Combined effects of arbekacin with other antibiotics against methicillin-resistant Staphylococcus aureus. IV. Combined effects of arbekacin with cefmetazole or flomoxef]

Antibacterial effects of combination use of arbekacin (ABK) with cefmetazole (CMZ) or flomoxef (FMOX) were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and the following results were obtained. 1. Antibacterial effects of combinations of ABK with CMZ and with FMOX were equally potent against MRSA at clinically expected 1 MIC of ABK in blood. However, at a sub MIC of ABK different effects were observed between the 2 combinations. The former combination was slightly less effective than the latter. 2. In either combination the potency of the antibacterial activity was less dependent on the concentration of CMZ or FMOX, but was strongly dependent on ABK concentrations. These results suggest that antibacterial effects of the combinations were highly dependent on antibacterial potency and concentration of ABK as previously reported for combinations of ABK with other drugs. 3. It appears that the antibacterial activity of the combination of the sub MIC of ABK with a beta-lactam is an important point in considering the effectiveness of a combination therapy.     

Combined effects of arbekacin with other antibiotics against methicillin-resistant Staphylococcus aureus. II. The combined effect of arbekacin with imipenem or cefminox]

Combined antibacterial effects of imipenem (IPM)+arbekacin (ABK) and cefminox (CMNX)+ABK against methicillin-resistant Staphylococcus aureus (MRSA) were examined and the obtained results are summarized below. 1. Either combination, IPM+ABK or CMNX+ABK, showed a strong antibacterial effect against MRSA when blood concentration of ABK were sustained at MIC as could be expected in clinical situations. While at sub MICs of ABK the antibacterial effect of these combination was slightly less than those of the previously reported combinations of ABK and other antibiotics. 2. Antibacterial effects of the combinations against MRSA were strongly dependent on the concentration of ABK and less dependent on the concentration of IPM or CMNX. As were observed in the previously tested combinations of ABK with other antibiotics, the antibacterial effect of the combination appeared to be highly dependent on the antibacterial activity and the concentration of ABK. 3. As IPM has potent antibacterial activities against Gram-negative bacteria (GNB) including Pseudomonas aeruginosa while CMNX has potent antibacterial activities against GNB except P. aeruginosa, it is likely that the combinations of IPM+ABK or CMNX+ABK are useful for treatment of infections with MRSA together with GNB.     

Combined effects of arbekacin with other antibiotics against methicillin-resistant Staphylococcus aureus. I. The combined effect of arbekacin with fosfomycin or clavulanic acid/ticarcillin]

As arbekacin (ABK) has a highly potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), its combined effects with fosfomycin (FOM) and clavulanic acid/ticarcillin (CVA/TIPC) against MRSA were examined. The obtained results are summarized as follows. 1. Against MRSA either combination, FOM+ABK or CVA/TIPC+ABK showed a strong antibacterial effect at the MIC or the sub MIC of ABK in the blood expected from clinical observations. The MIC of ABK by the combination use seemed to be equivalent to the MBC value. 2. Effective concentrations of antibiotics in these combinations appeared to be strongly dependent on the effective concentration of ABK and less dependent on that of FOM or CVA/TIPC. Therefore, the antibacterial activity of a combination seems to mostly depend on the antibacterial activity and the concentration of ABK. 3. As FOM and CVA/TIPC have antibacterial activities against Pseudomonas aeruginosa, combinations of ABK with these antibiotics are likely to be effective against double infection with P. aeruginosa in MRSA infected patients.     

Baicalin synergy with beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus and other beta-lactam-resistant strains of S. aureus

Bacterial resistance to antibiotics is a serious global problem and includes strains of beta-lactam-resistant Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Novel antimicrobials and/or new approaches to combat the problem are urgently needed. The Chinese herb Xi-nan Huangqin (Scutellaria amoena C.H. Wright) has been used in traditional Chinese medicine to treat a wide range of infectious diseases. In this study we have examined the antibacterial action of baicalin, a flavone isolated from the herb. When combined with 16 microg mL(-1) baicalin, minimum inhibitory concentrations (MICs) of benzylpenicillin against MRSA and penicillin-resistant S. aureus were reduced from 125 and 250 microg mL(-1) to 4 and 16 microg mL(-1), respectively. This activity of baicalin was dose-dependent. Viable counts showed that the killing of MRSA and beta-lactam-resistant S. aureus cells by 10 to 50 microg mL(-1) ampicillin, amoxycillin, benzylpenicillin, methicillin and cefotaxime was potentiated by 25 microg mL(-1) baicalin. From the study it was concluded that baicalin has the potential to restore the effectiveness of beta-lactam antibiotics against MRSA and other strains of beta-lactam-resistant S. aureus. In view of its limited toxicity baicalin offers potential for the development of a valuable adjunct to beta-lactam treatments against otherwise resistant strains of microorganisms.     

