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PubMed1984

Sisomicin, netilmicin and dibekacin. A review of their antibacterial activity and therapeutic use.

Sisomicin is a naturally occurring aminoglycoside antibiotic produced by Micromonospora inyoensis, while dibekacin and netilmicin are both semisynthetic aminoglycosides. Dibekacin is 3',4'-dideoxykanamycin B and netilmicin is 1-N-ethyl sisomicin. In both cases, these modifications render the agents insusceptible to some of the enzymes found in resistant strains of bacteria which inactivate the parent compounds. Antibacterial activity: All 3 drugs show bactericidal activity against a wide range of Gram-negative bacteria (including E. coli, Enterobacter, Klebsiella and Proteus spp. and Ps. aeruginosa) and also against staphylococci; however, in common with other amino-glycosides, streptococci are usually resistant (except when beta-lactam antibiotics are used in combination) and anaerobic organisms are not sensitive. Sisomicin is closely related structurally to gentamicin Cla, but in vitro studies have shown it to have superior activity to gentamicin against Ps. aeruginosa, closely paralleling the activity of tobramycin, while still possessing the high activity of gentamicin against Serratia and other Gram-negative rods. However, sisomicin is inactivated by virtually all bacterial enzymes which inactivate gentamicin and tobramycin. Nevertheless, it retains useful activity against a number of gentamicin-resistant strains of Ps. aeruginosa which are resistant by non-enzymatic (possibly permeability barrier) mechanisms; in this respect it closely resembles tobramycin. Dibekacin closely resembles tobramycin structurally and in vitro it seems to have a very similar antibacterial spectrum, including activity against some strains of Ps. aeruginosa resistant to gentamicin. Netilmicin has a generally broader antibacterial spectrum than gentamicin, tobramycin, sisomicin or debekacin and is resistant to inactivation by phosphorylating and adenylylating enzymes; however, it is inactivated by all acetylases, apart from acetylase 3-I. Its spectrum is therefore not as wide as that of amikacin against 'gentamicin-resistant' strains. Nonetheless, it is intrinsically more active than amikacin, weight-for-weight, against sensitive strains, apart possibly from Ps. aeruginosa. In fact, its activity against species of the Enterobacteriaceae and staphylococci sensitive to gentamicin is of the same order as the latter and possibly better for Klebsiella-Enterobacter species. All 3 agents show marked antibacterial synergy with a variety of beta-lactam antibiotics against a range of bacteria. Pharmacokinetically, sisomicin, netilmicin and dibekacin all behave like gentamicin. All 3 drugs are excreted in the urine unchanged and have beta-phase elimination half-lives of around 2 to

Aging↗
PubMed1983

Interactions between mezlocillin and sisomicin in vitro and in patients with normal and various degrees of impaired renal function.

During in vitro experiments using pooled human plasma at 37 degrees C, sisomicin alone showed only a small loss of activity of 12% in 24 hr. Incubation with 80 micrograms/ml mezlocillin did not alter the rate of inactivation. But, after the addition of 300 micrograms/ml mezlocillin to either 5.0 or 2.5 micrograms/ml sisomicin, the sisomicin half-life was reduced by 50% and 100% respectively. When the mean drug concentration ratios are compared, inactivation of sisomicin by mezlocillin was significantly less than that reported for carbenicillin or ticarcillin. Sisomicin pharmacokinetics were studied in 27 patients with normal and various degrees of impaired renal function (Part A) and were not changed by the simultaneous administration of mezlocillin 60 mg/kg (Part B). Furthermore, even in far advanced renal insufficiency, sisomicin inactivation by mezlocillin could not be demonstrated. The differing results obtained with mezlocillin compared to carbenicillin or ticarcillin might be explained by differences in the physico-chemical properties of the drugs in addition to the different kinetic behavior of mezlocillin in patients with impaired renal function.

Adolescent↗
PubMed1978

Sisomicin: in vitro activity and pharmacokinetics.

