Affinity of cefotiam for the alternative penicillin binding protein PBP3SAL used by Salmonella inside host eukaryotic cells.

BACKGROUND: Following the invasion of eukaryotic cells, Salmonella enterica serovar Typhimurium replaces PBP2/PBP3, main targets of ß-lactam antibiotics, with PBP2SAL/PBP3SAL, two homologue peptidoglycan synthases absent in Escherichia coli. PBP3SAL promotes pathogen cell division in acidic environments independently of PBP3 and shows low affinity for ß-lactams that bind to PBP3 such as aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime and cefalotin. OBJECTIVES: To find compounds with high affinity for PBP3SAL to control Salmonella intracellular infections. METHODS: An S. Typhimurium ΔPBP3 mutant that divides using PBP3SAL and its parental wild-type strain, were exposed to a library of 1520 approved drugs in acidified (pH 4.6) nutrient-rich LB medium. Changes in optical density associated with cell filamentation, a read-out of blockage in cell division, were monitored. Compounds causing filamentation in the ΔPBP3 mutant but not in wild-type strain-the latter strain expressing both PBP3 and PBP3SAL in LB pH 4.6-were selected for further study. The bactericidal effect due to PBP3SAL inhibition was evaluated in vitro using a bacterial infection model of cultured fibroblasts. RESULTS: The cephalosporin cefotiam exhibited higher affinity for PBP3SAL than for PBP3 in bacteria growing in acidified LB pH 4.6 medium. Cefotiam also proved to be effective against intracellular Salmonella in a PBP3SAL-dependent manner. Conversely, cefuroxime, which has higher affinity for PBP3, showed decreased effectiveness in killing intracellular Salmonella. CONCLUSIONS: Antibiotics with affinity for PBP3SAL, like the cephalosporin cefotiam, have therapeutic value for treating Salmonella intracellular infections.

Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2: A Combined in silico and in†vitro Study.

In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top-100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS-CoV-2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration-dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.

Penetration and exposure of cefotiam into the peritoneal fluid of abdominal surgery patients after intravenous administration.

The present study aimed to examine the peritoneal pharmacokinetics and pharmacodynamic exposure of intravenous cefotiam. One gram of cefotiam was administered to eight patients before abdominal surgery. Venous blood and peritoneal fluid (PF) samples were obtained at the end of infusion (0.5 h) and 1, 2, 3, 4, 5, and 6 h afterwards. The drug concentrations in the plasma and PF were determined, analyzed pharmacokinetically, and used for a stochastic simulation with minimum inhibitory concentration (MIC) data. Cefotiam penetrated well into the PF with the area under the drug concentration-time curve ratio of 0.88 +/- 0.18 (mean +/- SD, n = 8). Regarding the pharmacodynamic exposures against Escherichia coli and Klebsiella species, the probabilities of attaining the bacteriostatic target (40% of the time above MIC) in the PF using 0.5 g every 12 h, 1 g every 12 h, and 2 g every 12 h were 88.3-93.6%. However, 1 g every 8 h was needed for 89.7 and 91.6% probabilities of attaining the bactericidal target (70% of the time above MIC). These results should help us to understand better the peritoneal pharmacokinetics of cefotiam while also helping us to choose the appropriate dosage for intra-abdominal infections.

[Fundamental study on the selection of antimicrobial prophylactic agents in abdominal surgery].

Most infections after abdominal operations are endogenous and occur by disseminating bacteria present in the intestinal tract during operation. The risk of developing surgical site infection after abdominal operations is related to the extent of intestinal contamination during operation and to the density and type of bacteria in the intestinal tract. Although antimicrobial prophylactic agents must be active against contaminating bacteria during operation, it should not cover all contaminating bacteria but Staphylococcus aureus except MRSA, Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Proteus spp. and Bacteroides spp. As the isolation rate and type of bacteria from primary abdominal infections such as perforated peritonitis and biliary tract infection are resemble to those of bacteria contaminating during operations, antimicrobial prophylactic agents could be chosen considering activities against bacteria isolated from primary infections. According to the isolation rates of these bacteria and antibiotic susceptibilities, cefotiam (CTM) is considered to have most strong activities as prophylactic agent for abdominal surgery, followed by cefmetazole (CMZ) and cefazolin (CEZ), in this order. In order to establish the fundamental principle of antimicrobial prophylaxis in surgery, these results should be evaluated by clinical prospective randomized studies in the near feature.