Susceptibility of methicillin-resistant Staphylococcus aureus to various antibiotics. Classification by aminoglycoside-modifying enzymes and antibiotics active against MRSA]

MICs of 14 aminoglycoside antibiotics including 10 of those used clinically were determined against 50 strains of methicillin-resistant Staphylococcus aureus (MRSA) which had been isolated at a hospital in Osaka between 1986 and 1990. Arbekacin (ABK) inhibited the growth of all strains at less than or equal to 0.20-6.25 micrograms/ml, showing the most potent activities. Streptomycin showed good activities (1.56-6.25 micrograms/ml) against all strains except one resistant strain (greater than 100 micrograms/ml). Based on susceptibilities to kanamycin (98% resistant), tobramycin (84%), gentamicin (62%), amikacin (36%) and ABK (0%), MRSA strains were classified into 5 types; type 0 producing no aminoglycoside-modifying enzyme, type 1a producing APH(3'), type 1b producing AAD(4', 4'), type 2a producing APH (2')/AAC(6') and APH(3'), and type 2b producing APH(2')/AAC(6') and AAD(4', 4'). In addition to the aminoglycoside antibiotics, 13 known antibiotics including vancomycin (VCM) were found active against MRSA upon random screening. Taitomycin (0.013-0.050 micrograms/ml) was the most potent, and griseoluteins A and B (each 0.10-0.39 micrograms/ml), and macarbomycin (0.05-0.20 micrograms/ml) were more active than VCM (0.39-1.56 micrograms/ml). Novobiocin (less than or equal to 0.20-0.78 micrograms/ml) also showed good activities.     

Reliability of disc-diffusion susceptibility testing for arbekacin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus

We investigated the differences in judgments among four disc-diffusion methods on susceptibility testing of arbekacin (ABK), vancomycin (VCM) and teicoplanin (TEIC) against 37 strains of methicillin-resistant Staphylococcus aureus (MRSA). These results were compared with minimum inhibitory concentrations (MICs) obtained from micro broth-dilution method. A marked difference was noted in the judgment of susceptibility to TEIC in Tri-disc method, that is 2 strains (5.4%) fell into sensitive (+3) 34 strains (91.9%) into moderately sensitive (+2) and 1 strain (2.7%) into moderately resistant (+), while in Sensi-disc method all strains fell into sensitive (S). According to the MICs, no strain of the MRSA tested revealed resistance to ABK, VCM and TEIC. Consequently, these three antimicrobial agents were thought to be effective on MRSA infections. From these results, we concluded that Tri-disc method for glycopeptide against MRSA, especially for TEIC, is not recommendable as a disc-diffusion method in susceptibility testing.     

The effects of antibiotics combined with natural polyphenols against clinical methicillin-resistant Staphylococcus aureus (MRSA)

Novel therapies are needed to address the public health problem posed by methicillin-resistant STAPHYLOCOCCUS AUREUS (MRSA). In this study, we determined the effects of combinations of antibiotics and plant polyphenols against 20 clinical isolates of MRSA. The IN VITRO activities of 10 antibiotics and 15 natural polyphenols against the isolates were evaluated by determining minimum inhibitory concentrations (MICs). All isolates were susceptible to vancomycin and resistant to rifampicin, while susceptibilities to ciprofloxacin varied. Among the 15 natural polyphenols, kaempferol (3,4',5,7-tetrahydroxyflavone) and quercetin (3,3',4',5,7-pentahydroxyflavone) showed the lowest MICs. In checkerboard assays, combinations of rifampicin and either kaempferol or quercetin acted synergistically or partially synergistically against the clinical MRSA isolates. Rifampicin combined with kaempferol or quercetin exhibited good beta-lactamase inhibitory effects (57.8 % and 75.8 %, respectively) against a representative isolate according to nitrocefin analysis. The study results and ready availability and low toxicity of plant polyphenols warrant further investigations on the therapeutic potential of combination therapies for MRSA infections.     

