Dibekacin--a novel aminoglycoside antibioticl. Antimicrobial activity and parallel resistance in vitro

Dibekacin (Orbicin) is a new aminoglycoside antibiotic which chemically differs from tobramycin only by lack of an OH-group. The activity of dibekacin against E. coli, Klebsiella, Enterobacter, Serratia, Proteus indol-negative and indol-positive and Pseudomonas aeruginosa was compared with that of gentamicin, sisomicin, tobramycin and amikacin by tube dilution procedure. Dibekacin showed a high activity against P. aeruginosa including gentamicin-resistant strains. The development of resistance and cross-resistance in vitro in E. coli, Klebsiella, Proteus and P. aeruginosa to the five aminoglycosides was investigated. The experimentally produced resistance under increasing aminoglycoside concentrations was developing by multiple-step mutation. The frequency of cross-resistance is of great importance for the first choice of an aminoglycoside antibiotic in the hospitals. These in vitro studies have yielded that dibekacin and gentamicin are well suited for the first choice of an aminoglycoside in P. aeruginosa infection.     

Comparison of the antibacterial activity of amikacin (BB-K8) with other aminoglycosides against pathogens recently isolated from clinical materials (author's transl) ]

We determined the antibacterial activity of amikacin against 1,277 strains of pathogenic bacteria isolated from clinical materials during 1974, including beta hemolytic streptococci, pneumococci, enterococci, Staphylococcus aureus, Staph. epidermidis, Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Serratia, Proteus morganii and Pseudomonas aeruginosa, and compared the minimum inhibitory concentration (MIC) of this drug with gentamicin, dibekacin, tobramycin and kanamycin. 1)Antibacterial activity of amikacin against beta hemolytic streptococci, pneumococci and enterococci was as weak as the other four aminoglycosides, but against Staph. aureus, Staph. epidermidis, various groups of Enterobacteriaceae and Pseudomonas aeruginosa showed amikacin the good antibacterial activity as gentamicin, dibedacin and tobramycin, and also showed the good activity against kanamycin resistant strains. 2) Amikacin has the similar antibacterial spectrum as gentamicin, dibekacin or tobramycin, but its antibacterial activity is generally weakest among these four drugs. 3) On many strains tested the cross resistance is observed between amikacin and one of gentamicin, dibekacin and tobramycin, but several strains of Proteus morganii and Pseudomonas aeruginosa which have rather large MIC against gentamicin, dibekacin or tobramycin showed rather small MIC against amikacin.     

Gentamicin-susceptibility of various pathogens isolated from clinical materials]

We studied on the antibacterial activity of gentamicin against various pathogens isolated from clinical materials mainly isolated during 1974 and 1975, comparing with other antibiotics. Beta hemolytic streptococci, pneumococci and enterococci are less susceptible to gentamicin than staphylococci. Staph, aureus and Staph. epidermidis resistant to various antibiotics are very susceptible to gentamicin, and no resistant strain to this drug was found. Haemophilus influenzae, H. parainfluenzae and H. parahaemolyticus are very susceptible to gentamicin, and there is no resistant strain to this drug. Escherichia coli, Klebsiella, Citrobacter, Serratia and five species of Proteus are more susceptible to gentamicin and tobramycin than dibekacin and amikacin. A few resistant or less susceptible strains to gentamicin are found in E. coli, Citrobacerr, Serratia, Pr. morganii and Pr. rettgeri. Pr. inconstans is less susceptible to gentamicin than other species of Proteus. Antibacterial activity of gentamicin against Pseudomonas aeruginosa is very strong, but dibekacin and tobramycin are stronger. Gentamicin-resistant strains of Pseudomonas aeruginosa are now rather few.     

In vitro activity of sisomicin, an aminoglycoside antibiotic, against clinical isolates.