In vitro activity of cefotiam against oxacillin-resistant Staphylococcus epidermidis strains--reevaluation of beta-lactam antibiotics efficiency on MRSE.

We evaluated the efficacy of cefotiam (CTM) against Staphylococcus epidermidis (S. epidermidis) isolated from blood culture and central venous catheters. Of the S. epidermidis strains tested, 82.3% were methicillin (MPIPC)-resistant (MPIPC MIC > or = 0.5 microg/ml) and expressed the mecA gene, and 89.2% of these MPIPC-resistant S. epidermidis (MRSE) showed less than 8.0 microg/ml CTM MIC. In vitro killing kinetics of CTM against MRSE demonstrated that strains with high CTM MIC (> or = 4.0 microg/ml) showed high MPIPC MIC (> or = 4.0 microg/ml). All strains with low CTM MIC (< or = 2.0 microg/ml) showed MPIPC MIC lower than 2.0 microg/ml. In time-kill studies, CTM had high bactericidal activity against strains with low CTM MIC (< or = 2.0 microg/ml), regardless of whether they were mecA positive. These results demonstrated that MRSE isolates with low CTM MIC (< or = 2.0 microg/ml) are not easily induced CTM resistance by CTM treatment in vitro, and indicated the possibility that beta-lactams such as CTM could be an effective antibiotic agents against beta-lactam-sensitive MRSE infections.

[Role of Ph-SA in enhancing bactericidal activity of beta-lactam antibiotics].

OBJECTIVE: To identify the role of Ph-SA in inhibiting beta-lactamase secretion of S. aureus and in enhancing the bactericidal activity of antibiotics against antibiotic resistant bacteria. METHODS: To determine the effects of Ph-SA on beta-lactamase product of bacteria and on bactericidal activity of penicillin, the growth rate and lactamase activity of penicillin-resistant S. aureus cells in exponential growth were detected after treatment with 1.43 X 10(-4) micromol/mL (10 microg/mL) Ph-SA (Group 1), 2.81 x 10(-2) micromol/mL (10 microg/mL) penicillin (Group 2), 0.715 x 10(-4) micromol/mL(5 microg/mL) Ph-SA + 1.40 x 10(-2) micromol/mL (5 microg/mL) penicillin (Group 3) respectively; and a control group was detected for comparison. The same method was used to detect whether Ph-SA could enhance bactericidal activity of Cefazolin. Results It was revealed that 1.43 x 10(-4) micromol/mL (10 microg/mL) Ph-SA could inhibit beta-lactamase activity significantly, whereas no marked bactericidal activity was detected. The growth rate of bacteria cells treated with 0.715 x 10(-4) micromol/mL Ph-SA + 1.40 x 10(-2) mol/mL penicillin and that of bacteria cells treated with 0. 715 x 10(-4) micromol/mL (5 microg/mL) Ph-SA + 1.05 x 10(-2) micromol/mL (5 microg/mL) Cefazolin were the same as those treated by 2.81 x 10(-)2 micromol/mL (10 microg/mL)penicillin and 2.10 x 10(-2) micromol/mL (10 microg/mL) Cefazolin respectively, while the beta-lactamase activities of both groups were lower than control. CONCLUSION: Ph-SA may be of value in enhancing the bactericidal activity of antibiotics and in alleviating the resistance of bacteria by inhibition of beta-lactamase activity.

Flupenthixol and cefotiam: effects on vitamin A metabolism in rats.

