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Erysipelothrix rhusiopathiae, a Gram-positive bacillus, is reported to cause for cutaneous infections and endocarditis. We report a case of E. rhusiopathiae bacteremia without severe clinical illness. The patient, a 74-year-old man, is suffering from a chronic lymphoid leukemia (LLC). Following a trauma, the patient developed a bruise on the left inch. Because the site of shock seemed clinically infected, oral amoxicilline-acid clavulanic (AAC) treatment was started after withdrawn 1 set of blood cultures. These blood culture specimens yielded a Gram-positive bacillus identified as E. rhusiopathiae by mass spectrometry MALDI-TOF (Microflex Brüker). The strain was sensitive to beta-lactam, fluoroquinolones and macrolides, resistant to vancomycin (natural resistance), and amikacin but sensitive to gentamicin. After 5 days of treatment by AAC, the patient became apyretic. One year after this episode, we reported no further symptoms of infection, or endocarditis. The natural resistance of E. rhusiopathiae in glycopeptides underlines the importance of a microbiological diagnosis. Indeed, vancomycine can be the treatment of first intention in Gram-positive bacillus bacteremia. The identification of bacteria using mass spectrometry is available the same day of the blood culture positivity and allows to prescribe the most adapted antibiotic treatment for the patient.

We report a human case of infective endocarditis caused by Streptococcus canis. Identification was carried out from positive blood culture using mass spectrometry and SodA gene sequencing. S. canis related zoonotic invasive infections may have been previously underdiagnosed due to inadequate identification of group G Streptococcus species.

We studied the activity of the combination of sulbactam and ceftriaxone against a Klebsiella pneumoniae strain producing TEM-3, a new extended-broad-spectrum beta-lactamase, in an endocarditis model. In vitro, ceftriaxone was strongly inactivated in the presence of TEM-3 (MBC, 128 micrograms/ml with an inoculum of 5 x 10(5) CFU/ml). A marked inoculum effect was demonstrated with sulbactam: effective concentrations of inhibitor needed to reduce the MIC and MBC of ceftriaxone to similar levels increased from 1 microgram/ml in the presence of an inoculum of 5 x 10(5) CFU/ml to 20 micrograms/ml in the presence of an inoculum of 1 x 10(7) CFU/ml. In vivo, sulbactam given at 200 mg/kg of body weight every 12 h, a dosage higher than that previously reported to be effective against rabbit endocarditis caused by other microorganisms, was not sufficient to restore the complete activity of ceftriaxone given at 30 mg/kg once daily for 4 days. This insufficient activity may be correlated with the presence of a high level of beta-lactamase inside the vegetations, as indicated by a quantitative in vitro assay of beta-lactamase activity in the cardiac vegetation, suggesting an insufficient inactivation of the extended-broad-spectrum beta-lactamase in vivo.

We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.

To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three cephalosporins, cefotiam, cefmenoxime, and ceftriaxone, in a rabbit model of experimental Escherichia coli endocarditis after 4 days of treatment. The MBCs of cefotiam, cefmenoxime, and ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves at 10 times the MBC were similar for the three cephalosporins. In serum, the elimination half-life of ceftriaxone was twice as much as the elimination half-life of cefotiam or cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively). Ceftriaxone was much more effective than cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with cefotiam and 2.41 +/- 2.6 with ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although ceftriaxone and cefmenoxime exhibited a similar rate of killing and percentage of protein binding, ceftriaxone was more effective than cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for ceftriaxone, but not for cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum cephalosporin may be effective in severe gram-negative infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared drug with the same intrinsic activity.

The serum protein binding, extravascular diffusion and urinary excretion of teicoplanin were studied in rabbits. Extravascular diffusion was studied after a 20 min iv infusion, and after one or five im injections (7.5 mg/kg), and was compared with the results obtained after im administration of vancomycin (7.5 and 15 mg/kg). In an experimental model of Staphylococcus aureus endocarditis, the efficacy of both antibiotics was also investigated. We observed teicoplanin serum protein binding of 87 +/- 4%. The serum concentrations of teicoplanin showed a three-phase exponential decline: T1/2 alpha, 0.11 +/- 0.01 h; T1/2 beta, 1.4 +/- 0.4 h; T1/2 gamma, 8.3 +/- 2.2 h. Teicoplanin appeared to be slightly secreted by renal tubules. The extravascular diffusion and the therapeutic efficacy of both drugs were studied with intervals between two injections based on the same multiple of beta half-life. Teicoplanin, like vancomycin, appeared slowly in extravascular fluid and the diffusibility of both drugs was similar. Peak extravascular concentrations of teicoplanin after 5 im injections were greater when the compound was administered every 16 h, rather than every 24 h and, for this drug, iv administration induced higher peak extravascular concentrations (P less than 0.01) than im injection. In the experimental model of S. aureus endocarditis, vancomycin 9 mg/kg/12 h and teicoplanin 4.5 mg/kg/16 h were similarly active and more effective than teicoplanin 4.5 mg/kg/24 h.