Sisomicin, a new aminoglycoside antibiotic which is produced by Micromonospora myoensis, was studied against 565 clinical isolates of gram-negative bacilli and gram-positive cocci. With the exception of Serratia marcescens, over 90% of isolates of gram-negative bacilli were inhibited by 1.56 mug/ml or less of sisomicin. Sisomicin was slightly more active than gentamicin and tobramycin aganist isolates of Escherichia coli, Proteus mirabilis and Klebsiella spp. It was substantially more active than butirosin and kanamycin against all gram-negative bacilli. Isolates of gram-negative bacilli which were resistant to gentamicin and tobramycin were also resistant to sisomicin. Most of these isolates were sensitive to amikacin.     

Effect of aminoglycosides on proximal tubular membranes of the human kidney

Summary The effect of the aminoglycosides amikacin, gentamicin, netilmicin sisomicin and tobramycin on the proximal tubule of the human kidney was investigated in 78 healthy subjects. Fifteen adults were each given gentamicin, sisomicin or tobramycin 3 mg/kg bodyweight, 10 subjects received netilmicin 3 mg/kg or amikacin 15 mg/kg additionally seven subjects amikacin 10 mg and six subjects netilmicin 6 mg on three consecutive days. The principal enzyme of the brush border membrane of the proximal tubule, alanine aminopeptidase (AAP), was determined enzymatically and immunologically in 24-hour urines. The effects of the various aminoglycosides on the membranes were different. Less of membrane AAP was greatest after amikacin and was least after tobramycin. There was no difference between gentamicin, netilmicin, and sisomicin, which had an effect intermediate between the other two compounds. The elimination of AAP occurred at intervals whicht might possibly have been caused by impairment of cell cycles.     

In vitro activity of dactimicin and other aminoglycosides against bacteria producing aminoglycoside-modifying enzymes

Dactimicin is a new pseudo-disaccharide aminoglycoside, originally isolated from cultures of Dactylosporangium matsuzakienzae sp. nov., which is chemically related to astromicin. In this study the in vitro activity of dactimicin has been determined against strains of bacteria producing characterized aminoglycoside-modifying enzymes and has been compared with that of gentamicin, tobramycin, netilmicin and amikacin. Minimum inhibitory concentrations were determined using an agar incorporation technique in Mueller-Hinton agar with an inoculum of approximately 10(4) cfu. Dactimicin was resistant to inactivation by a number of different acetyltransferases (AAC), produced by species of the Enterobacteriaceae, most of which inactivated gentamicin, tobramycin and netilmicin. The exception was an AAC(3')-I produced by an isolate of Escherichia coli, which inactivated gentamicin and dactimicin but not tobramycin, netilmicin and amikacin. Dactimicin was inactivated by the adenyltransferases (AAD) AAD(2") and AAD(9), produced by Pseudomonas aeruginosa, but not by an AAD(4')(4"), produced by a strain of Staphylococcus aureus, nor by an AAD(2") produced by a strain of E. coli. Dactimicin was inactivated by a combination of a phosphotransferase (APH) APH(2") and an AAC(6') produced by strains of S. aureus. The results suggest that dactimicin may retain useful antibacterial activity against many gentamicin-resistant strains of bacteria belonging to the Enterobacteriaceae and some gentamicin-resistant strains of S. aureus.     

Netilmicin Sulfate: A Comparative Evaluation of Antimicrobial Activity,Pharmacokinetics, Adverse Reactions and Clinical Efficacy