We examined the alterations in vitamin A metabolism as a result of flupenthixol or cefotiam administration. The impact of these drugs on indices of vitamin A status was evaluated in Brown Norway and Long-Evans rats. Intramuscular drug administration for 28 d resulted in a decline in systemic retinol. Changes in circulating retinol with time for chronic dosing showed drug treatment (P<0.001) and time (P<0.03) to be significant factors, but rat strain (P=0.33) was not a significant factor. Flupenthixol was the most active retinol-lowering compound (P<0.005). At the end of the 28 d period, hepatic retinyl ester hydrolase activity was greater in drug-treated rats than in controls (P<0.05). With regard to effects on liver reserves: (1) flupenthixol treatment resulted in vitamin A depletion (P<0.05); (2) cefotiam treatment stimulated vitamin A accumulation; (3) distinctive patterns of retinol and its esters were seen in response to treatment. It is reasonable to assume that the drugs interfere with vitamin A in at least two ways: (1) lowering of plasma retinol, an early event in the interaction, may be caused by inhibition of hepatic holo-retinol-binding protein secretion or stimulation of clearance, or both; (2) when plasma retinol levels are persistently low, and as the hepatic deposits of the xenobiotics build up, there are changes in the vitamin A pool size and composition of the liver. Candidate enzymes are retinyl ester hydrolase and cytochrome P450. The relationship between these two events will be studied in further detail.

[Antimicrobial activity of fosfomycin against beta-lactamase-producing methicillin-sensitive Staphylococcus aureus and methicillin-sensitive coagulase-negative staphylococci].

Antimicrobial activity of fosfomycin (FOM), cefazolin (CEZ), cefmetazole (CMZ), cefotiam (CTM) and piperacillin (PIPC) against clinical isolates of methicillin-sensitive Staphylococcus aureus (MSSA) (beta-lactamase-producing or non-producing) and methicillin-sensitive coagulase-negative Staphylococci (MSCNS) (beta-lactamase-producing or non-producing) were determined to make clear the differences in antimicrobial activity of FOM and beta-lactam antibiotics. The antimicrobial activity of PIPC against beta-lactamase-producing strains of MSSA was lower than that against non-producing ones, judging from the distribution patterns of susceptibility of the strains to PIPC. There were no differences in the antimicrobial activity of FOM, CEZ and CMZ for the producing and non-producing strains. The activity of FOM against MSCNS was comparable to that against MSSA, although those of CEZ, CMZ, CTM and PIPC were decreased. FOM, CEZ, CMZ and CTM showed bactericidal activity against TH4278 (MIC [microgram/ml]: FOM, 1; CEZ, 0.5; CMZ, 1; CTM, 0.5; PIPC, 1) of beta-lactamase-producing MSSA at 1 microgram/ml for 6 h, but PIPC did not at the same condition. FOM and CMZ at MIC suppressed regrowth of the strain, but CEZ, CTM and PIPC did not. In conclusion, FOM, which is not affected by beta-lactamase, demonstrated strong bactericidal activity at low concentration against the beta-lactam-resistant strains due to beta-lactamase production.

[Surveillance of susceptibility of clinical isolates to cefmetazole between 2000 and 2002].

The antibacterial activity of cefmetazole (CMZ) against clinical isolates from 15 medical institutions all over Japan was evaluated yearly for two years from June 2000 to March 2002 and compared with that of other parenteral beta-lactams, cefazolin (CEZ), cefotiam (CTM), sulbactam/cefoperazone (SBT/CPZ), and flomoxef (FMOX). In the first surveillance from June 2000 to March 2001, 575 isolates of 13 species were tested, and 548 isolates of the same 13 species were tested in the second surveillance from April 2001 to March 2002. In these surveillances spanning two years, the MIC90s of CMZ against the bacterial species tested hardly differed. Changes in percent resistance of each species to CMZ (MIC of CMZ > or = 32 micrograms/mL) were as follows: methicillin-susceptible Staphylococcus aureus (MSSA, 0%-->0%), methicillin-resistant Staphylococcus aureus (MRSA, 73%-->87%), Staphylococcus epidermidis (19%-->32%), other coagulase-negative Staphylococcus spp. (other CNS, 13%-->18%), Escherichia coli (4%-->1%), Klebsiella pneumoniae (3%-->4%), Klebsiella oxytoca (0%-->0%), Proteus mirabilis (2%-->2%), Proteus vulgaris (14%-->7%), Morganella morganii (7%-->0%), Providencia spp. (17%-->0%), Peptostreptococcus spp. (0%-->0%), Bacteroides fragilis (10%-->11%), and other Bacteroides spp. (79%-->88%). The change in percent resistance of MRSA, S. epidermidis, other CNS, and other Bacteroides spp. tended to increase. In addition, the percent resistance of B. fragilis was 10%. It is necessary to pay much attention to the trends observed in these species. Compared to other drugs tested, against MSSA, the activity of CMZ was inferior to that of CEZ, CTM, and FMOX and superior to that of SBT/CPZ. Against MRSA, S. epidermidis, and CNS, the tested drugs exhibited little activity. Against Gram-negative bacteria, the activity of CMZ was almost superior to that of CEZ and CTM, and inferior to that of FMOX. Against B. fragilis and other Bacteroides spp., the activity of CMZ was almost superior to that of CEZ and CTM, and comparable to or inferior to that of SBT/CPZ and FMOX. No remarkable changes in the activity of CMZ were observed in this study compared with studies conducted before CMZ was launched. This result suggests that CMZ still maintains potent activity.

