspensions (103 CFU/10 μl) were injected into a cavity in the left tibiae. Thereafter, K-wires were removed and cultured in tryptic soy broth and then 5% sheep blood agar mediums. Sliced sections were removed from the tibiae, stained with hematoxylin-eosin, and semi-quantitatively evaluated with X-rays. The addition of fosfomycin into PDL did not affect the X-ray and histopathological evaluation scores; however, the addition of gentamicin lowered them. The addition of gentamicin showed a protective effect after the 28th day of X-ray evaluations. PDL-only coating provided no protection, while adding fosfomycin to PDL offered a 20% level protection and adding gentamicin offered 80%. Furthermore, there were 103 CFU level growths in the gentamicin-added group, while the other groups had 105. Thus, the addition of fosfomycin to PDL does not affect the efficacy of prophylaxis, but the addition of gentamicin does. We therefore do not advise the use of fosfomycin as a single antimicrobial agent in coating for IRI prophylaxis.

Topics: Animals; Antibiotic Prophylaxis; Bone Wires; Coated Materials, Biocompatible; Disease Models, Animal; Fosfomycin; Gentamicins; Methicillin-Resistant Staphylococcus aureus; Osteomyelitis; Polyesters; Rats; Staphylococcal Infections; Treatment Outcome

Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drug's pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.

Topics: Animals; Antimalarials; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Fosfomycin; HeLa Cells; Humans; Malaria; Mice; Mice, SCID; Molecular Structure; Plasmodium berghei; Plasmodium falciparum; Prodrugs; Structure-Activity Relationship

Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBClog values were 32/>512 μg/ml for fosfomycin, 4/>64 μg/ml for rifampin, 1/2 μg/ml for ampicillin, 2/>256 μg/ml for linezolid, 16/32 μg/ml for gentamicin, 1/>64 μg/ml for vancomycin, and 1/5 μg/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8× and 16× MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by ≈4 log10 CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.

Topics: Acetamides; Ampicillin; Animals; Anti-Bacterial Agents; Bacterial Adhesion; Biofilms; Calorimetry; Daptomycin; Disease Models, Animal; Drug Therapy, Combination; Enterococcus faecalis; Foreign Bodies; Fosfomycin; Gentamicins; Gram-Positive Bacterial Infections; Guinea Pigs; Linezolid; Male; Microbial Sensitivity Tests; Oxazolidinones; Rifampin; Vancomycin

The efficacy of daptomycin, imipenem, or rifampin with fosfomycin was evaluated and compared with that of daptomycin-rifampin in a tissue cage model infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Strain HUSA 304 was used. The study yielded the following results for MICs (in μg/ml): fosfomycin, 4; daptomycin, 1; imipenem, 0.25; and rifampin, 0.03. The study yielded the following results for minimum bactericidal concentration (MBC) (in μg/ml): fosfomycin, 8; daptomycin, 4; imipenem, 32; and rifampin, 0.5. Daptomycin-rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Daptomycin; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Foreign-Body Reaction; Fosfomycin; Imipenem; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rats; Rats, Wistar; Rifampin; Staphylococcal Infections

There is currently an emerging need for developing improved approaches for preventing urinary tract infections (UTIs) occurring during diagnostic or interventional procedures of the lower urinary tract. We aimed to establish a rat model to assess the use of transurethral antibiotic administration and to provide evidence that this could be used as a preventive therapy.. Animals received fosfomycin trometamol (FOF) either urethrally or orally prior to the procedure. A third group was generated as treatment controls and did not receive any medication. Urethral dilation was conducted to recapitulate an interventional procedure prior to intravesical Escherichia coli administration in all three groups. Finally, sham-operated animals were introduced as a fourth group which did not receive antibiotics or E. coli. Colony counts of urine and tissue cultures for the identification of E. coli and histopathological examinations of the bladder and prostate were conducted.. Evaluation of infection intensities in cultures as well as histopathological examination of the bladder and prostate demonstrated a preventative role of transurethral FOF administration. In terms of efficiency, local administration of FOF was similar to oral administration.. These results suggest that transurethral antibiotic administration is a promising alternative for preventing UTIs occurring during diagnostic or interventional procedures of the lower urinary tract.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Fosfomycin; Male; Rats; Rats, Wistar; Urethra; Urinary Tract Infections