Bacteriological evaluations of combination therapies with minocycline and beta-lactams for methicillin-resistant Staphylococcus aureus. II. cefuzonam plus minocycline]

We performed an in vitro assessment of the antibacterial activity of therapy with cefuzonam (CZON) plus minocycline (MINO) against methicillin-resistant Staphylococcus aures (MRSA) infections. 1. Studies using MINO-susceptible and MINO-resistant MRSA strains suggested that the antibacterial activity of CZON + MINO was dependent on the antibiotic action of MINO, similarly to the case with cefotiam (CTM) + MINO. 2. The antibacterial activity (including the FIC index) of this combination was slightly inferior to that of CTM + MINO. However, the time course of antibacterial efficacy of CZON + MINO in MRSA pretreated with MINO was comparable to that of CTM + MINO. 3. CZON + MINO appeared to be a very useful combination in patients with mixed infections due to MRSA and Gram-negative bacteria.     

In vitro combination effect of pazufloxacin with various antibiotics against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus

The in vitro combination effects of pazufloxacin (PZFX) with various antibiotics were investigated by the checkerboard dilution method using piperacillin (PIPC), tazobactam/piperacillin (TAZ/PIPC), ceftazidime (CAZ), cefozoprane (CZOP), imipenem/cilastatin (IPM/CS), meropenem (MEPM), panipenem/betamipron (PAPM/BP), amikacin (AMK) and isepamicin (ISP) for clinical isolates of 27 Pseudomonas aeruginosa strains, vancomycin (VCM), teicoplanin (TEIC) and arbekacin (ABK) for clinical isolates of methicillin-resistant 26 Staphylococcus aureus (MRSA) strains, respectively. The following results were obtained. 1. For 27 P. aeruginosa strains, the synergistic effects were observed with the combination of PZFX and CAZ or MEPM (11.1%: 3 strains), and PZFX and CZOP or PAPM/BP (3.7%: 1 strain), respectively. The additive and synergistic effects of PZFX were observed with the combination in all beta-lactams tested in the strains more than 50%. No antagonistic effect was observed. The additive effects were also observed with the combination of PZFX and AMK or ISP in the strains more than 50% of the test strains and no antagonistic effect was observed. 2. For 26 MRSA strains, no antagonistic effect was observed with the combination of all antibiotics tested. The indifference was observed with the combination of PZFX and VCM or ABK in the strains more than 60%, and the additive effects were observed with the combination of TEIC in the strains more than 80%. In conclusion, no antagonistic effect was observed in PZFX with the combination of beta-lactams and anti-MRSA agents, suggesting that the combination therapy of PZFX with these antibiotics would be possible to use for the infections caused by P. aeruginosa and MRSA.     

Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a substantial contributor to morbidity and mortality. In search of a natural products capable of inhibiting this multidrug resistant bacteria, we have investigated the antimicrobial activity of emodin (EM) isolated from Rheum palmatum L. (Polygonaceae) against 17 different strains of the bacterium. New antimicrobial activity was found using the paper disc diffusion method, agar dilution as well as checkerboard method. Against the 17 strains, the disc diffusion test was in the range of 18–30?mm, and the minimum inhibitory concentrations (MICs) of EM were in the range of 1.5–25 μg/mL. From those results we performed the checkerboard test to determine the synergism of EM in combination with ampicillin (AM) or oxacillin (OX) against all strains. The combined activity of EM and two antimicrobial agents (AM, OX) against all strains resulted in a fractional inhibitory concentrations index (FICI) ranging from 0.37–0.5 and from 0.37–0.75, respectively. The effect of EM with AM and OX was found to be synergistic or partially synergistic. We found that EM reduced the MICs of AM and OX. EM and in combination with AM or OX could lead to the development of new combination antibiotics against MRSA infection.     

Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a substantial contributor to morbidity and mortality. In search of a natural products capable of inhibiting this multidrug resistant bacteria, we have investigated the antimicrobial activity of emodin (EM) isolated from Rheum palmatum L. (Polygonaceae) against 17 different strains of the bacterium. New antimicrobial activity was found using the paper disc diffusion method, agar dilution as well as checkerboard method. Against the 17 strains, the disc diffusion test was in the range of 18-30?mm, and the minimum inhibitory concentrations (MICs) of EM were in the range of 1.5-25 μg/mL. From those results we performed the checkerboard test to determine the synergism of EM in combination with ampicillin (AM) or oxacillin (OX) against all strains. The combined activity of EM and two antimicrobial agents (AM, OX) against all strains resulted in a fractional inhibitory concentrations index (FICI) ranging from 0.37-0.5 and from 0.37-0.75, respectively. The effect of EM with AM and OX was found to be synergistic or partially synergistic. We found that EM reduced the MICs of AM and OX. EM and in combination with AM or OX could lead to the development of new combination antibiotics against MRSA infection.     