Antibacterial activity of peritoneal exudate in patients treated with 2 g cefotiam for surgical anti-microbial prophylaxis.

The objective of this study was to investigate the presence of antibacterial activity in peritoneal exudate (PE) of patients treated with cefotiam (CFT). CFT (2 g) was administered as a 'single-shot' antimicrobial prophylaxis to 6 patients at the beginning of colorectal resection. Samples of PE were collected from each patient on days 1, 2 and 3 after surgery. CFT was detectable in the samples of day 1 for 5 of the 6 patients. The influence of PE on antibacterial activity of the antimicrobial drug was evaluated carrying out the MICs of CFT against Escherichia coli K-12, E. coli (ATCC 10798), Klebsiella pneumoniae (ATCC 1003), Proteus rettgeri (Sanelli) and Staphylococcus aureus (ATCC 29213) with and without the addition of PE. The presence of PE enhanced the antimicrobial activity of CFT against gram-negative strains, but not against S. aureus (ATCC 29213). These results suggest the presence of substances in PE that possess endogenous antibacterial activity. Thus, antimicrobial activity in PE cannot be predicted by evaluating pathogen sensitivity in vitro only.

Effect of antibiotics on rat leukocyte function.

Many antibiotics are used to treat infection in clinical practice. Actions of these drugs involve specific immune enhancement and improved overall phagocytic and bactericidal capacities of polymorphonuclear leukocytes and macrophages at the site of infection. In this study, we examined the effects of antibiotics on chemotaxis and phagocytosis by reacting macrophages with 7 different antibiotics, specifically ampicillin (ABPC), cephalexin (CEX), cefotiam (CTM), amikacin (AMK), clindamycin (CLDM), tetracycline (TC) and bleomycin (BLM). At 1 microgram/ml, there were significant differences in chemotaxis between control and experimental groups treated with agents other than ABPC and CEX (CLDM: p < 0.05, AMK: p < 0.01, CTM, TC and BLM: p < 0.001). At 10 micrograms/ml, there were significant differences in chemotaxis between the control group and all treated groups (ABPC and CLDM: p < 0.01, CEX, CTM, AMK, TC and BLM: p < 0.001). At 100 micrograms/ml, all antibiotics significantly inhibited chemotaxis (p < 0.001). Phagocytosis was evaluated by determining both the ratio and index of phagocytosis. There was a significant difference in the phagocytosis ratio between the control group and the group treated with 10 micrograms/ml of BLM (p < 0.001). At 100 micrograms/ml, all agents but ABPC significantly reduced phagocytosis in a dose-dependent manner. Agents other than ABPC similarly reduced the phagocytosis index. Significant differences were noted between the control group and groups treated with BLM or AMK (BLM: 10 micrograms/ml: p < 0.01, 100 micrograms/ml: p < 0.001, AMK: 100 micrograms/ml: p < 0.01).

[Antimicrobial activities of clindamycin against clinical isolated Streptococcus pneumoniae].

We investigated antimicrobial activity of clindamycin (CLDM) against clinically isolated Streptococcus pneumoniae in 1996. The results are summarized as follows; 1. The detection frequencies of macrolides (MLs)-resistance against penicillin (PC)-susceptible S. pneumoniae (PSSP) was 48.0% and those against PC-intermediate S. pneumoniae (PISP)/ PC-resistant S. pneumoniae (PRSP) was 92.0%. 2. It was found that the ratio of MLs-inducible resistant strains of PSSP was 24.6% and that of PISP/PRSP was 66.0%. MLs-constitutive resistant strains of PSSP accounted for 24.0% and that of PISP/PRSP for 26.0%. MLs-constitutive resistant strains was relatively frequent in PSSP and MLs-inducible resistant strains was frequent in PISP/PRSP. 3. CLDM showed strong antimicrobial activity against MLs-inducible resistant strains. The MIC70 of CLDM against PSSP was < or = 0.025 microgram/ml and that against PISP/PRSP was 0.1 microgram/ml. From these results, it was suggested that CLDM is effective against the infection of PISP/PRSP where the detection frequency of MLs-inducible strains was high. 4. Antimicrobial activity of CLDM was found to be strong against MLs-inducible resistant strains, but to be weak against MLs-constitutive resistant strains. When S. pneumoniae is detected, susceptibility of the strain to CLDM should be examined.