The objective of this study was to evaluate the in vitro and in vivo efficacies of therapies including fosfomycin against clinical Staphylococcus aureus isolates with reduced susceptibility to vancomycin (hGISA). Time-kill curves were performed over 24 h. Peritonitis in C57BL/6 mice was induced by intraperitoneal inoculation of 10(8) CFU/ml. Four hours later (0 h), therapy was started and the treatment groups were: control (not treated), fosfomycin (100 mg/kg/5 h), vancomycin (60 mg/kg/5 h), imipenem (30 mg/kg/5 h), fosfomycin plus linezolid, fosfomycin plus vancomycin and fosfomycin plus imipenem, receiving subcutaneous therapy over 25 h. Bacterial counts in peritoneal fluid, bacteraemia and mortality rates were determined. In vitro, fosfomycin showed a synergistic effect when combined with the other antimicrobials tested. In the animal model, fosfomycin combinations were effective and significantly reduced the bacteraemia rates achieved in the control, imipenem and vancomycin groups (p < 0.05). The best combination in vivo was fosfomycin plus imipenem. Also, fosfomycin plus linezolid was significantly better than vancomycin alone, reducing the bacterial concentration in the peritoneal fluid. In conclusion, in vitro and in vivo, fosfomycin in combination with linezolid, vancomycin or imipenem exerted a good activity. Fosfomycin plus imipenem was the most active combination, decreasing 3 log CFU/ml, and appears to be a promising combination for clinical practice.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Ascitic Fluid; Bacteremia; Bacterial Load; Disease Models, Animal; Drug Therapy, Combination; Female; Fosfomycin; Humans; Imipenem; Linezolid; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Oxazolidinones; Peritonitis; Staphylococcal Infections; Treatment Outcome; Vancomycin

The activity of fosfomycin was evaluated in an experimental methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis model. Eighteen rats were treated for 4 weeks with 150 mg of fosfomycin/kg of body weight intraperitoneally once daily or with saline placebo. After treatment, animals were euthanized and the infected tibiae were processed for quantitative bacterial culture. Bone cultures were positive for methicillin-resistant S. aureus in all 9 (100%) untreated controls and in 2 of 9 (22.2%) fosfomycin-treated rats. Thus, fosfomycin treatment was significantly more efficacious than placebo. No development of resistance was observed after the 4-week treatment period.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Fosfomycin; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Osteomyelitis; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Tibia; Treatment Outcome

The in vivo activities of daptomycin, fosfomycin, and a combination of both antibiotics against a clinical isolate of methicillin-resistant Staphylococcus aureus (daptomycin MIC, 0.25 μg/ml; fosfomycin MIC, 0.5 μg/ml) were evaluated in a rat model of osteomyelitis. A total of 37 rats with experimental osteomyelitis were treated for 4 weeks with either 60 mg/kg of body weight of daptomycin subcutaneously once daily, 75 mg/kg fosfomycin intraperitoneally once daily, a combination of both drugs, or a saline placebo. After the completion of treatment, animals were euthanized, and the infected tibiae were processed for quantitative bacterial culture. Bone cultures were found to be positive for methicillin-resistant S. aureus in 9 of 9 (100%) animals of the placebo group, in 9 of 9 (100%) animals treated with daptomycin, in 1 of 10 (10%) fosfomycin-treated rats, and in 1 of 9 (22.2%) rats comprising the combination group. Results of bacterial counts in the bone samples were expressed as log(10) CFU/g of bone and analyzed by using the Mann-Whitney U test followed by Bonferroni's multiple-comparison test. Based on bacterial counts, treatment with daptomycin was significantly superior to placebo, although it remained inferior to treatment with fosfomycin. No synergistic or antagonistic effect was observed for the combination therapy. No development of resistance against daptomycin or fosfomycin was observed after the 4-week treatment period.