In vitro activity of sisomicin and gentamicin was compared in serial dilution tests for 619 bacterial strains (Staphylococcus aureus, E. coli, Proteus mirabilis, Proteus vulgaris, Enterobacter, Klebsiella, Pseudomonas aeruginosa, Salmonella, Serratia marcescens). Mean MIC of sisomicin was lower by one geometrical dilution step compared with gentamicin for Pseudomonas, Proteus vulgaris, Klebsiella, and Serratia, while it was almost identical with the other species. Resistance (MIC greater than 5 microgram/ml) against sisomicin was observed in 2% of Pseudomonas strains, resistance against gentamicin in 8%. Ten healthy adult volunteers had serum peak levels (after i,m. injection of 40 mg and 80 mg sisomicin) of 2.7 and 3.2 microgram/ml. Urine recovery (in 24 hrs) was 76%. Continuous i.v. infusion of sisomicin or gentamicin (6.6 mg/hour in 7 healthy adult volunteers) yielded in serum levels of 0.64 and 1.03 microgram/ml respectively. Biological half-life (90 minutes), urine recovery (60% in the fourth hour), renal clearance and skin blister levels at the end of infusion were almost identical for both antibiotics; total clearance was somewhat higher with sisomicin than with gentamicin.

Adult↗
PubMed1980

[Fundamental and clinical studies on sisomicin in children (author's transl)].

Fundamental and clinical studies on sisomicin, a new aminoglycoside antibiotic were carried out and the following results were obtained. 1. Antibacterial activity of sisomicin was superior to that of gentamicin, amikacin, cefazolin and ampicillin against S. aureus and Ps. aeruginosa. Against E. coli and K. pneumoniae, it was superior to that of amikacin, cefazolin, ampicillin and equal or slightly superior to that of gentamicin. 2. Mean serum levels of sisomicin were 18.0 +/- 0.5 microgram/ml, 15.7 +/- 1.3 microgram/ml, 9.6 +/- 0.6 microgram/ml, 3.2 +/- 0.4 microgram/ml, 1.7 +/- 0.2 microgram/ml and 0.95 microgram/ml at 1/2, 1, 2, 4, 6 and 8 hours after a single intramuscular administration of sisomicin 2.0 mg/kg to 3 children. Mean half-life time was 1.6 +/- 0.2 hours. Mean urinary recovery was 60.4 +/- 7.5% within 6 hours after administration of sisomicin 1.6-2.1 mg/kg to 4 children. 3. Sisomicin was given intramuscularly to 13 children with acute pyelitis (11), acute cystitis (1) and stomatitis gangrenosa and cervical lymphadenitis (1). The daily dose was 2.0 -4.2 mg/kg, divided into twice. Clinical response was excellent in 8 and good in 5. In bacteriological examinations, 13 pathogens (E. coli 9, K. pneumoniae 2, Ps. aeruginosa 2) were eradicated after administration. No adverse reactions were observed.

Acute Disease↗
PubMed1981

[Sisomicin pharmacokinetics in rat tissues in single and long-term administration].

The pharmacokinetics of sisomicin administered intramuscularly to rats in daily doses of 12.5 and 25 mg/kg for 30 days was studied. After a single administration of the drug in the above doses the highest and the lowest levels of sisomicin were observed in the kidney cortical layer and liver, respectively. The antibiotic level in the tissues rose with an increase in the antibiotic dose and duration of the drug use. The two-fold rise in the dose resulted in an elevation in the sisomicin level in the kidney cortical layer by 1.7 times, in the medullary layer by 3 times, and in the blood serum, lungs and spleen by 2.3, 1.2 and 1.5 times, respectively. After treatment with a dose of 25 mg/kg for 8 days the antibiotic level in all tissues studied was higher than that after the first administration of the drug: in the cortical and medullary layers of the kidneys by 5-7 times and in the blood serum and other tissues by 1.2-2 times. When sisomicin was used repeatedly in any dose, stabilization of or some decrease in the mean integral concentration of the antibiotic in the kidney cortical layer and a continuous increase of this value with respect to the medullary layer (up to the 30th day) were noted. The difference between the antibiotic levels in the kidney layers after the repeated administration of the drug was less pronounced than that after a single administration of the drug. The cumulation index of sisomicin in the kidney cortical layer persisted at the same level and that in the medullary layer gradually increased. In this connection it is concluded that correlation between the sisomicin nephrotoxic effect and the level of the antibiotic in the kidney cortical layer is more pronounced than that in the medullary layer.

Animals↗
PubMed1980

Antimicrobial activity of netilmicin in comparison with gentamicin, sisomicin, tobramycin, and amikacin and their resistance patterns.