The authors studied the activity of fosfomycin (FOS) and/or gentamicin (GEN) against a Klebsiella pneumoniae strain resistant to all beta-lactams--except cephamycins and imipenem--by production of a plasmid mediated extended broad-spectrum beta-lactamase-TEM-3, to all aminoglycosides--except gentamicin--by production of a plasmid mediated 6' aminoglycoside acetyltransferase IV, to sulfonamides and to tetracyclines. In vitro, the combination FOS (MIC = MBC = 32 mg/l) + GEN (MIC = MBC = 2) appeared indifferent (FIC = 0.75; FBC = 1). In vivo, on experimental endocarditis in rabbits, FOS alone was ineffective, GEN alone was active but only at high dose regimen, FOS - GEN combination was active as compared with controls. Fosfomycin - gentamicin combination may be an alternative in the therapy of severe infections due to multiresistant Enterobacteriacae.

The clinical course, prognostic factors, and management of 50 cases of late prosthetic valve endocarditis, occurring more than two months after valve replacement, were reviewed. Twenty nine cases that presented from 1971 to 1980 were compared with 21 cases that presented from 1981 to 1985. Apart from an appreciable decrease in the frequency of neurological complications between the first period (38%) and the second period (10%) no differences in clinical or bacteriological features were seen. Seventeen (59%) of the 29 cases in the earlier period and four (19%) of the 21 cases in the later period died. The rationale for antimicrobial treatment was similar during both periods. Cardiac surgery was performed in eight of 29 cases between 1971 and 1980 and in 11 of 21 between 1981 and 1985; the mean (SD) time between diagnosis of endocarditis and operation was 28 (19) days and 43 (44) days respectively. Six of the eight cases operated on in the first period died as did two of the 11 operated on in the second period. Twenty seven of the 29 cases presenting between 1971 and 1980 were treated with anticoagulants--either warfarin (15 of 27) or heparin sodium (12 of 27). Sixteen of the 21 cases presenting later were given anticoagulants and 15 of these cases were given heparin sodium. Control of anticoagulation was inadequate in nine of the 27 cases treated with anticoagulants during the first period and in only two of 16 treated during the second period. During the first treatment period neurological complications were more frequent when control of anticoagulation was inadequate.

We studied the effect of a nonsteroidal anti-inflammatory drug, diclofenac, in rabbits on the kinetics of three cephalosporins: cefotiam, cefmenoxime and ceftriaxone, and compared the antibacterial effect of these antibiotics, given alone or with diclofenac, in experimental endocarditis. Diclofenac significantly increased (P less than .05) the area under the curve in tissue-cage fluid of ceftriaxone and cefotiam-treated animals, and the terminal half-life of ceftriaxone in their sera (3.45 +/- 0.4 vs. 2.8 +/- 0.5 hr). Diclofenac reduced urinary excretion of cefotiam only. Cefmenoxime pharmacokinetics remained unchanged by diclofenac. The alteration of ceftriaxone kinetics appeared to be due to nonrenal mechanisms and could suggest reduction of biliary excretion. In Escherichia coli endocarditis, diclofenac enhanced the concentration (P less than .05) of cefotiam (23 +/- 16 vs. 8.9 +/- 5 micrograms/g) and ceftriaxone (13.2 +/- 3 vs. 8.5 +/- 4 micrograms/g) in infected vegetations, but not that of cefmenoxime. The antibacterial effect of ceftriaxone increased with diclofenac (5.5 +/- 1 vs. 7.2 +/- 1 log10 colony forming unit/g of vegetation). In vitro, neither protein binding to rabbit serum proteins nor intrinsic activity on the E. coli strain of each antibiotic was modified by diclofenac. These results suggest that anti-inflammatory drugs could increase antibiotic efficacy by altering their pharmacokinetics. The renal and nonrenal site of interaction may be involved for drugs belonging to the same class. Results obtained in tissue-cage fluid were predictive of the interference at the infected site.

The pharmacokinetics of gentamicin and latamoxef (moxalactam) were examined in serum, normal heart valves, sterile cardiac vegetations and vegetations infected with Escherichia coli. Penetration of antibiotics into heart valves and vegetations was rapid; the maximum concentration was achieved in both sites at the end of a 20 min iv infusion. However, both antibiotics penetrated better into vegetations than into normal heart valves. In rabbits with left-sided endocarditis, similar antibiotic levels were found in infected vegetations after one or 22 im injections. After 11 im injections (one every 8 h) of latamoxef (15 mg/kg) the bacterial titre (cfu/g) was significantly reduced, but not nil, despite concentrations about 40 times the MBC for this antibiotic in the vegetations. Afer 22 im injections, vegetations in rabbits receiving latamoxef were sterile and were significantly reduced in those receiving gentamicin (1.5 mg/kg/im), concentrations of which in the vegetations were inferior to the MBC. Our results suggest that the in-vivo antibacterial effect depends on local antibiotic levels, kinetics of killing and duration of contact between antibiotic and bacteria.