Netilmicin, the 1-N-ethyl derivative of sisomicin, is a new aminoglycoside antibiotic that was recently marketed in the United States. Its role in therapeutics is not yet established. The pharmacokinetic profile of netilmicin is very similar to that of gentamicin. Its antimicrobial spectrum and clinical efficacy is similar to that of gentamicin, tobramycin and amikacin. It is less active in vitro against Pseudomonas aeruginosa than gentamicin and tobramycin, but in clinical trials the efficacy of netilmicin against this organism has been similar to other aminoglycosides. Netilmicin is active against some gentamicin and tobramycin-resistant strains of gram-negative bacilli, particularly those harboring adenylating and phosphorylating enzymes. Most of these strains are sensitive to amikacin as well, and amikacin is also active against most netilmicin-resistant strains of these bacteria. Therefore, amikacin remains the aminoglycoside of choice against gentamicin tobramycin and netilmicin-resistant gram-negative bacilli. In comparison to other currently available aminoglycosides, a lower frequency of nephrotoxicity and ototoxicity has been observed in laboratory animals given netilmicin. This has not been unequivocally demonstrated in humans. The frequency of nephrotoxicity in humans has been similar to that of other aminoglycosides. The frequency of ototoxicity associated with netilmicin in humans has been low but not significantly less than with other aminoglycosides, except in one trial. If further studies document a significantly lower frequency of ototoxicity with netilmicin, it may become the aminoglycoside of choice for patients with significant risk factors for ototoxicity, such as advanced age, renal impairment, concomitant ototoxic drug therapy and prolonged aminoglycoside administration.     

Antibacterial activities of various aminoglycosides against clinically isolated methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) were isolated from samples collected from various patients during 1986, and antibacterial activities of 6 aminoglycosides (AGs) (netilmicin (NTL), gentamicin (GM), sisomicin (SISO), dibekacin (DKB), tobramycin (TOB) and amikacin (AMK] and 4 beta-lactam antibiotics (cefazolin (CEZ), cefmetazole (CMZ), cloxacillin (MCIPC) and methicillin (DMPPC) against these MRSA were evaluated. Among these 6 AGs, NTL was the most potent, and its MIC50 and MIC80 were 1.56 and 3.13 micrograms/ml, respectively. Antibacterial activities of GM, SISO, DKB and TOB were weak, and MIC50's of GM and DKB were both 100 micrograms/ml, while those of SISO and TOB were 50 and greater than 100 micrograms/ml, respectively. Frequency of highly resistant specimens to AMK was rather low and its MIC50 and MIC80 were 12.5 and 25 micrograms/ml, respectively. As for antibacterial activities of the above 4 beta-lactam antibiotics, the MIC50 and MIC80 of CMZ were 6.25 and 12.5 micrograms/ml, respectively, and therefore, its antibacterial activity to MRSA is relatively good. However, MIC50's of CEZ, MCIPC and DMPPC were all greater than 100 micrograms/ml, showing poor antibacterial activities. Recently, MRSA became a problem in various fields of clinical practice, and a number of literatures reporting refractory infections caused by MRSA have been published. Since MRSA is featured as multiply resistant bacteria, it is known that MRSA is resistant to the majority of existing antibiotics (penicillins, cephems, macrolides, AGs, etc.). In 1985, we reported results of our study concerning the antibacterial activities of a number of CEPs and some of AGs against multiply resistant S. aureus including MRSA.(ABSTRACT TRUNCATED AT 250 WORDS)     

国产丁胺卡那霉素对常见致病菌的体外抗菌作用研究

本文对480株常见致病菌,包括金黄色葡萄球菌、大肠杆菌、痢疾杆菌、绿脓杆菌、克雷白氏杆菌、肠杆菌、变形杆菌等,作了6种氨基糖甙类抗菌素的体外试管双倍稀释法敏感度试验。该6种抗菌素是国产丁胺卡那霉素、日本产丁胺卡那霉素、卡那霉素、庆大霉素、妥布霉素和链霉素。结果表明国产丁胺卡那霉素具有广谱抗菌作用,体外抗菌活性和日本产丁胺卡那霉素一致。丁胺卡那霉素对480株临床分离的致病菌的抗菌活性,明显优于庆大霉素、妥布霉素、卡那霉素和链霉素。丁胺卡那霉素对耐庆大霉素、妥布霉素或卡那霉素以及呈多耐药性的菌株,均具有显著的抗菌活力。     

