First microbiological approach to dactimicin, a novel aminoglycoside antibiotic

Dactimicin (ST 900) is the first aminoglycoside antibiotic of Dactylosporangium origin. This drug shows resistance to many enzymes that destroy aminoglycosides. In this first approach, the authors have pointed out the activity of dactimicin against Gram-negative rods, particularly Klebsiella, Enterobacter, Serratia and Gram-positive bacteria, especially methicillin susceptible and resistant staphylococci. Dactimicin showed remarkable antibacterial activity against all strains tested; however this activity was strongly influenced by the inoculum size. The bactericidal activity of dactimicin towards some Gram-positive and Gram-negative bacteria was also evaluated.     

Microbiological characterization of dactimicin: antibacterial activity towards gram-positive and gram-negative bacteria

Dactimicin is the first aminoglycoside antibiotic of Dactylosporangium origin, consisting of a pseudo-disaccharide and an amino acid. It has also a formimidoyl moiety instead of the deoxystreptamine found in other aminoglycosides. The authors considered the antibacterial activity of dactimicin compared with amikacin, gentamicin and the fortimicins against Gram-positive and Gram-negative bacteria. Dactimicin showed remarkable antibacterial activity against all strains tested: in particular the MIC90 values ranged from 2 mg/l for Citrobacter sp. to 32 mg/l for Proteus sp. Methicillin-resistant staphylococci were poorly susceptible to all aminoglycosides tested, while dactimicin showed good activity against the methicillin-susceptible strains. MBCs and killing curves indicated that this drug is rapidly bactericidal against all strains tested.     

Dactimicin, a new, less toxic aminoglycoside antibiotic active against resistant bacteria

Dactimicin is a new member of the pseudodisaccharide group of antibiotics. It possesses an unusual N-formimidoyl group which differentiates it from astromicin. Dactimicin is active against wide variety of bacteria, including resistant strains with aminoglycoside-modifying enzymes. However, AAC(3)-I enzyme slowly acetylates dactimicin. Animal toxicity studies show that the ototoxicity and nephrotoxicity of dactimicin are lower than those of amikacin and gentamicin. No notable abnormal findings have been found in pharmacological and toxicological studies.     

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.     

Efficacy of dactimicin in the treatment of experimentally induced intra-abdominal infections

A reproducible experimental model of intra-abdominal infections in rats has been worked out in order to simulate intra-abdominal sepsis in patients. A 1-cm segment of ileum was isolated on its vascular pedicle. The intestine was then divided at each end of the segment and intestinal continuity was reestablished by an end-to-end anastomosis. Dactimicin is a new aminoglycoside antibiotic and has a broad antibacterial spectrum including both Gram-positive and Gram-negative aerobic bacteria. The experimental model was used to compare the efficacy of dactimicin alone and in combination with metronidazole with the combination gentamicin and metronidazole in the treatment of intra-abdominal infections. Many of the untreated animals (70%) died within 2 days. Within 7 days 40% of the animals receiving dactimicin died. Animals treated with dactimicin plus metronidazole or gentamicin plus metronidazole had a significantly decreased mortality and increased cure rates during the experimental period. Only 5% of these animals died. Thus the combination dactimicin and metronidazole seems to be useful in the treatment of intra-abdominal infections.     

Efficacy of dactimicin plus clindamycin compared with gentamicin plus clindamycin in the treatment of experimental intra-abdominal infections in rats

A reproducible experimental model of intra-abdominal infections in rats has been developed in order to simulate intra-abdominal sepsis in patients. A 1-cm segment of ileum was isolated on its vascular pedicle. The intestine was then divided at each end of the segment and intestinal continuity was re-established by an end-to-end anastomosis. Dactimicin is a new aminoglycoside antibiotic with a broad antibacterial spectrum including both aerobic Gram-positive and Gram-negative bacteria. The experimental model was used to compare the efficacy of dactimicin in combination with clindamycin with the combination gentamicin/clindamycin in the treatment of intra-abdominal infections. Of the untreated animals, 70% died within two days. Animals treated with dactimicin plus clindamycin or gentamicin plus clindamycin exhibited significantly decreased mortality and increased cure rates during the experimental period. Only 5% of these animals died. Thus the combination dactimicin/clindamycin seems to be useful in the treatment of intra-abdominal infections.     

