fosfomycin and Peritonitis

Consecutive adult patients requiring emergency abdominal surgery were randomly allocated to preoperative treatment with metronidazole-gentamicin (M-G) or metronidazole-fosfomycin (M-F). Postoperative continuation of antibiotics depended on the estimated risk of septic complications. Peroperatively the cases were stratified as group A, acute inflamed appendicitis, or absence of septic disorder--no postoperative antibiotics, group B, gangrenous appendicitis or cholecystitis or intestinal obstruction without resection, or operations with contamination regarded as minor (gastrotomy or enterotomy)--three further doses of antibiotics, or group C, perforated appendicitis, perforation of the alimentary tract, generalized peritonitis or gross contamination--antibiotics continued for 5 days. Assessment for septic complications was made in 381 patients (191 M-G, 190 M-F). The total incidence was 4.8% (M-G 7.8%, M-F 1.6%, p less than 0.01). The difference was mainly due to higher infection rate in patients stratified to group C and randomized to M-G. Stratification thus permitted restricted duration of antibiotic treatment with a low septic complication rate, significantly less with M-F than with M-G regimen.

Topics: Abdomen, Acute; Adolescent; Adult; Aged; Appendicitis; Cholecystitis; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fosfomycin; Gentamicins; Humans; Male; Metronidazole; Middle Aged; Peritonitis; Postoperative Complications; Random Allocation; Sepsis

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

Peritonitis is still the main infectious complication among patients on peritoneal dialysis. For treatment of peritoneal dialysis-related peritonitis, the intraperitoneal administration of antibiotics admixed to peritoneal dialysis fluids (PDFs) should be preferred. However, the influence of diverse PDFs on the activity of frequently used antibiotics has been investigated insufficiently. Thus, the present study set out to investigate the in vitro activity of fosfomycin against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus in commercially available PDFs. Time-kill curves in four different PDFs (Dianeal®, Extraneal®, Nutrineal®, and Physioneal®) were performed over 24 h with two different concentrations of fosfomycin (150 and 400 mg/L) and without antibiotics as control. Cation-adjusted Mueller Hinton broth (CA-MHB) was used as a comparator solution. In blank PDFs, bacterial growth of each organism evaluated was reduced when compared to CA-MHB. For S. aureus in blank Physioneal®, a reduction under the limit of detection was observed within 24 h. The activity of fosfomycin was reduced in all PDFs when compared to CA-MHB except for P. aeruginosa in Nutrineal® where the activity of fosfomycin was increased when investigated at 400 mg/L. Against E.coli, bactericidal activity was demonstrated in Extraneal®, Nutrineal®, and Physioneal®. Fosfomycin resistance (MIC > 1024 mg/L) was observed for P. aeruginosa in CA-MHB at both concentrations and in Nutrineal® at 150 mg/L. Fosfomycin is active in PDFs particularly against the frequently isolated enterobacterium E. coli. The choice of the respective PDF considerably influences the microbiological outcome in vitro. Further studies are warranted to investigate the clinical relevance of these findings.

Topics: Anti-Bacterial Agents; Dialysis Solutions; Escherichia coli; Fosfomycin; Humans; Microbial Sensitivity Tests; Peritoneal Dialysis; Peritonitis; Pseudomonas aeruginosa; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis

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

For treatment of peritoneal dialysis-related peritonitis, intraperitoneal administration of antibiotics remains the preferable route. For home-based therapy, patients are commonly supplied with peritoneal dialysis fluids already containing antimicrobial agents. The present study set out to investigate the compatibility of fosfomycin with different peritoneal dialysis fluids, namely, Extraneal

Topics: Anti-Bacterial Agents; Dialysis Solutions; Disk Diffusion Antimicrobial Tests; Drug Interactions; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Peritoneal Dialysis; Peritonitis

Blood and dialysate concentrations of fosfomycin were determined after intravenous and intraperitoneal application of 4 mg/liter in patients undergoing automated peritoneal dialysis. Maximum serum concentrations after intravenous (287.75 ± 86.34 mg/liter) and intraperitoneal (205.78 ± 66.78 mg/liter) administration were comparable. Ratios of intraperitoneal to systemic exposure were 1.12 (intraperitoneal administration) and 0.22 (intravenous administration), indicating good systemic exposure after intraperitoneal application but limited penetration of fosfomycin into the peritoneal fluid after the intravenous dose.

Topics: Adult; Aged; Female; Fosfomycin; Humans; Injections, Intraperitoneal; Injections, Intravenous; Male; Middle Aged; Peritoneal Dialysis; Peritonitis

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

Relapsing peritonitis is often due to bacterial colonization of the Tenckhoff catheter and may require removal of the catheter in patients on peritoneal dialysis. The efficacy of a Tenckhoff catheter decontamination procedure was examined in 9 pediatric patients aged 1.5-18 years and compared to the outcome of a historical control group. After repeated dialysate cultures had become negative and cell count was normalized (< 100/ul), intraluminal urokinase (5000 IU/ml) and intraluminal high concentrated antibiotics (vancomycin, fosfomycin, cefotaxim) were instilled sequentially for 3 h and 1 h respectively. This procedure was performed once daily for three days. In addition, the connector was exchanged on the last day. This regimen prevented relapsing peritonitis in all study patients, whereas in the control group in 75.8% of events further relapses occurred, necessitating removal of the Tenckhoff catheter in 7/19 (36.8%) episodes. No side effects of intraluminal urokinase were recorded in any of the patients. We conclude that intraluminal urokinase and intraluminal high concentrated antibiotics combined with connector device exchange are highly effective for prevention of further relapses of peritonitis and reduce the need for Tenckhoff catheter exchange.