Antibacterial activity of various antibacterial agents against methicillin-resistant Staphylococcus aureus, and difference in antibacterial activity between aminoglycosides by coagulase type. Comparison of isolates obtained in the period from 1982 to 1986 and isolates in recent 6 months

The sensitivity of methicillin-resistant Staphylococcus aureus (MRSA) isolated in our hospital during the period from November 1988 through April 1989 to various antibacterial agents was examined. Isolates were obtained from blood (4 isolates), sputum (40), bile (1), ascites (1) and urine (4). All isolated MRSA were resistant to cefazolin, cefmetazole, cefuzonam, flomoxef, and tobramycin. More than 80% of the isolates were resistant to fosfomycin and amikacin. 60% were resistant to ofloxacin (OFLX). 46% were sensitive to minocycline. 50% or more of the isolates were sensitive to gentamicin (GM), dibekacin (DKB) and astromicin (ASTM). 88% were sensitive to netilmicin. All the isolates were sensitive to vancomycin and arbekacin. The incidence of OFLX-resistant isolates was increased compared with the results of the previous study. Most of the isolates were coagulase type II. GM, ASTM and DKB were less active against type IV isolates, but they had sufficient antibacterial activity against the type II isolates.     

In vitro combination effects of cefsulodin, moxalactam and cefoperazone with four aminoglycosides on nonfermenting nosocomial gram-negative bacteria

The activity of moxalactam, cefsulodin and cefoperazone on 67 non-fermenting gram-negative bacterial strains isolated from patients with nosocomial infections was tested either alone or in combination with gentamicin, tobramycin, amikacin and netilmicin, respectively, by use of the checkerboard agar dilution technique. Cefsulodin was most active against Pseudomonas aeruginosa, cefoperazone was the most active cephalosporin tested against Pseudomonas fluorescens-putida and Acinetobacter antitratus. Cefoperazone-aminoglycoside interactions were found to be synergistic in only 2--5% of all strains, cefsulodin and moxalactam in combination with aminoglycosides were most potent against P. aeruginosa. Cefsulodin-gentamicin interactions were superior to other cephalosporin-amino-glycoside combinations.     

Antimicrobial activity of dactimicin in vitro compared with that of dibekacin, netilmicin, sisomicin and micronomicin

Antimicrobial activity of dactimicin, a pseudo-disaccharide aminoglycoside antibiotic, was compared with those of dibekacin, netilmicin, sisomicin and micronomicin using clinical isolates of four Gram-positive and sixteen Gram-negative bacteria. Dactimicin was more active than the reference amino-glycosides against Serratia marcescens, especially gentamicin-resistant Serratia sp., Proteus vulgaris, P. rettgeri and Klebsiella oxytoca, but less active against Pseudomonas aeruginosa and P. mirabilis. Dactimicin was equally active as the references excepting netilmicin against Gram-positive bacteria and some Gram-negative bacteria including Escherichia coli, K. pneumoniae, Morganella morganii, Haemophilus influenzae, Citrobacter freundii, Enterobacter aerogens, E. cloacae, Acinetobacter calcoaceticus and Campylobacter jejunii. Dactimicin was active against resistant strains possessing various aminoglycoside-modifying enzymes including AAC(3)-1, by which dactimicin was acetylated.     

Crystal Structure and Specific Binding Mode of Sisomicin to the Bacterial Ribosomal Decoding Site

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Factors influencing the inactivation of aminoglycosides by beta-lactams.

Aminoglycosides and beta-lactam antibiotics were tested alone and in combination, via bioassay, in the presence of pH buffers at 6.5, 7.5 and 8.5; human serum; MgCl2 and CaCl2; clavulanic acid and beta-lactamase. Results show: inactivation of gentamicin, tobramycin, sisomicin and netilmicin is influenced by pH; clavulanic acid can inactivate gentamicin and tobramycin; and inactivation is influenced by salt concentration and constituents.     