Topics: Animals; Anti-Bacterial Agents; Daptomycin; Disease Models, Animal; Fosfomycin; Male; Methicillin-Resistant Staphylococcus aureus; Osteomyelitis; Rats; Rats, Sprague-Dawley

Foreign body-associated infectious disease is currently one of the most problematic hospital-acquired infections. Patients with placement of urinary catheters are especially susceptible to such infection, that is biofilm infection. In this study, we focused on the therapeutic efficacy of prulifloxacin (PUFX) against Pseudomonas aeruginosa OP 14-210, isolated from a patient with complicated urinary tract infection. This microbe formed a biofilm on the surface of a polyethylene tube (PT) placed in a rat bladder without surgical manipulation. In addition, we attempted to eradicate the biofilm by treatment with a combination of PUFX and fosfomycin (FOM). A single oral administration of PUFX at a dose of 20 mg/kg was effective against P. aeruginosa as a biofilm, yielding a significant reduction in CFU per PT of approximately 1 log(10) CFU/PT compared with that in untreated controls. A similar therapeutic effect was also observed in levofloxacin-treated rats, and albeit slightly weaker, in ciprofloxacin-treated animals as well. Because 3 days' consecutive treatment with each fluoroquinolone did not further decrease the viable cell counts on the PT, we tested the efficacy of combining PUFX and FOM. These two drugs, administered once a day for 3 days, at doses of 20 and 100 mg/kg, respectively, resulted in significant decreases of viable cell counts on the PT of more than 1.5 log(10) CFU/PT compared with PUFX alone (P < 0.05). As seen by scanning electron microscopy, destruction and disappearance of multilayer biofilms occurred after treatment with this drug combination. Such combination therapy with PUFX and FOM may be advantageous for treating biofilm-related infectious diseases.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Catheters, Indwelling; Dioxolanes; Disease Models, Animal; Drug Therapy, Combination; Female; Fluoroquinolones; Fosfomycin; Humans; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Piperazines; Polyethylene; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Rats; Urinary Catheterization; Urinary Tract Infections

To study the in vitro and in vivo efficacy of fosfomycin, alone and in combination with ceftriaxone or vancomycin, against two strains of Streptococcus pneumoniae: HUB 2349 (fosfomycin and ceftriaxone, MICs 16 and 2 mg/L) and ATCC 51916 (MICs 4 and 32 mg/L).. Pharmacokinetics/pharmacodynamics data were collected from the study of eight infected animals after a single intravenous dose of 300 mg/kg of fosfomycin. Time-kill curves were plotted using CSF antibiotic concentrations achievable clinically. In the rabbit model, we studied the efficacy and effects on inflammation of treatment with fosfomycin 1200 mg/kg/day, ceftriaxone 100 mg/kg/day and vancomycin 30 mg/kg/day, over 26 h.. Fosfomycin peak level in serum was 324.48 +/- 102.1 mg/L at 0.5 h; CSF penetration was 49.2%. Time-kill curves showed that fosfomycin was bactericidal against the ATCC 51916 strain and that the addition of fosfomycin to ceftriaxone or vancomycin was synergic against the HUB 2349 strain. Resistance to fosfomycin was detected both when fosfomycin was studied alone and in combination. In the rabbit model, fosfomycin showed bactericidal activity only against the ATCC 51916 strain. Combinations of fosfomycin with ceftriaxone or vancomycin were bactericidal against both strains; they improved efficacy and decreased CSF inflammatory parameters over monotherapies, without showing statistical differences in comparison with the combination of ceftriaxone and vancomycin.. Fosfomycin in combination with ceftriaxone or vancomycin appeared to be effective for the treatment of experimental cephalosporin-resistant pneumococcal meningitis. These combinations are possible alternatives in cases of allergy or intolerance to first-line drugs or in rare meningitis caused by highly cephalosporin-resistant pneumococci.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporin Resistance; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Fosfomycin; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae; Vancomycin