[Antibacterial activities of combination uses of isepamicin and beta-lactams in vitro against clinically isolated strains. Part 1. Activities against Staphylococcus aureus].

In order to evaluate antibacterial activities of combination uses of isepamicin (ISP) and beta-lactams in vitro, minimum inhibitory concentrations (MICs) these drugs were examined singly and in combination against clinically isolated Staphylococcus aureus. The results are summarized as follows; 1. MICs of ISP + cefazolin (CEZ), ISP + cefotiam (CTM) and ISP + flomoxef (FMOX) were low and the activities against methicillin (DMPPC)-susceptible S. aureus (MSSA) were dependent on the concentration of ISP. Combined effects were observed when the concentrations of ISP were at sub-MIC levels (1/2 approximately 1/4 concentrations). 2. MICs of ISP + CEX, ISP + CTM, ISP + FMOX, ISP + imipenem and ISP + panipenem were low and the activities against DMPPC-resistant S. aureus (MRSA) were dependent on the concentration of ISP, and were similar to those against MSSA. Combined effects were observed when the concentrations of ISP were at sub-MIC levels of ISP. Lower MIC50 or MIC90 was observed at ISP concentrations of 4 approximately 16 micrograms/ml. 3. The blood Cmax of ISP exceeded 20 micrograms/ml at one-time administration of ISP 400 mg, and these results suggested that antibacterial activities of combination uses of ISP and beta-lactams was clinically effective against MRSA infections.

Autolysis of methicillin-resistant Staphylococcus aureus is involved in synergism between imipenem and cefotiam.

Imipenem-induced autolysis and the activity of imipenem plus cefotiam were studied in 16 strains of methicillin-resistant Staphylococcus aureus (MRSA). The degree of imipenem-induced autolysis and the rate of synergistic action of imipenem plus cefotiam varied among strains and did not correlate with susceptibility to either imipenem or cefotiam. However, the degree of autolysis correlated well with susceptibility to the synergistic action of imipenem plus cefotiam. In methicillin-susceptible S. aureus strains, both imipenem-induced autolysis and the synergistic activity of the combined drugs were less than those observed in MRSA strains. Differences in the degree of autolysis were not due to differences in autolytic enzyme production. The autolysis of imipenem-pretreated MRSA was enhanced further by cefotiam, while treatment of cells in the reverse order did not enhance autolysis. These findings indicate that cell wall impairment in MRSA is caused by exposure to imipenem but not to cefotiam and that this difference in drug actions results in synergism between imipenem and cefotiam. The possible participation of penicillin-binding proteins PBP 2' and PBP4 in the observed effect is discussed.

Dual mechanisms of GABAA response inhibition by beta-lactam antibiotics in the pyramidal neurones of the rat cerebral cortex.

1. The effects of beta-lactam antibiotics on the gamma-aminobutyric acid (GABA)-induced Cl- current were investigated in pyramidal neurones freshly dissociated from the rat frontal cortex by the use of a nystatin-perforated patch recording mode under voltage-clamp conditions. 2. The GABA-induced inward current increased in a concentration-dependent manner with an EC50 of 6.7 x 10(-6) M at a holding potential of -40 mV. The GABA response was accompanied by an increase in the membrane conductance and reversed at near the Cl- equilibrium potential. 3. All beta-lactams (penicillin, imipenem, aztreonam and cefotiam) inhibited the 10(-5) M GABA-induced response in a concentration-dependent manner with an IC50 and Hill coefficient of 1.3 x 10(-3) M and 0.64 for penicillin, 9.6 x 10(-4) M and 0.83 for imipenem, 2.5 x 10(-3) M and 9.99 for aztreonam, and 2.9 x 10(-4) M and 1.03 for cefotiam. 4. Imipenem inhibited the GABA-response competitively while penicillin inhibited the same response in a noncompetitive fashion. 5. The inhibitory action of imipenem showed no voltage-dependency, whereas the effect of penicillin was voltage-dependent. 6. It is thus proposed that some classes of beta-lactams, including imipenem may have a mechanism that is different from penicillin and competitively affects the GABAA receptor.