Antibacterial activities and PK/PD parameters of aminoglycosides against recent clinical isolates of gram-negative rods

We examined antibacterial activities and PK/PD parameters of six kinds of aminoglycosides against seven bacterial species of clinical isolates in 2001. Aminoglycoseides examined were gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), netilmicin (NTL), and isepamicin (ISP), and bacterial isolates used were each 50 strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Proteus spp., Serratia marcescens and Pseudomonas aeruginosa. All aminoglycosides showed good activities with low MICs against 6 species of Enterobacteriacea except S. marcescens. Eight strains (3.2%) among them were resistant to one or more aminoglycosides. Resistance to multiple aminoglycosides were detected in 16 strains (32%) of S. marcescens, among which 13 strains were resistant to AMK but susceptible to ISP. Three (6%) strains of P. aeruginosa were resistant to multiple drugs, one of which was resistant to all six aminoglycosides, and others were moderately susceptible to AMK and ISP, and susceptible to GM, AMK and ISP. Using a ratio of peak serum concentration to MIC90 (Cmax/MIC90) or a ratio of area under the curve to MIC90 (AUC/MIC90) as a pharmacokinetic and pharmacodynamic (PK/PD) parameter, we estimated the efficacy of the drug. An excellent effect of ISP, which was injected intramuscularly or intravenously at a dose of 400 mg, was expected for strains of Enterobacteriacea except S. marcescens. The Cmax/MIC90 ratios for S. marcescens were comparably higher in GM and ISP and that for P. aeruginosa were rather high in TOB when compared to other aminoglycosides. Another PK/PD parameter, AUC/MIC90 ratio, was high enough in NTL and ISP for Enterobacteriacea, suggesting good efficacy of these drugs. The (AUC/MIC90) ratios for S. marcescens were comparably high in GM and ISP, and that for P. aeruginosa were high in TOB, DKB, and ISP.     

The antimicrobial activity of sisomicin against fresh clinical isolates

Antimicrobial activities of sisomicin (SISO) against clinical isolates obtained in the second half of 1986 were investigated together with other 4 aminoglycosides (AGs) (gentamicin (GM), tobramycin (TOB), dibekacin (DKB), amikacin (AMK] and 2 cephems (cefotiam, cefotaxime), and were compared to the results reported in the period of late 1970's through early 1980's in Japan. 1. The incidence of SISO-resistant Staphylococcus aureus in the present study was 18% and is comparable to that of the other studies suggesting that the incidence of SISO resistant strains remains on the stable level. The incidence of SISO-resistant Pseudomonas aeruginosa showed the tendency of slight increase. 2. SISO-resistant strains of Enterobacter spp., Serratia marcescens and Citrobacter freundii did not show increase from the 1970/1980 levels. 3. Isolation rates of SISO-resistant indole(+) Proteus varied depending on strains. Isolation rates of SISO-resistant P. vulgaris and Morganella morganii were both as low as 4%, but that of Providencia rettgeri was as high as 60%. Refering to an American study reporting that the Genus Providencia including P. rettgeri showed high incidence of resistance to SISO as well as to GM or TOB, we pointed out that the antimicrobial activity of AGs against Genus Providencia should be evaluated separately from those of other indole(+) Proteus strains. 4. No SISO-resistant strains of Escherichia coli, Klebsiella pneumoniae or P. mirabilis were found. 5. SISO had good antimicrobial activity against most of the investigated species and SISO may still be regarded as one of the clinically useful AGs.     