利福霉素等6种抗菌药物对金葡球菌体外抗菌作用比较研究

目的 比较利福霉素、甲氧西林、氟氧头孢、美洛培南、奈替米星、万古霉素对mecA基因阳性和mecA基因阴性的金葡球菌的体外抗菌活性。方法 采用多重PCR方法检测金葡球菌的mecA基因携带情况,采用平皿二倍稀释法进行6种抗菌药物的最低抑菌浓度的测定。结果 6种抗菌药物对mecA 基因阴性的金葡球菌的MIC50和MIC90分别为甲氧西林（2、4mg/L), 利福霉素（0．125、0．25mg/L）,氟氧头孢（0．5、2mg/L）,美洛培南（0．25、0．25mg/L）,奈替米星（2、2mg/L）,万古霉素（2．2mg/L）。对mecA基因阳性的金葡球菌的MIC50和MIC90分别为甲氧西林（＞256、＞256mg/L),利福霉素（0．031、0．031mg/L）,氟氧头隐(32、64mg/L）,美洛培南（64、128mg/L）、奈替米星（32、64mg/L）,万古霉素（4、4mg/L）。结论 6种抗菌药物对mecA基因阴性的金葡球菌均有很强的体外抗菌活性,但对mecA基因阳性且对甲氧西林耐药的金葡球菌,氟氧头孢、美洛培南和奈替米星的体外抗菌活性差,万古霉素和利福霉素具有很强的体外抗菌活性,特别是利福霉素对于MRSS的抗菌活性明显强于MSSA。     

In vitro and in vivo effects of combinations of cefotaxime or other beta-lactams with rolitetracycline on methicillin-resistant Staphylococcus aureus

Combinations of cefotaxime (CTX) or other five beta-lactams with rolitetracycline (RTC) were examined using the checkerboard method for their synergistic effects against 27 strains of methicillin-resistant Staphylococcus aureus (MRSA), and the combination of CTX and RTC was further evaluated for its synergistic effect in vitro and in vivo against 1 or 2 strains. Synergy occurred against 44% of the strains when RTC was combined with CTX, 22 to 30% with cefazolin, methicillin, and ceftizoxime, and 4 to 11% with latamoxef and cefmetazole. No antagonism was found with any combinations tested. Killing curve studies also showed that CTX/RTC was synergistic between 3 and 24 hours after the beginning of exposure, and the synergy was especially strong at 24 hours and potencies of combined bactericidal effect determined at 24 hours were in the following order: the 2 antibiotics given simultaneously, CTX given 2 hours before RTC, and CTX given 2 hours after RTC. In addition, the 2 drugs in combination synergistically inhibited (a) mortality in mice infected intraperitoneally with MRSA and (b) formation of subcutaneous abscess induced by MRSA in mice. The results of our study indicate that beta-lactams, especially CTX, had synergistic effects in vitro when combined with RTC against MRSA and that the combination of CTX and RTC was also synergistic in vivo.     

Neocitreamicins I and II, novel antibiotics with activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci

Two novel antibiotics, neocitreamicins I and II, were isolated from a fermentation broth of a Nocardia strain. This producing strain was obtained using an in situ diffusion chamber that facilitates the cultivation of soil microorganisms. The structures of neocitreamicins I and II were elucidated using UV, MS, and NMR data, and found to be related to the polycyclic xanthone antibiotics of the citreamicin class. The neocitreamicins showed in vitro activity against Gram-positive bacteria including strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.     

Antibacterial activity of hydroxychalcone against methicillin-resistant Staphylococcus aureus

Anti-candidal hydroxychalcone, 2,4,2′-trihydroxy-5′-methylchalcone (THMC), was investigated for its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). THMC showed the minimum inhibitory concentrations of 25.0–50.0 μg/ml against tested 20 strains, at which the effect was based on a bacteriostatic action. THMC of 25.0 μg/ml completely inhibited the incorporation of radio-labelled thymidine and uridine into MRSA cells. In combination with antibiotics, the fractional inhibitory concentration indices were 0.47 for gentamicin and 0.79 for vancomycin, indicating that THMC acts synergistically with these agents. THMC would be a potent therapeutic agent for MRSA infections.     

Flavonoids with activity against methicillin-resistant Staphylococcus aureus from Dalea scandens var. paucifolia

Bioassay-guided fractionation of the ethyl acetate extract of the roots of Dalea scandens (Miller) R. Clausen var. paucifolia led to the isolation of new flavonoids, 2( S)-5'-(-1"',1"'-dimethylallyl)-8-(3",3"-dimethylallyl)-2',4',5,7-tetrahydroxyflavanone, 2( S)-5'-(1"',1"'-dimethylallyl)-8-(3",3"-dimethylallyl)-2'-methoxy-4',5,7-trihydroxyflavanone and 5'-(1"',1"'-dimethylallyl)-8-(3",3"-dimethylallyl)-2',4',5,7-tetrahydroxyflavone. Structure elucidation was carried out by spectroscopic methods. All three compounds showed significant activity against both methicillin-susceptible and methicillin-resistant Staphylococcus aureus.     