Topics: Adolescent; Cefotaxime; Child; Child, Preschool; Drug Therapy, Combination; Fosfomycin; Humans; Infant; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Prospective Studies; Recurrence; Thrombolytic Therapy; Urokinase-Type Plasminogen Activator; Vancomycin

The kinetics of intraperitoneal killing of proliferating bacteria was studied in pigs given fosfomycin. Eight animals were given intra-abdominal injection of Escherichia coli and Bacteroides fragilis (10(9) cfu of each species) mixed in sterile faces. Three hours later, half of the animals received an intravenous dose of 1 g fosfomycin (0.05 g/kg). Host defences rapidly decreased the density of E. coli in all animals in the first hour. After 2h, growth of E. coli started and continued throughout the experiment in pigs not receiving fosfomycin. B. fragilis was slowly eliminated in the first 5 6 h, then numbers increased in all animals. Fosfomycin caused a reduction in E. coli density, by 10(2.19) +/- 0.29 (mean +/- S.E.M.) cfu/ml, or more than 150 times within 1 h, while the concentration of B. fragilis was unaltered. After 10 h the difference in E. coli density between fosfomycin treated and untreated animals was 10(4.96) cfu/ml (P less than 0.01). Fosfomycin eradicated E. coli in faecal peritonitis but not B. fragilis, which is resistant in vitro. There was a prolonged elimination of the drug from peritoneal exudate in pigs infected with bacteria in sterile faeces compared to the elimination in uninfected pigs or pigs infected only with bacteria.

Topics: Animals; Bacteroides fragilis; Escherichia coli; Exudates and Transudates; Feces; Fosfomycin; Peritonitis; Swine

Topics: Adult; Aged; Bacterial Infections; Cefotaxime; Female; Fosfomycin; Humans; Male; Middle Aged; Moxalactam; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis

An approximately steady state of bacterial density intraperitoneally has been observed in bacterial peritonitis. This state, which follows an initial (0-4 h) phase of rapid elimination of bacteria, was now studied in a model of porcine peritonitis. Twelve pigs were intra-abdominally infected with 10(10) CFU each of Escherichia coli and Bacteroides fragilis. Six of the pigs received no antibiotic and six were given two doses of fosfomycin (anti-aerobic), 1 g i.v., with the aim of disturbing possible equilibrium between rapid proliferation and destruction of the sensitive E. coli. Levels of fosfomycin up to 90 times the minimum inhibitory concentration (1 mg/l) were detected in the peritoneal exudate, but the antibiotic had no discernible effect on E. coli density or elimination pattern compared with B. fragilis in the same pig or with observations in controls. The results favoured the concept of slow-replicating E. coli and hence declining activity of the defence mechanisms a few hours after the induction of peritonitis.

Topics: Animals; Bacillus; Bacteria; Dose-Response Relationship, Drug; Escherichia coli; Fosfomycin; Immunity; Peritoneal Cavity; Peritonitis; Swine

Twenty-one peritonitis in patients on continuous ambulatory peritoneal dialysis were treated by pefloxacin and intraperitoneal fosfomycin. Recovery occurred in 19 cases, there were two relapses. No major side effects was observed. This treatment seems to be easy to perform and effective.

Topics: Drug Therapy, Combination; Female; Fosfomycin; Humans; Male; Pefloxacin; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis

Fosfomycin (FOM) is a synthetic antibiotic having a unique structural formula and bactericidal mechanism and a broad spectrum of antimicrobial activity against various bacterial species. It has higher activity in vivo than in vitro. As therapy, FOM-Na in a daily dose of 4 g (2 g X 2) was given by intravenous drip infusion for 5 to 10 days to 6 cases with infectious diseases (2 cases of acute cholecystitis, 3 cases of acute localized peritonitis due to phlegmonous appendicitis and 1 case of acute diffuse peritonitis due to perforative appendicitis). The clinical response was rated as "excellent" in 1 case, "good" in 4 cases, "fair" in 1 case and "poor" in none. No adverse effects were observed in any of the patients. Six clinical isolates were obtained, and these consisted of 4 strains of Escherichia coli and 1 strain each of Klebsiella pneumoniae, and Bacteroides fragilis. The MICs of FOM were from 6.25 to 12.5 micrograms/ml for E. coli, 50 micrograms/ml for K. pneumoniae, and 100 micrograms/ml for B. fragilis. FOM-Na was administered to the 6 cases intravenously in a dose of 2 g before surgery, and tissue specimens and body fluid samples were taken during the operation. The FOM concentration was determined by bioassay with a Proteus sp. (MB 838) as the test organism. The mean FOM concentration in bile from the common bile duct was 61.85 +/- 17.13 micrograms/ml (n = 5) at 95 to 108 minutes after FOM-Na intravenous bolus injection. The mean FOM concentration in the gall bladder bile was 80.06 +/- 92.36 micrograms/ml, while that in the gall bladder wall was 146.65 +/- 39.10 micrograms/g. The mean FOM concentration in purulent ascites was 58.20 +/- 13.29 micrograms/ml, 36.22 +/- 14.63 micrograms/g in the appendix wall and 12.64 +/- 11.34 micrograms/ml in pus in the appendix. The FOM concentrations in the infected tissues and body fluids thus exceeded the MICs of FOM for the pathogenic bacteria. Therefore, FOM-Na appears to be a very useful drug when used for chemotherapy of infections encountered in the surgical field.

Topics: Acute Disease; Adolescent; Adult; Aged; Appendix; Ascitic Fluid; Bile; Child; Cholecystitis; Drug Resistance, Microbial; Female; Fosfomycin; Gallbladder; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Peritonitis