The antimicrobial activity of netilmicin, gentamicin, sisomicin, tobramycin and amikacin was determined by means of the microdilution test. 1000 fresh isolates of strains of Staphylococcus aureus, Pseudomonas aeruginosa and 7 species of the Enterobacteriaceae were tested. The activities were compared and cross-resistances were analyzed which appeared among the various drugs. Against amikacin, only 0.5% of all strains (3 P. aeruginosa, 1 S. aureus, 1 P. mirabilis) were resistant. Of the other drugs, netilmicin was the most active drug against S. aureus, Klebsiella spp., Enterobacter spp. and Escherichia coli. Against E. coli, too, sisomicin showed its best activity, and further against Citrobacter spp., Proteus spp. and P. aeruginosa. A total of 12% of all pathogens was gentamicin-resistant. With one exception, these pathogens showed cross-resistance to at least one of the other drugs. In 39% of the cases a cross-resistance between gentamicin and tobramycin was noted, in 26% a gentamicin-tobramycin-sisomicin cross-resistance, in 17% gentamicin-tobramycin-sisomicin-netilmicin cross-resistance, in 11% a gentamicin-sisomicin-netilmicin cross-resistance. A complete cross-resistance was observed between gentamicin and sisomicin with S. aureus, Serratia spp. and Proteus mirabilis, between gentamicin and tobramycin with E. coli, Citrobacter spp. and Enterobacter spp.

Amikacin↗
PubMed1972

Comparative activity of sisomicin, gentamicin, kanamycin, and tobramycin.

Gentamicin, sisomicin, tobramycin, and kanamycin were compared in parallel tests in vitro and in vivo against a variety of bacterial strains and species. A number of differences were seen in vitro, in particular: (i) the lower activity of kanamycin, (ii) the greater activity of tobramycin against Pseudomonas, (iii) the greater activity of gentamicin and sisomicin against Serratia, and (iv) the generally similar results with tobramycin, gentamicin, and sisomicin against species other than Pseudomonas and Serratia, with the ranking in order of decreasing activity being sisomicin, gentamicin, and tobramycin. Analysis of disc test results suggested that the gentamicin disc is not adequate for testing the susceptibility of all bacteria to sisomicin or tobramycin. In vivo tests did not confirm all specifics of in vitro tests; results of in vivo tests indicated that sisomicin may be the most active. It is suggested that the place of each of the antibiotics in human therapy can best be evaluated by more rigorous in vivo tests and clinical studies rather than extensive in vitro comparisons.

Aminoglycosides↗
PubMed1980

Intraocular penetration of sisomicin in rabbits.

The intraocular penetration of sisomicin, an aminoglycoside antibiotic, was studied in 47 normal rabbits following subconjunctival and/or intramuscular (IM) injections. Sisomicin levels were determined in the cornea and the aqueous humor of the injected eye as well as in the aqueous of the fellow eye by means of the cylinder-plate bioassay technique. When the IM route alone was used, the eye tissue concentrations remained negligible. One hour after subconjunctival injection, highly therapeutic sisomicin concentrations were achieved in the aqueous humor of both injected and fellow eyes, but the level dropped to very low concentrations 12 hours after the injection. The concomitant administration of sisomicin intramuscularly and subconjunctivally resulted in a significant delay of the clearance of sisomicin from the eye tissues. The use of the combined subconjunctival-IM regimen for administering aminoglycoside antibiotics needs further evaluation.

Animals↗
PubMed1982

Combined action of decreasing concentrations of azlocillin and sisomicin on Pseudomonas aeruginosa as assessed in a dynamic in vitro model.

The effect of decreasing concentrations of azlocillin and sisomicin on Pseudomonas aeruginosa was examined. Logarithmically growing bacterial cultures were incubated in an ultrafiltration cell, and after adding the antibiotics, the culture medium was diluted every 20 min without any decrease in cell density. The turn-over of medium resulted in the elimination of azlocillin with a half-life of 75 min. This simulated serum kinetics in vivo. When testing sisomicin, small amounts of this agent were added during every dilution step to achieve a half-life of 120 min. Growth conditions were comparable in all experiments. The simultaneous combination of azlocillin and sisomicin resulted in strong synergism as assessed by higher killing rates and more prolonged growth inhibition of surviving bacteria. Comparable results were observed when both drugs were added at intervals of 40 min. When applied at intervals of 120 min, the combined effect of azlocillin and sisomicin was reduced, but still superior to the effect of double the concentration of each compound alone. Thus, neither pre-treatment with azlocillin nor with sisomicin impaired the antibacterial activity of the combination partner. This seems to be of clinical importance since the agents may be administered at different times during combined therapy.

Azlocillin↗
PubMed1981

Gentamicin, tobramycin, and sisomicin disc susceptibility tests. Revised zone standards for interpretation.