Effect of arbekacin on the production of toxic shock syndrome toxin 1 by methicillin-resistant Staphylococcus aureus

The effect of arbekacin (ABK), vancokmycin (VCM) and teicoplanin (TEIC) on the production of toxic shock syndrome toxin-1 (TSST-1) by methicillin-resistant Staphylococcus aureus was examined. In logarithmic-phase cultures, ABK, VCM and TEIC inhibited TSST-1 production by 85, 10 and 25%, respectively, at the concentration of one-fourth the each MIC. In stationary-phase cultures, ABK inhibited TSST-1 production by 50% or 90% compared with the control at the concentration of 4.0 micrograms/ml or 5.0 micrograms/ml respectively. VCM and TEIC did not inhibit TSST-1 production at the concentration of 8.0 micrograms/ml or lower. In human blood cultures, TSST-1 production was inhibited by ABK by 50% at 0.04 microgram/ml (1/256 of Cmax), but not inhibited by VCM and TEIC at the concentration of 1/16 of Cmax or lower. It has been already known that ABK has higher bactericidal activity than VCM and TEIC. ABK combined the inhibition of TSST-1 production with high bactericidal activity in both bacterial growth phases, and therefore ABK should be considered for the treatment of TSST-1-mediated MRSA-infection.     

Synergistic effects of berberines with antibiotics on clinical multi-drug resistant isolates of methicillin-resistant Staphylococcus aureus (MRSA)

N-Methyl-dihydroberberine (M-Ber) was synthesized, and antibacterial activities of Berberine (Ber) and M-Ber alone and combined with antibiotics were studied against ten clinical MRSA isolates. MICs/MBCs (μg/ml, alone) ranges were 32–128/64–256 (Ber) and 64–128/256–1,024 (M-Ber) by a broth microdilution method. Significant synergies of Ber (M-Ber)/Azithromycin and Ber (M-Ber)/Levofloxacin combinations were observed by the chequerboard test. The Ber (M-Ber)/Ampicillin and Ber (M-Ber)/Cefazolin combinations showed indifference. These results demonstrated that Ber and M-Ber enhanced the in vitro inhibitory efficacy of Azithromycin and Levofloxacin, which had potential for combinatory therapy of patients infected with MRSA.     

Antibacterial effects of antibiotics and cell-free preparations of probiotics against Staphylococcus aureus and Staphylococcus epidermidis associated with conjunctivitis

Conjunctivitis, caused by bacterial infections, represents health concern and diagnosis of the disease is pivotal for the proper selection of the treatment. The main causes of bacterial conjunctivitis vary in different countries. The current study investigated the common bacterial causes of bacterial conjunctivitis from eye clinics' attendants and evaluated the effectiveness of different therapeutic approaches. Eye swabs from patients, diagnosed with conjunctivitis, were assessed microbiologically and the isolated bacteria were identified using the standard biochemical identification and sequencing of the 16S rRNA gene. Antibiotics' susceptibility of the conjunctivitis-associated bacterial pathogens was evaluated against nineteen broad-spectrum antibiotics. In the meanwhile, cell-free preparations from probiotic Lactobacillus and Bifidobacterium strains were used to evaluate their antagonistic activities. Findings from this study showed that out of 52 specimen, 17 eye swabs from patients with conjunctivitis were bacterial culture-positive. The identity of the bacterial species, using the biochemical identification system, was Staphylococcus aureus (4 isolates) and S. epidermidis (13 isolates). Staphylococcus spp. showed susceptibility to linezolid, vancomycin, novobiocin, and fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and levofloxacin). However, isolates from the two Staphylococcus spp. expressed resistance to penicillin G, oxacillin, and cephalexin. As alternatives to antibiotics, the growth of Staphylococcus spp., including isolates with antibiotic resistance, was inhibited by cell-free preparations of the 4 probiotic Lactobacillus and the 2 Bifidobacterium strains. These findings provide evidence that topical antibiotics such as fluoroquinolones are still effective antimicrobial agents against staphylococci associated with conjunctivitis whereas probiotic preparations could be promising for further research to pave the way for their therapeutic applications against ophthalmic diseases.