Biofilms are a major concern for clinicians in the treatment of infectious disease because of the resistance to a wide range of antibiotics. Using a rat air pouch model, methicillin-resistant Staphylococcus aureus (MRSA) growing as a biofilm was treated with a combination of fosfomycin (FOM) and arbekacin (ABK) or by the agents alone. This model has the advantage of permitting frequent sampling of exudates for bacterial counts and anti-bacterial activity, and morphological examination of the biofilm structure and inflammatory process in the pouch tissues. A clear synergistic effect was observed in the rats treated with a combination of fosfomycin and arbekacin. Morphological studies using scanning electron microscopy and histological staining showed dramatic changes of the biofilm structure as well as the inflammatory response in the rats. These results suggested an enhancement of bactericidal activity of arbekacin penetrating through the biofilm layer by virtue of fosfomycin. A possible mechanism of the synergistic effect is discussed.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Biofilms; Dibekacin; Disease Models, Animal; Drug Synergism; Fosfomycin; Granuloma; Male; Methicillin Resistance; Microbial Sensitivity Tests; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus

The effect of coadministration of fosfomycin (FOM) on nedaplatin-induced nephrotoxicity in rats was investigated for 6 days. FOM decreased nedaplatin-induced nephrotoxicity, as shown by reduced blood urea nitrogen (BUN), serum creatinine levels, and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Further, there were fewer histopathological signs of nephrotoxicity in the groups treated with the combination of nedaplatin and FOM as compared with the nedaplatin-alone group. The concentration of nedaplatin was significantly lower in the renal cortex of rats treated with the combination of nedaplatin and FOM as compared with those treated with nedaplatin alone (p < 0.05). In conclusion, the concomitant administration of FOM and nedaplatin may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of nedaplatin.

Topics: Acetylglucosaminidase; Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Fosfomycin; Injections, Intraperitoneal; Kidney Tubular Necrosis, Acute; Male; Organoplatinum Compounds; Random Allocation; Rats; Rats, Wistar

We examined the effect of fosfomycin (FOM) on the inflammatory response induced by carrageenan in the rat. Air pouches were induced subcutaneously on the backs of rats and injected with carrageenan. The rats were treated with either vehicle or FOM at a dose of 100 mg/kg 1 h before carrageenan challenge. After carrageenan challenge (48 h), the air pouches were removed and analyzed. The volume, protein amounts and cell counts in the exudate obtained from FOM-treated animals were significantly reduced compared with that from vehicle-treated animals. The contents of PGE(2) and TNF-alpha, and mRNA for cyclooxygenase-2 were also markedly suppressed in FOM-treated rats. Histological examination showed suppression of the inflammatory response in the pouch tissues from FOM-treated rats.

Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL5; Dinoprostone; Disease Models, Animal; Exudates and Transudates; Fosfomycin; Inflammation; Models, Animal; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The fosmidomycin derivative FR900098 represents an inhibitor of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase with potent antimalarial activity. Prodrugs of FR900098 with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield phosphodiaryl esters. One diaryl ester prodrug demonstrated efficacy in mice infected with the rodent malaria parasite Plasmodium vinckei comparable to i.p. drug administration.

Topics: Aldose-Ketose Isomerases; Animals; Antimalarials; Disease Models, Animal; Fosfomycin; Malaria; Mice; Multienzyme Complexes; Organophosphonates; Oxidoreductases; Plasmodium; Prodrugs; Treatment Outcome