In vitro and in vivo antibacterial activity of KY-109, a new orally active cephalosporin

The in vitro and in vivo antimicrobial potencies of KY-109, a pro-drug of KY-087, were compared with those of amoxicillin, cephalexin (CEX), and cefaclor (CCL). The following results were obtained. KY-087, which is the active form of KY-109, had broad antimicrobial spectrum against Gram-positive and Gram-negative organisms, but showed low antimicrobial activity against Enterobacter sp., Serratia, and Pseudomonas sp. The antimicrobial activities of KY-087 against clinically isolated Gram-positive organisms were superior to those of CEX and CCL. The antimicrobial activities of KY-087 against Gram-negative organisms, such as Enterobacter sp., Serratia, and Pseudomonas sp., were less active. KY-087 showed dose-related bactericidal activity against Staphylococcus aureus and Escherichia coli. The therapeutic efficacy of KY-109 against experimental intraperitoneal infections caused by Gram-positive and Gram-negative organisms in mice was comparable to that of CEX but inferior to that of CCL. In experimental granuloma pouch models in rats and kidney infection in rabbits, therapeutic efficacy of KY-109 was either comparable or superior to that of CEX and CCL.     

Comparative nephrotoxicity and tissue accumulation of dactimicin, amikacin and gentamicin

Dactimicin (ST 900) is a new pseudo-disaccharide aminoglycoside antibiotic which has been shown to be active against systemic infections in mice. Few data have so far been reported on dactimicin tissue accumulation or its potential nephrotoxicity. In this study, nephrotoxicity and renal tissue concentrations of gentamicin, amikacin and dactimicin were compared in Wistar rats. Liver, heart and lung accumulation of these drugs were also evaluated. Groups of 5 rats were respectively injected with 100 mg/kg body weight of the different drugs daily for 7 days. Five control rats were also injected with saline. Twenty-four hours after the last injection, all rats were sacrificed and bled to death. Blood samples were taken for BUN and serum creatinine assay. Kidney, liver, heart and lung tissues, as well as blood, were removed and processed for microbiological assay of gentamicin, amikacin and dactimicin. The results of this study showed that dactimicin, as well as amikacin, did not induce any significant increase in BUN and serum creatinine, while gentamicin administration resulted in severe uraemia in all rats. Consequently a much higher accumulation of gentamicin than amikacin and dactimicin was achieved in serum and tissues.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2006

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 876 strains of Gram-positive bacteria, 1764 strains of Gram-negative bacteria, and 198 strains of anaerobic bacteria obtained from 30 medical institutions during 2006 was measured. The results were as follows; 1. MEPM was more active than the other carbapenem antibiotics tested against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MEPM was also active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus. 2. As for Pseudomonas aeruginosa, all of the MEPM-resistant strains were resistant to imipenem (IPM). MEPM showed low cross-resistant rate both againt IPM-resistant P. aeruginosa (41.8%) and ciprofloxacin-resistant P. aeruginosa (33.3%). 3. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 4.3% (6 strains) in Escherichia coli, 1.1% (1 strain) in Citrobacter freundii, 21.7% (5 strains) in Citrobacter koseri, 3.1% (4 strains) in Klebsiella pneumoniae, 3.3% (3 strains) in Enterobacter cloacae, 0.8% (1 strain) in Serratia marcescens, and 4.9% (2 strains) in Providencia spp. The proportion of metallo-beta-lactamase strains was 3.1% (10 strains) in P. aeruginosa. 4. Of all species tested, there were no species, which MIC90 of MEPM was more than 4-fold higher than those in our previous study. Therefore, there is almost no significant decrease in susceptibility of clinical isolates to meropenem. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem at present, 11 years after available for commercial use.     

LL-D49194 antibiotics, a novel family of antitumor agents: taxonomy, fermentation and biological properties

A novel family of antitumor antibiotics, designated LL-D49194, was isolated from the fermentation broth of an actinomycete strain identified as Streptomyces vinaceus-drappus. LL-D49194 alpha 1 and beta 2 were active against Gram-positive and inactive against Gram-negative bacteria in vitro. The beta 1 component was not active against either Gram-positive or Gram-negative bacteria. These antibiotics exhibited significant in vivo activities against several murine tumors, albeit with differing potencies.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2002

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 899 strains of Gram-positive bacteria, 1500 strains of Gram-negative bacteria, and 158 strains of anaerobic bacteria obtained from 28 medical institutions during 2002 was measured. The results were as follows; 1. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MIC90 of MEPM against Pseudomonas aeruginosa was the lowest of the drugs tested. MEPM showed low cross-resistant rate against both imipenem-resistant P. aeruginosa and ciprofloxacin-resistant P. aeruginosa. MEPM was active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE). 2. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli and 1.9% (2 strains) in Klebsiella pneumoniae. Carbapenems including MEPM were active against these ESBL strains. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem; at present, 7 years after available for commercial use.     