Studies were undertaken to reevaluate interpretive zone standards for gentamicin and tobramycin disc tests. Disc tests with an investigational aminoglycoside, sisomicin, were also evaluated. The data suggest modification of zone standards for gentamicin disc tests to R (resistant) less than or equal to 12 mm and S (susceptible) greater than or equal to 16 mm. Currently recommended standards for tobramycin disc tests (R less than or equal to 12 mm and S greater than or equal to 15 mm) were found to be satisfactory. For 10-microgram sisomicin discs, zone standards of R less than or equal to 12 mm and S greater than or equal to 15 mm were also appropriate. Although gentamicin is structurally similar to sisomicin, it was less active against Pseudomonas aeruginosa. The activity spectrum of sisomicin against the collection of 470 bacterial isolates studied more nearly resembled that of tobramycin. Data analysis suggested that tobramycin disc tests might be used to predict susceptibility to sisomicin. However, these two drugs differ in their susceptibilities to aminoglycoside-inactivating enzymes produced by some resistant strains. In those institutions where such strains are endemic, the class concept of disc testing may not be applicable.

Anti-Bacterial Agents↗
PubMedDate not supplied

A comparative trial of sisomicin therapy by intermittent versus continuous infusion.

One hundred and thirty-nine febrile episodes in 120 patients were treated with sisomicin after a combination of carbenicillin and a cephalosporin antibiotic had failed. These patients were randomized to receive sisomicin either by continuous or by intermittent infusion. The response rate for patients treated with sisomicin was 61 percent by continuous infusion and 46 percent by intermittent infusion, which was not statistically significant. Pneumonia, septicemia, and soft tissue infections were the most frequent infections. Most (96 percent) of the identified pathogens were gram-negative bacilli with the most frequent being Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. The response rate was higher in those patients whose neutrophil count increased or remained the same while on therapy. The worst response was obtained if there was a decrease in the neutrophil count during therapy. The major toxicity of sisomicin was found to be azotemia and occurred in 17 percent of episodes treated by continuous infusion and in 21 percent treated by intermittent infusion. Hearing loss in the high frequency range occurred in five patients. Sisomicin is effective in the treatment of gram negative infections in neutropenic cancer patients.

Adolescent↗
PubMed1975

Clinical pharmacology of sisomicin.

Studies were conducted in 30 patients with neoplastic diseases. Twelve patients received sisomicin intramuscularly at doses of 20 mg/m(2) and 40 mg/m(2). The mean peak serum concentration occurred at 1 h and was 2.5 mug/ml and 4.0 mug/ml, respectively. Ten patients received intravenous sisomicin at doses of 30 mg/m(2) during 30-min infusion. Mean peak serum level determined at 30 min was 5.1 mug/ml. The levels gradually decreased and at 6 h was 0.6 mug/ml. The serum half-life was 160 min. Serum levels determined in eight patients who received sisomicin by continuous infusion at doses of 30 mg/m(2) every 6 h were greater than 1.4 mug/ml during the 6-h period. The urinary excretion of sisomicin during the 6-h period after intramuscular administration of 20 mg/m(2) and 40 mg/m(2) was 49 and 61%, respectively. The pharmacology of sisomicin is similar to gentamicin.

Adolescent↗
PubMed1981

Transfer of sisomicin to unborn and suckling guinea pigs.

When guinea pigs received a single intramuscular injection of sisomicin (25 mg/kg) at week 8 of pregnancy, fetal sisomicin concentration at 2 h was highest in the kidneys, followed by the plasma and the cochlea; at 4 h it was not detected in the plasma or the cochlea. When dams were treated with 25 mg/kg during weeks 1-5 of pregnancy, fetal sisomicin concentration in the kidneys was 9 times greater than in the cochlea; in 3-week-old animals, a drug concentration of 4 microgram/g was detected only in the kidneys. When dams were treated during weeks 5-9 of pregnancy, the neonatal drug concentration was highest in the kidneys and the cochlea; no plasma concentration was detected. At 3 weeks of age, the concentration was highest in the kidneys and the cochlea. When lactating dams received sisomicin, only kidneys of suckling animals contained sisomicin at 0.4 microgram/g.

Animals↗
PubMed1980

Comparison of sisomicin and gentamicin in the treatment of serious systemic infections.