Shiga toxin-producing Escherichia coli (STEC) cause significant disease; treatment is supportive and antibiotic use is controversial. Ciprofloxacin but not fosfomycin causes Shiga toxin-encoding bacteriophage induction and enhanced Shiga toxin (Stx) production from E. coli O157:H7 in vitro. The potential clinical relevance of this was examined in mice colonized with E. coli O157:H7 and given either ciprofloxacin or fosfomycin. Both antibiotics caused a reduction in fecal STEC. However, animals treated with ciprofloxacin had a marked increase in free fecal Stx, associated with death in two-thirds of the mice, whereas fosfomycin did not. Experiments that used a kanamycin-marked Stx2 prophage demonstrated that ciprofloxacin, but not fosfomycin, caused enhanced intraintestinal transfer of Stx2 prophage from one E. coli to another. These observations suggest that treatment of human STEC infection with bacteriophage-inducing antibiotics, such as fluoroquinolones, may have significant adverse clinical consequences and that fluoroquinolone antibiotics may enhance the movement of virulence factors in vivo.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Toxins; Ciprofloxacin; Coliphages; Disease Models, Animal; Escherichia coli Infections; Escherichia coli O157; Fosfomycin; Humans; Intestines; Male; Mice; Shiga Toxins

There have been some reservations about the treatment of enterohemorrhagic Escherichia coli (EHEC) infection with antibiotics to prevent the occurrence of hemolytic uremic syndrome (HUS). However, the administration of antimicrobial agents for EHEC infection is under discussion. Therefore, we used an experimental mouse model to assess the advantage/disadvantage of two major antibiotics, levofloxacin (LVFX) and fosfomycin (FOM). Germ-free IQI mice were inoculated with EHEC O157 strain EDL931 or #7. Bacteria colonized feces at 10(9)-10(10) CFU/g, and Shiga toxins (STXs) were detected in the feces. From 1 day after infection, mice were assigned to LVFX (20 mg/kg) once daily or FOM (400 mg/kg) once daily. A significant decrease in overall mortality was observed after treatment of LVFX, with EHEC disappearing immediately from the feces of mice. FOM also reduced mortality for one strain, the STX level decreased gradually. LVFX exhibited higher therapeutic efficacy than FOM. Strain differences were observed in the model during the treatment.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Toxins; Diarrhea; Disease Models, Animal; Escherichia coli Infections; Escherichia coli O157; Feces; Fosfomycin; Germ-Free Life; Humans; Levofloxacin; Mice; Ofloxacin; Shiga Toxins; Treatment Outcome