The resistance of recent clinical isolates against isepamycin, other aminoglycosides and injectable beta-lactams

Clinical isolates collected from clinical facilities across Japan in 1998 were tested against five aminoglycosides and three beta-lactams. The resistance of 50 strains each of methicillin sensitive Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter sp., Serratia sp., Pseudomonas aeruginosa and Proteus sp. (P. mirabilis 25 strains and P. vulgaris 25 strains) to the aminoglycosides isepamicin (ISP), amikacin (AMK), gentamicin, tobramycin and dibekacin, and to the beta-lactams imipenem, ceftazidime and piperacillin (all three known to be effective against P. aeruginosa) were investigated using a micro liquid dilution method with the following results: 1. ISP was effective against all strains except for 14% of MRSA, 2% of Proteus sp., and 4% of P. aeruginosa. 2. Six strains of MRSA were resistant to all eight drugs; however, in these cases ISP exhibited a relatively low minimum inhibitory concentration (MIC) compared to the other compounds. 3. Four strains of MRSA were resistant to all drugs except ISP. MRSA was the only isolate to demonstrate a resistance to seven or more drugs. 4. Twenty-one strains of MRSA and 1 strain of P. aeruginosa were resistant to six drugs; however, all of these were susceptible to both ISP and AMK. 5. Against all strains tested, ISP generally exhibited a lower MIC compared to AMK. These results suggest that, even ten years after its entering the market, ISP is still an aminoglycoside having a high anti-bacterial activity against a wide range of clinical isolates.     

Fortimicins A and B, new aminoglycoside antibiotics. IV. In vitro study of fortimicin A compared with other aminoglycosides.

The in vitro antimicrobial activity of fortimicin A, the most active member of the fortimicin complex, was compared with that of amikacin, gentamicin, sagamicin and tobramycin against 352 strains of Enterobacteriaceae and other medically significant organisms. Against most of these organisms fortimicin and amikacin had comparable levels of antimicrobial activity, generally slightly less than that of gentamicin, sagamicin or tobramycin. Fortimicin had relatively weak activity against Pseudomonas aeruginosa strains. Fortimicin shows many of the characteristics of other aminoglycoside antibiotics: (i) improved activity at alkaline pH, (ii) rapid, bactericidal action, (iii) reduced activity with increasing inoculum levels, and (iv) synergistic activity with penicillin against enterococci. The activity of fortimicin was compared to that of gentamicin, tobramycin and amikacin against a group of 95 naturally occurring, antibiotic-resistant Gram-negative bacilli other than Pseudomonas. The organisms were isolated from clinical sources and selected primarily for gentamicin resistance by the sensitivity disc test. Fortimicin showed excellent activity against this group of organisms. At a concentration of 6.2 mcg/ml, fortimicin inhibited the most strains (92.6%) followed by amikacin (90.5%), gentamicin (23.2%) and tobramycin (8.4%).     

In vitro activity of netilmicin and cefotaxime compared to that of other aminoglycosides

In vitro activity of netilmicin, cefotaxime, amikacin, dibekacin, gentamicin and tobramicin was compared against clinical isolates in Antibiotic Medium 3 at pH 7.1 and human plasma water at pH 7.8. Except against Pseudomonas aeruginosa the aminoglycosides were generally more active in plasma water than in broth. Against P. aeruginosa higher concentrations were required to inhibit or kill the strain in the plasma water. Cefotaxime was not tested against these organisms. Against E. coli, K. pneumoniae and Proteus species cefotaxime was found to be more active than the aminoglucosides, both in broth and plasma water. Its activity against Staph. aureus was markedly less than that of the aminoglycosides. Tobramicin showed a higher activity in plasma water only against Proteus species.     

Antimicrobial activity of cefotiam combinations against Enterobacteriaceae moderately susceptible or resistant to this new cephalosporin

The interaction of cefotiam with each of the four aminoglycosides gentamicin, tobramycin, netilmicin and amikacin were studied by the broth microdilution method ("checkerboard" technique) against 36 strains of Enterobacteriaceae chosen for their moderate susceptibility (MIC: 4-32 mg/l) or resistance (MIC: 64-512 mg/l) to cefotiam. A high rate of synergistic combinations was found with all the aminoglycosides: 81% with gentamicin, 76% with amikacin, 67% with tobramycin and netilmicin. The therapeutic value of these interactions appeared excellent.