In vitro antibacterial activity of prulifloxacin, a new oral quinolone, and comparative susceptibility rate at clinical breakpoint MIC

In vitro drug sensitivity of clinically isolated bacteria against prulifloxacin (PUFX), which is a new quinolone, was investigated, and the antibacterial activity and susceptibility rate at clinical breakpoint were compared with those of norfloxacin, ofloxacin (OFLX), ciprofloxacin, tosufloxacin, fleroxacin, sparfloxacin and levofloxacin (LVFX). The following results were obtained. 1) PUFX showed a broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. 2) MIC80 of PUFX was 0.25 and 1 microgram/ml, against methicillin susceptible Staphylococcus aureus and Streptococcus pneumoniae, respectively and below 0.125 microgram/ml against Gram-negative Enterobacteriaceae. MIC90 of PUFX against Pseudomonas aeruginosa, which has MIC not exceeding 4 micrograms/ml to OFLX, was 0.5 microgram/ml. 3) PUFX was judged as active against the bacteria under the criteria proposed presented by "the Sensitivity Determination Committee for Antibiotics, Japan Society of Chemotherapy: Break Point for Respiratory Infectious Diseases and Sepsis". It is suggested that the sensitivity of each bacterial species to PUFX was high. 4) From the correlation analysis of MIC, PUFX was shown to have two to eight times higher antibacterial acitivity than LVFX for Citrobacter freundii, Serratia marcescens and Pseudomonas aeruginosa. 5) PUFX showed potent short-time bactericidal activity against S. aureus and P. aeruginosa.     

Netilmicin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Netilmicin is a semisynthetic aminoglycoside derived from sisomicin. It is active against most Gram-negative and some Gram-positive bacteria, including many gentamicin-resistant strains. Netilmicin has proved to be effective in Gram-negative infections of the urinary tract, skin and skin structure, and lower respiratory tract, as well as in intra-abdominal infections, septicaemia and other miscellaneous infections. In some trials, the more easily implemented once daily administration of netilmicin has been as effective as multiple dosing regimens. However, further investigation is required to confirm that efficacy and safety are not compromised with once daily administration. Comparative studies have generally revealed similar clinical and bacteriological efficacies between netilmicin and gentamicin, amikacin or tobramycin. As with other aminoglycosides, the principal adverse effects of netilmicin are nephrotoxicity and ototoxicity. Although animal studies strongly suggest that these are less common with netilmicin than with related drugs, there appears to be no difference in their incidence in clinical use; in clinical trials the incidence of nephrotoxicity and ototoxicity has been low, with the symptoms in many cases being minor and reversible. Netilmicin is, therefore, an effective antibacterial drug for the parenteral treatment of severe infections, offering theoretical advantages in safety which may indicate its use for patients believed to be at risk of adverse effects.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2004

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 907 strains of Gram-positive bacteria, 1790 strains of Gram-negative bacteria, and 192 strains of anaerobic bacteria obtained from 30 medical institutions during 2004 was measured. The results were as follows; 1. MIC90 of MEPM for almost all of enterobacteriaceae and Haemophilus influenzae were 4-fold to 32-fold lower than those of other carbapenems. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and H. influenzae. MEPM were active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus. 2. As for Pseudomonas aeruginosa, imipenem (IPM) showed high cross-resistant rate againt meropenem-resistant P. aeruginosa (87.9%). MEPM showed low cross-resistant rate both againt IPM-resistant P. aeruginosa (49.2%) and ciprofloxacin-resistant P. aeruginosa (38.0%). 3. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli, 8.0% (2 strains) in Citrobacter koseri, 2.5% (3 strains) in Klebsiella pneumoniae, 2.5% (2 strains) in Enterobacter cloacae, 0.9% (1 strains) in Serratia marcescens, and 2.2% (2 strains) in Proteus mirabilis. The proportion of metallo-beta-lactamase strains was 1.6% (5 strains) in P. aeruginosa. 4. Of all species tested, Peptostreptococcus spp. was the only species, which MIC90 of MEPM was more than 4-fold higher than that in our previous study using clinical isolates during 2002 (0.25 microg/ml --> 1 microg/ml). Therefore, there is almost no siginificant decrease in susceptibility of clinical isolates to meropenem. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem at present, 9 years after available for commercial use.     