Antibiotic therapy for infection with Shiga-toxin-producing Escherichia coli O157:H7 is controversial because of the possibility of its inducing hemolytic uremic syndrome and acute encephalopathy. In a previous study, mice with protein-calorie malnutrition were found to be highly susceptible to this pathogen. The efficacy of oral antibiotic therapy in malnourished mice infected with O157 organisms was assessed. Mice fed a low-protein calorie diet were infected intragastrically with 2 x 10(6) colony-forming units of a Shiga-toxin-producing strain of Escherichia coli O157:H7. Infected mice were orally given a therapeutic dose of an antibiotic, including norfloxacin, fosfomycin, kanamycin, ampicillin, clarithromycin or trimethoprim-sulfamethoxazole for 3 days: mice on protocol A received the antibiotic on days 1-3, starting on the day after infection, and mice on protocol B received the antibiotic on days 3-5. The duration of fecal pathogen excretion was shorter and the toxin level in the stool and blood lower in the mice that received protocol A than in untreated mice; all of the mice treated on protocol A survived the lethal infection. All antibiotics except trimethoprim-sulfamethoxazole, administered on protocol B, exhibited the same effect as that exhibited by the respective antibiotic administered on protocol A. Only the mice treated with protocol B of trimethoprim-sulfamethoxazole had a higher toxin level in the blood than untreated controls, resulting in 95% mortality. These results suggest that the antibiotics used in this study, except for trimethoprim-sulfamethoxazole, could reduce the risk of hemolytic uremic syndrome and acute encephalopathy following Escherichia coli O157:H7 infection in humans, and that fosfomycin, in particular, may be relevant for testing in humans.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Bacterial Toxins; Brain Chemistry; Disease Models, Animal; Disease Progression; Escherichia coli Infections; Escherichia coli O157; Feces; Fosfomycin; Kanamycin; Mice; Mice, Inbred C57BL; Norfloxacin; Protein-Energy Malnutrition; Reference Values; Sensitivity and Specificity; Shiga Toxins; Statistics, Nonparametric; Survival Rate; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Though O157 can cause a life-threatening diseases, the therapeutic protocol using antibiotics for the infection is still controversial. Main reasons for hesitating the uses of antibiotics for the infection is their possibility to enhance the release of verotoxins (VT). We have recently established the mouse model of O157 infection using germfree mice. Using this animal model of O157 infection, we examined therapeutic efficacy of antibiotics. Fosfomycin (FOM) and norfloxacin (NFLX) were selected for in vivo examination, because of their lower MIC under anaerobic condition (MIC:FOM = 0.78; NFLX = 0.10 microgram/ml) than those of the other antibiotics including kanamycin, doxycycline, minocycline, choramphenicol, cefaclor and ampicilin. When germfree BALB/c mice were orally infected with 1 x 10(5)CFU of O157 (clinically-isolated strain, TI001) at day 0, all mice died at 8 to 9 d after the infection. Oral treatment of the mice with FOM (500 mg/kg/d, twice a day) or NFLX (50 mg/kg/d, twice a day) everyday for 5 days starting at 3 hr after the infection significantly improved the survival rate from 0% to 83.3%, and 100%, respectively. VT could not be detected in the feces of the mice in either groups, suggesting that neither of these antibiotics enhanced the release of VT. Interestingly, when FOM treatment was started at 3, 6, 12 or 24 hr after the infection, the survival rate was 100%, 100%, 0% and 0%, respectively. Thus, in conclusion, FOM and NFLX are both useful as the therapeutic agents for O157 infection. However, the treatment should be started in the early phase after the infection.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Toxins; Disease Models, Animal; Escherichia coli Infections; Escherichia coli O157; Fosfomycin; Germ-Free Life; Male; Mice; Mice, Inbred BALB C; Norfloxacin; Shiga Toxin 1; Time Factors

The bactericidal activity of pefloxacin and fosfomycin alone and in combination against Pseudomonas aeruginosa was evaluated in an experimental rabbit endocarditis model after 24 h of treatment. Two strains with intermediate susceptibility to pefloxacin and good susceptibility to fosfomycin were tested. The serum kinetics obtained during administration of 400 mg every 12 h in humans were simulated in the animals using computer-controlled variable-flow infusion. Fosfomycin was administered as a continuous infusion at a constant flow, allowing a steady-state concentration of 47.4 +/- 11.9 mg/ml to be reached in serum. In valvular vegetations, pefloxacin was less bactericidal than fosfomycin, and in combination treatment, it reduced (but did not abolish) the bactericidal effect of fosfomycin. The duration of the pretreatment interval (12-48 h) had a negative effect on the bactericidal activity of both drugs, especially that of fosfomycin.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Fosfomycin; Half-Life; Humans; Infusions, Intravenous; Pefloxacin; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Random Allocation; Treatment Outcome