The serum protein binding, extravascular diffusion and urinary excretion of pefloxacin were studied in rabbits. The effect of furosemide on the urinary excretion of pefloxacin was investigated. In an experimental model of Escherichia coli endocarditis, diffusion into heart valves and infected vegetations and bactericidal effect of pefloxacin were also studied. We observed a serum protein binding of 25%. Extravascular concentrations found were within the range of the minimal inhibitory concentrations for most susceptible strains. Pefloxacin appeared to be reabsorbed by renal tubules (fractional excretion: 61 +/- 21%). Furosemide significantly increased the renal excretion of pefloxacin through a tubular process. We observed a good penetration of pefloxacin into normal heart valves and infected vegetations. Pefloxacin reduced the colony counts in infected vegetations after seven im injections of the drug (given as 15 mg/kg/12 h).

In a rabbit model of Escherichia coli endocarditis, we studied the penetration into infected vegetations and the antibacterial effect of ceftriaxone. Ceftriaxone was given at different dosages, alone or with an interfering agent, diclofenac, a nonsteroidal anti-inflammatory drug, to determine the predictive value of the antibiotic levels in serum or infected vegetations on the antibacterial efficacy. Diclofenac increased the serum terminal half-life of ceftriaxone and increased its extravascular diffusion in tissue cage fluid, as well as in infected vegetations, allowing us to obtain various antibiotic concentrations in the infected site. Two hours after the fourth injection, around the time of peak level in serum, we observed a linear relationship between (i) serum and local antibiotic levels in vegetations, (ii) local antibiotic levels in a range of 142 to 600 X MBC and bacterial titer (log10 CFU/g) in vegetations, and (iii) serum antibiotic levels in a range of 800 to 1,400X MBC and bacterial titer in vegetations. In vivo, antibacterial effect was obtained only with high antibiotic levels in vegetations (greater than or equal to 220X MBC). This was confirmed by incubating vegetations sampled from infected animals in rabbit serum containing ceftriaxone (ex vivo experiment). Given once daily at a therapeutic dosage (30 mg/kg) for 4 days, ceftriaxone exhibited good efficacy (log10 CFU/g of vegetation = 2.41 +/- 2.7 versus 7.41 +/- 0.92 in control animals) and prevented regrowth of bacteria until 24 h after the last injection. We concluded that (i) provided the dose is sufficient, a long-acting cephalosporin can prove effective in severe gram-negative infections even when given infrequently, and (ii) serum antibiotic levels around the peak value, reflecting high effective local levels, could predict the therapeutic efficacy and represent a simple test to monitor the clinical course of a severe infectious process.

The therapeutic effectiveness of pefloxacin was evaluated in 15 patients admitted to an intensive care unit and suffering from septicaemia or endocarditis. Seven of these patients had a focal infection (acute anterior mediastinitis or epiduritis). Pefloxacin was combined with an aminoglycoside in 13 cases and with rifampicin in 1 case. Blood cultures became or remained negative in all patients. The associated focus of infection was sterilized in 5 patients; a pefloxacin-resistant pathogen was subsequently isolated in 2 other patients. Three patients died some time after the infectious episode. The minimum inhibitory concentration of pefloxacin ranged from 0.25 to 2 mg/l. The bactericidal activity of the serum at peak concentration was greater than or equal to 1/8 in all cases and greater than or equal to 1/32 in 10 cases. No resistant mutants were selected during treatment. However, 8 strains of a species different from that of the initial pathogen were isolated from a site other than the primary focus. Pefloxacin can therefore be used successfully in the treatment of systemic infections, but close monitoring of bacterial ecology is required.

We evaluated the activities of ceftriaxone (15 mg/kg), netilmicin (6 mg/kg), and their combination given intramuscularly once daily for 4 days for the treatment of experimental Escherichia coli endocarditis in rabbits. In vitro, a greater rate of killing and an increased trough serum bactericidal titer (P less than 0.01) were achieved with the combination. In vivo, the combination had a greater bactericidal effect (P less than 0.01) and resulted in a greater number of sterile vegetations (P less than 0.05) than single-drug therapy. Thus, in vivo, an increased effect can be obtained despite a single daily dose of a long-acting cephalosporin and an aminoglycoside.