Impact of metal ions on netilmicin-melanin interaction

Netilmicin, which is mainly used as the sulfate, is a semisynthetic, water soluble aminoglycoside antibiotic obtained by chemical modification of sisomicin. It is active against both Gram-positive and Gram-negative bacteria, including strains which are resistant to other aminoglycosides. Netilmicin form complexes with melanin. The aim of the presented work was to examine the effect of Cu2+, Zn2+, Ca2+ and Mg2+ on netilmicin binding to synthetic DOPA-melanin. It has been demonstrated that metal ions decrease the amount of antibiotic bound to melanin as compared with netilmicin-melanin complexes obtained in the absence of metals. It has been also shown that only one class of binding sites participates in netilmicin-[melanin-metal ion] complexes formation with the association constant K approximately 10(3) M(-1). The obtained results demonstrate that Cu2+, Zn2+, Ca2+ and Mg2+ ions modify the interaction between netilmicin and melanin biopolymer. The blocking of some active centers in melanin molecules by metal ions, which potentially exist in living systems, may influence the clinical therapeutic efficiency as well as the undesirable side effects of netilmicin.     

In vitro antibacterial activity of prulifloxacin,a new oral fluoroquinolone

We compared antibacterial activity of NM394, which is the active metabolite of a prodrug of new fluoroquinolone prulifloxacin (PUFX), against clinical isolates of bacteria with those of ciprofloxacin (CPFX), levofloxacin (LVFX), gatifloxacin (GFLX), tosufloxacin (TFLX) and fleroxacin (FLRX). 1. NM394 showed a broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. 2. MIC80 of NM394 for methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis were 0.5 microgram/ml, 2 micrograms/ml and 4 micrograms/ml, respectively. MIC80 of NM394 for Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae was lower than 0.06 microgram/ml. MIC80 of NM394 for Serratia marcescens and Pseudomonas aeruginosa were 0.25 microgram/ml and 2 micrograms/ml, respectively. 3. Short-time bactericidal activity of NM394 against P. aeruginosa was stronger than those of CPFX, GFLX, LVFX and TFLX. 4. Short-time bactericidal activity of NM394 at Cmax concentration against 12 strains of P. aeruginosa was stronger than those of CPFX, LVFX, GFLX and TFLX.     

Pyrrolomycins C, D and E, new members of pyrrolomycins

Pyrrolomycins C, D and E, new members of pyrrolomycins produced by Actinosporangium vitaminophilum SF-2080, have been isolated by chromatography on a basic alumina column. Three antibiotics have chlorinated pyrrole nuclei linked directly or via carbonyl function to the dichlorophenol moiety. Pyrrolomycins C and E are active against Gram-positive bacteria, while the spectrum of pyrrolomycin D is broad including Gram-positive, Gram-negative bacteria and fungi.     

Lydicamycin, a new antibiotic of a novel skeletal type. I. Taxonomy, fermentation, isolation and biological activity

A novel antibiotic, designated lydicamycin, was isolated from the fermentation broth of an actinomycete strain identified as Streptomyces lydicus. Lydicamycin was active against Gram-positive bacteria and a certain yeast, but inactive against Gram-negative bacteria.     

Helvecardins A and B, novel glycopeptide antibiotics. III. Biological properties

Helvecardins (HVCs) A and B were strongly active against aerobic and anaerobic Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), but they were inactive against Gram-negative bacteria and fungi. Though HVC A showed only slightly stronger antimicrobial activity than beta-avoparcin (AVP), its in vivo protective activity against S. aureus infection in mice was greatly superior to AVP.     

PS-5, a new beta-lactam antibiotic. II. Antimicrobial activity.

PS-5, a new beta-lactam antibiotic, has relatively potent antimicrobial activity against Gram-positive and Gram-negative bacteria, especially the Enterobacter groups, Serratia marcescens, the Proteus groups and Klebsiella pneumoniae. The activity of PS-5 against many beta-lactamase-producing organisms is greater than that of cefoxitin or cefazolin. PS-5 has good therapeutic activity in mice infected with Staphylococcus aureus Smith or Enterobacter cloacae 45.