Fosfomycin is an antibacterial substance of low molecular weight and negligible binding to plasma proteins exhibiting in-vitro activity against most pathogens involved in bacterial meningitis including pneumococci. Due to these properties the drug has been recommended for therapy of central nervous system (CNS) infections. For this reason, fosfomycin at doses of 10, 40, 80 and 160 mg/kg/h iv, was investigated in the rabbit model of pneumococcal meningitis. Bacterial counts in cerebrospinal fluid (CSF) before, and 2, 5 and 8 h after initiation of therapy were quantitated by plating on blood agar. Fosfomycin concentrations in serum and CSF were determined by the agar well diffusion method. The MIC and MBC of fosfomycin for the Streptococcus pneumoniae type 3 strain used was 4 and 32 mg/L, respectively. The MIC of ceftriaxone was 0.016 mg/L. In vitro, both drugs showed an additive effect (fractional inhibitory concentration index = 0.75). In vivo at each dose tested, fosfomycin was less active than ceftriaxone (means +/- S.D.): delta log cfu/mL/h at 10 mg/kg/h + 0.130 +/- 0.062 (n = 2), at 40 mg/kg/h -0.217 +/- 0.185 (n = 3), at 80 mg/kg/h -0.270 +/- 0.121 (n = 3), at 160 mg/kg/h -0.331 +/- 0.118 (n = 3) vs -0.647 +/- 0.193 at 10 mg/kg/h ceftriaxone (n = 3). CSF penetration of fosfomycin as estimated by the CSF-to-serum concentration ratio at 8 h was 0.55 +/- 0.22 (n = 11). For bactericidal activity CSF concentrations of at least ten times the MIC were necessary. Coadministration of both drugs (1 mg/kg/h ceftriaxone + 40 mg/kg/h fosfomycin) tended to be more active than either drug alone (in-vivo drug interaction = 1.3). In conclusion, fosfomycin at very high doses reduced bacterial counts in CSF. However, fosfomycin CSF concentrations usually observed in patients with meningitis receiving fosfomycin were not bactericidal in this model. At all doses tested the bactericidal rate was lower than that of ceftriaxone. Fosfomycin is therefore unsuitable as a single agent, but may be used as a reserve antibiotic in combination with a newer cephalosporin for pneumococcal meningitis unresponsive to conventional therapy.

Topics: Animals; Anti-Bacterial Agents; Blood Bactericidal Activity; Cerebrospinal Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Fosfomycin; Glucose-6-Phosphate; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcal Infections; Streptococcus pneumoniae

The in vivo activity of the combination of daptomycin and fosfomycin against a beta-lactamase-producing, highly gentamicin-resistant strain of Enterococcus faecalis in a relapse model of rat endocarditis was studied. Minimum inhibitory concentrations (MICs) (micrograms per milliliter) for these agents against this strain were 4 (daptomycin) and 16 (fosfomycin). Time-kill studies demonstrated synergistic bactericidal activity when daptomycin (0.5 micrograms/ml) and fosfomycin (32 micrograms/ml) were combined. There was no significant difference between the number of valves sterilized by daptomycin alone [six (35%) of 17 valves sterilized] and daptomycin+fosfomycin [ten (59%) of 17 valves sterilized] p = 0.3. These results suggest that the in vitro bactericidal synergism demonstrable between these two agents against strains of enterococci will not necessarily translate into greater therapeutic efficacy in clinical infections.

Topics: Animals; Daptomycin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecalis; Fosfomycin; Gram-Positive Bacterial Infections; Male; Microbial Sensitivity Tests; Peptides; Rats; Rats, Inbred Strains

An experimental model of infected subcutaneous fibrin clots in rabbits was used to study the synergism between cefotaxime and fosfomycin in infection with methicillin and gentamicin resistant Staphylococcus aureus (MGRSA), and to determine the efficacy of a simplified schedule of administration. The bactericidal activity of cefotaxime and fosfomycin against MGRSA was investigated giving the drugs in one full or two divided doses either alone or in combination. The pharmacokinetics of the drugs were correlated with the antibacterial efficacy obtained over 12 hours of treatment. The results confirmed that the combination of cefotaxime and fosfomycin is highly synergistic in experimental MGRSA infection. Higher bactericidal activity was obtained with a regimen of 6-hourly drug administration which resulted in persistent levels of both drugs in serum as well as at the site of infection.

Topics: Analysis of Variance; Animals; Cefotaxime; Disease Models, Animal; Drug Administration Schedule; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Gentamicins; Male; Methicillin; Penicillin Resistance; Rabbits; Staphylococcal Infections; Staphylococcus aureus

Topics: Animals; Disease Models, Animal; Endocarditis, Bacterial; Fosfomycin; Gentamicins; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Body Temperature; Disease Models, Animal; Fosfomycin; Humans; Nephritis; Rats; Time Factors