The purpose of this study was to evaluate the possible benefit of fosfomycin (FOM) as prophylactic antibiotic in terms of antimicrobial activity and the potential of inducibility of β-lactamase, compared with cefazolin, cefotiam, cefmetazole, and piperacillin that are commonly used as perioperative agents. The in vitro activity of FOM against aerobic Gram-negative bacteria using Mueller-Hinton agar or nutrient agar supplemented with glu cose-6-phosphate (G6P) as tested medium increased within arange from 2 to 256 times the activity in the medium without G6P. However, thesusceptibility of Gram-positive bacteria to FOM remained largely unchanged With or Without G6P. There Was no aerobiC-or anaerobic-bacteria Which Changed susCeptibility againSt β-lactam antibiotics under variousl tested medium conditions. FOM demonstrated strong bactericidal activity against Escherichia coli and Pseudomonas aeruginosa in a dose dependent manner, and decreased viable cell counts of Staphylococcus aureus. In the case of P. aeruginosa, transmission electron micrographs study revealed that numerous lysed cells were present 2 hours after treatment with FOM at four times the MIC. First and second generation cephalosporins induced AmpC-type β-lactamase in a dose dependent manner among β-lactamase inducible strains of P. aeruginosa and Enterobacter cloacae. On the other hand, inducible activity of FOM on β-lactamase production was less than 1/25 to 1/65 compared with those of cephalosporins. In addition, FOM maintained strong antimicrobial activity for over then 20 years after marketing, because of the excellent stability against various types of β-lactamase produced by plasmid-carrying bacteria and clinical isolates. FOM was not extruded by four types of efflux systems, such as MexAB-OprM, MexCD-OprJ, MexXY/OprM and MexEF-OprN, however β-lactam antibiotics were substrates of MexAB-OprM and MexCD-OprJ. In conclusion, FOM provides adequate coverage for both aerobic Gram-positive and Gram-negative bacteria causing postoperative infections. Further, FOM would not select/concentrate β-lactamase producing bacteria in the clinical fields and would not be a substrate for multidrug efflux system of P. aeruginosa.

View full abstract

Tendency of isolated bacteria from infections in general surgery during the period from April 2003 to March 2004 were investigated in a multicenter study in Japan, and the following results were obtained.
In this series, 455 strains including 14 strains of Candida spp. were isolated from 191 (75.2%) of 254 patients with surgical infections. Two hundred and thirty-nine strains were isolated from primary infections, and 216 strains were isolated from postoperative infections. From primary infections, anaerobic Gram-positive bacteria and aerobic Gram-negative bacteria were predominant, while aerobic Gram-positive bacteria were predominant from postoperative infections. The isolation rate of aerobic Gram-positive bacteria, such as Enterococcus spp. and Staphylococcus aureus were higher from both types of infections. Among anaerobic Gram-positive bacteria, the isolation rate of Peptostreptococcus spp. was the highest from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coil was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa in this order, and from postoperative infections, E. coil was the most predominantly isolated, followed by P. aeruginosa, E.cloacae, and K. pneumoniae. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both types of infections. The isolation rate of anaerobic Gram-positive bacteria from primary infections and that of aerobic Gram-positive bacteria from postoperative infections were high in the last several years.
In this series, we noticed no vancomycin-resistant Gram-positive cocci, but a few strains of moderately arbekacin-resistant MRSA. Carbapenm-resistant P. aeruginosa was seen in less than 10 per cents. Last year we noticed that there were cefazolin-resistant E. coil producing extended spectrum β-lactamase, but there was no highly cefazolin-resistant E. coli in this year. In the next series, increase of both anaerobic bacteria and Enterococcus spp. should be carefully followed up.

View full abstract

Monte Carlo simulation was enmloyed to determine pharmacodynamic target attainment rates for several meropenem dosage regimens against E. coli and P. aeruginosa populations. Percent Time above MIC (%T>MIC) exposures for several meropenem dosage regimens were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the injection antibiotics include of Meropenem susceptibility test surveillance program. The probabilities of attaining bacteriostatic responses (30%T>MIC) and bactericidal responses (50%T>MIC) exposures were high for all dosage regimens against populations of E. coli. Against P. aeruginosa, the 1000mg 3.0 infusion q⁸ dosage regimen provided the hightest target attainment rates.
Further study of these dosage recommendations in clinical trials is suggested.

View full abstract

As a basic study of combination therapy for bacterial meningitis, in vitro combined effect of meropenem (MEPM) and various antimicrobial agents against β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR) and penicillin-resistant Streptococcus pneumoniae (PRSP) was investigated.
The following findings were obtained.
1. In the checker board assay using 23 clinical isolates of BLNAR, MEPM+ cefotaxime (CTX), MEPM+ampi cillin (ABPC), and MEPM+rifampicin (RFP) showed synergistic effect (21 strains, 6 strains, 4 strains, respectively) or additive effect (2 strains, 17 strains, 19 strains, respectively).
2. In the checker board assay using 19 clinical isolates of PRSP, MEPM+ CTX, MEPM+teicoplanin (TEIC), and MEPM+RFP showed synergistic effect (5 strains, 8 strains, 1 strain, respectively), additive effect (14 strains, 11 strains, 17 strains, respectively) or indifference (0 strain, 0 strain, 1 strain, respectively).
3. The time-kill assay with BLNAR demonstrated synergistic bactericidal effect of MEPM+ CTX and MEPM+RFP, but not MEPM+ABPC.
4. The time-kill assay with PRSP demonstrated synergistic or additive bactericidal effect of MEPM+CTX, MEPM+TEIC, and MEPM+ RFP.
5. There were no antagonistic effect in any combination tested in this study.
These findings suggest that combination therapy with MEPM and various antimicrobial agents tested in this study are useful in treating bacterial meningitis caused by BLNAR and PRSP.

View full abstract