Sixty-nine hospitalized patients with serious systemic infections, mainly surgical wound infections, soft-tissue abscesses, peritonitis, or pneumonia, were treated either with sisomicin or gentamicin by parenteral administration for periods ranging from 5 to 14 days. In general, sisomicin-treated patients received a mean daily dosage of 2.6 to 3.9 mg/kg and gentamicin-treated patients 3.0 to 5.1 mg/kg. The results, based on the combined clinical and bacteriological responses, showed an overall cure rate of 74% for the 34 patients on sisomicin compared with 37% of the 30 patients on gentamicin for whom a definite evaluation could be made. This difference was statistically significant (p = 0.005). The bacteriological findings also suggest that sisomicin was more effective than gentamicin in eliminating Pseudomonas aeruginosa from infected patients. Local tolerance was good to both drugs. A change in auditory function was reported in 1 patient on gentamicin. Mild changes in renal function, possibly drug related, were recorded in 5 patients (1 on sisomicin and 4 on gentamicin).

Bacterial Infections↗
PubMed1975

Biotransformation, a new approach to aminoglycoside biosynthesis. I. Sisomicin.

Utilizing a mutant of Micromonospora inyoensis which requires the addition of 2-deoxystreptamine for sisomicin production, the bioconversion of 2-deoxstreptamine containing pseudodisaccharides and pseudotrisaccharides into sisomicin was demonstrated. The trisaccharides tested were structurally related minor components found in the sisomicin or gentamicin fermentations. Based upon the specificity of the structural configuration of those compounds which were converted to sisomicin versus those which were not, a pathway for the biosynthesis of sisomicin is proposed.

Aminoglycosides↗
PubMed1976

Micromonospora-produced sisomicin components.

A sisomicin fermentation carried out in the presence of (methyl-14C)-L-methionine resulted in a crude mixture, composed of methyl-14C-labeled sisomicin as a major component; and two 4''-C-desmethylsisomicin (66-40B and 66-40D) isomer-like components, an unidentified component and a gentamicin A-like antibiotic as minor components. When (methyl-14C)-L-methionine was added in an early stage of the fermentation (24 hours), incorporation of methyl-14C-label into polar components (e.g., gentamicin A-like antibiotic) preceded that into sisomicin. Chromatographic evidence for the bioconversion of (methyl-14C)-gentamicin A to a radioactive sisomicin-like product (possibly (3''-N-methyl-14C)-sisomicin) was seen, when a Micromonospora blocked mutant was incubated in the presence of the former antibiotic.

Anti-Bacterial Agents↗
PubMed1985

[Quantitative indicators of gentamicin and sisomicin interaction with isolated subcellular fractions of the liver and kidneys and intracellular distribution of these antibiotics].

Interaction of gentamicin and sisomicin with isolated subcellular fractions of the rat liver and the kidney cortical layer was studied. Distribution of the antibiotics was investigated in a system with the volume ratio of the main components (organoids and cytosol-dissolved drug) simulating the natural volume ratio of the cytoplasm and organoids in the cells. It was shown that lysosomes were the most active elements in binding antibiotics. The microsomes and mitochondria were less active. By the binding capacity the subcellular structures of the kidneys were superior to the analogous structures of the liver. Dissociation of the organoid complexes with the antibiotics was possible, the mobility of the sisomicin complexes being higher than that of the gentamicin complexes. During intracellular distribution the major amount of every of the above aminoglycosides was absorbed by the organoids. Up to 20 per cent of gentamicin and up to 30 per cent of sisomicin remained in the cytoplasm in the active form. The characteristic features of the intracellular distribution of sisomicin (build up of high levels of the free antibiotic in the cytoplasm and relatively easy dissociation of the antibiotic complexes with the organoids of the kidney cortical layer) may define the higher activity of sisomicin as compared to that of gentamicin against intracellularly located microorganisms and its lower potential nephrotoxicity.

Animals↗
PubMed1983

In vitro and in vivo action of mezlocillin and azlocillin combined with sisomicin.

Combined action in vitro and in vivo of ureidopenicillins (azlocillin and mezlocillin) with sisomicin has been studied with employment of strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. In vitro effects of these combinations were most spectacular with Pseudomonas aeruginosa; azlocillin and sisomicin were potently synergistic. Other tested microorganisms reacted also but less markedly. Evaluation of therapeutic efficacy of ureidopenicillins combined with sisomicin was performed on 90 rabbits, infected intravenously with heavy inocula. Synergistic action has been confirmed in vivo during treatment of infections evoked by Escherichia coli and Pseudomonas aeruginosa. Therapy of these infections may be successful with doses of azlocillin or mezlocillin combined with sisomicin diminished by half, as compared with treatment of these infections with above antibiotics applied singly. Further decrease of sisomicin dosage in combined therapy of P. aeruginosa infections with ureidopenicillin is possible.

Animals↗