Specificity of p-aminohippurate transport system in the OK kidney epithelial cell line.

Substrate specificity of the p-aminohippurate (PAH) transport system was investigated in the OK kidney epithelial cells. PAH uptake by OK cells from the basal side was inhibited by beta-lactam antibiotics such as benzylpenicillin (PCG) and cefazolin. The inhibition of PAH uptake by PCG was competitive and the Ki value was calculated as 108.8 microM. Transcellular transport of PCG across OK cell monolayers occurred unidirectionally from the basal to apical side, and transcellular transport and basolateral uptake were inhibited by PAH, probenecid and beta-lactam antibiotics. The basolateral uptake of cefazolin and cefotiam was also inhibited by PAH and probenecid. The basolateral uptake of PAH and PCG were not affected by aliphatic dicarboxylates with 3 or 4 carbon atoms, but were strongly inhibited by those with 5 or 6 carbon atoms. The inhibitory effect became weaker for a longer dicarboxylate with 7 carbon atoms, then increased again with increasing number of carbon atoms. Such a pattern of inhibition by dicarboxylates is essentially the same with that observed in rat renal proximal tubules in situ. These findings suggest that the PAH transport system in OK cells has a substrate specificity similar to that in rat renal proximal tubules, which is involved in the active secretion of various organic anions including drugs.

Synergistic enhancement of in vitro antimicrobial activity of imipenem and cefazolin, cephalothin, cefotiam, cefamandole or cefoperazone in combination against methicillin-sensitive and -resistant Staphylococcus aureus.

Synergistic enhancement of the in vitro antimicrobial activity of imipenem combined with cephalosporins against methicillin-resistant Staphylococcus aureus (MRSA) has been reported. In order to investigate which cephalosporin is more effective in enhancing the activity of imipenem against MRSA, the in vitro antimicrobial activities of imipenem, cefazolin, cephalothin, cefotiam, cefamandole and cefoperazone, alone and in combination, against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA were assessed. Using the checkerboard Mueller-Hinton agar dilution method, strong synergy was found in 97% to 100% of MRSA strains for imipenem and all tested cephalosporins except cefoperazone; fractional inhibitory concentration (FIC) indices were < or = 0.5. Among the cephalosporins studied, cefamandole most markedly increased the activity of imipenem against MRSA, followed, in order of decreasing effect, by cefotiam, cephalothin, cefazolin, and cefoperazone. The synergistic effect of imipenem combined with cefamandole or cefotiam was confirmed using the broth dilution method with 2% of NaCl.

[Basic studies on combination effects of arbekacin and beta-lactam antibiotics on methicillin-resistant Staphylococcus aureus].

Combination effects were studied with arbekacin (ABK) and beta-lactam antibiotics including imipenem/cilastatin (IPM/CS), flomoxef (FMOX), and cefotiam (CTM) for bactericidal activities, post-antibiotic effects (PAE's) and bactericidal activities of beta-lactam antibiotics after removal of ABK using methicillin-resistant Staphylococcus aureus (MRSA) strain 1936. The following results were obtained. 1. When ABK was administered in combination with IPM/CS, FMOX or CTM against MRSA strain 1936, low FIC index was not obtained. 2. Higher bactericidal activity was observed when ABK was given before beta-lactam than when beta-lactam was given before ABK. 3. Combination of ABK and each of beta-lactam antibiotic led a longer PAE than ABK alone. 4. When each beta-lactam antibiotic was administered after a treatment and removal of ABK, greater bactericidal activity and growth inhibition were observed than when administered each beta-lactam alone. These findings basically demonstrated that ABK was effectively bactericidal against MRSA when administered in combination with beta-lactam antibiotic such as IPM/CS, FMOX or CTM, even when the FIC index did not indicate a favorable effect.