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Sisomicin treatment of serious neonatal infections. A clinical and pharmacokinetic study.

23 infants, 20 of which had verified or clinically highly suspected serious infections in the neonatal period, were treated with a new antibiotic aminoglycoside, sisomicin, i.m. in doses from 2.8 to 6.6 mg/kg/24 h. Clinical cure was obtained in 18 of 20 caes, and marked improvement in one case. Adverse effects were only observed in two infants with tenderness at the injection sites. Serum concentrations and half-life estimations showed that the concentrations were similar to those obtained for gentamicin, and that half-life was independent of postnatal age, but highly correlated to the gestational age and to body weight. Consideration should therefore be given to the prolonged half-life of the drug in immature and low birth weight infants.

Anti-Bacterial Agents↗

In vitro comparison of netilmicin, a semisynthetic derivative of sisomicin, and four other aminoglycoside antibiotics.

One hundred isolates of Pseudomonas and Enterobacteriaceae, of which 85 were chosen because of their resistance to gentamicin or amikacin, were tested for susceptibility to netilmicin (SCH 20569), a new semisynthetic derivative of sisomicin, and to four other aminoglycosides. Tests were performed in Mueller-Hinton agar and, with 43 of these isolates, also in Mueller-Hinton broth. Most isolates of Escherichia coli, Klebsiella, Enterobacter, Citrobacter, and Serratia that were gentamicin resistant proved to be susceptible to netilmicin and amikacin. Tests of representative isolates of this group showed that they owed their resistance to the production of aminoglycoside-adenylylating enzymes. Four isolates of Serratia, detected by their resistance to amikacin, were also highly resistant to netilmicin but were susceptible to gentamicin. These isolates produced aminoglycoside-acetylating enzymes. Gentamicin-resistant Proteus and Providencia were, in general, highly resistant to netilmicin but were susceptible to amikacin. These isolates also produced aminoglycoside-acetylating enzymes. Most gentamicin-resistant strains of Pseudomonas were resistant to netilmicin, either by enzymatic aminoglycoside modification or by other undefined mechanisms. Thus, like amikacin, netilmicin extends the aminoglycoside susceptibility pattern of Enterobacteriaceae to include gentamicin-resistant isolates that produce aminoglycoside-adenylylating enzymes. It is ineffective against strains, some of them susceptible to amikacin, gentamicin, or tobramycin, that produce aminoglycoside-acetylating enzymes.

Amikacin↗

In vitro comparison of gentamicin, tobramycin, sisomicin, and netilmicin.

The antimicrobial activity of gentamicin, tobramycin, sisomicin, and netilmicin (Sch 20569) was compared against 150 strains of organisms. Netilmicin was shown to be the least effective against Pseudomonas strains but to have slightly better activity against Staphylococcus aureus and Escherichia coli than the other agents. The effect of calcium and magnesium in enhancing the differences in activity of these aminoglycosides against Pseudomonas strains was also demonstrated.

Aminoglycosides↗

Biotransformation of sisomicin to gentamicin C2b.

Sisomicin was transformed to gentamicin C(2b) by Micromonospora rhodorangea NRRL 5326. The mechanisms involved in the biotransformation are the 6'-N-methylation and the (4'-5')-reduction. The progression of the methylation was followed by the isotope technique, but the reduction reaction was not monitored.

Gentamicins↗

Enhancement of antistaphylococcal activity of nafcillin and oxacillin by sisomicin and netilmicin.

The in vitro activity of sisomicin, netilmicin, nafcillin, and oxacillin against 35 strains of Staphylococcus aureus isolated from blood cultures of patients with endocarditis or septicemia was studied. The effects of combinations of either of the two newer aminoglycosides and either of the two penicillinase-resistant penicillins on the killing of S. aureus were investigated. All S. aureus strains were susceptible to the four antibiotics. Enhancement of antistaphylococcal activity was demonstrated by the antibiotic combinations.

Blood↗

Comparative distribution of gentamicin, tobramycin, sisomicin, netilmicin, and amikacin in interstitial fluid in rabbits.

We compared the penetration of five aminoglycosides into interstitial fluid (IF). IF was obtained in rabbits from Silastic tissue cages. Intramuscular injections were made: 1.5 mg/kg per dose for gentamicin (G), tobramycin (T), sisomicin (S), and netilmicin (N) and 7.5 mg/kg per dose for amikacin (A). Serum levels and IF concentrations were studied for 12 h after a single injection. IF levels were also compared in a six-injection study (one injection every 8 h). Peak serum levels were significantly higher with A than with G, T, S, and N, which gave similar concentrations. In IF, G gave the highest levels 1 h after the first injection. At 4 and 8 h, the concentrations achieved with G and A were similar but significantly greater than those achieved with T, S, and N. Twelve hours after a single injection, N gave higher IF levels than the other drugs except A. In the six-injection study, the IF levels of G and A reached 4.6 +/- 1.5 and 5.27 +/- 1.1 microgram/ml, respectively, at 48 h. S and N gave identical concentrations (2.07 +/- 0.25 and 2.42 +/- 0.42 microgram/ml, respectively). T induced the lowest levels (1.17 +/- 0.30 microgram/ml). Thus, in this rabbit model, the IF concentrations achieved with G and A were above the minimal inhibitory concentrations for most susceptible strains. Possible relations between IF aminoglycoside concentrations and therapeutic efficiency or toxicity are pointed out but deserve further studies.

Amikacin↗

Clinico-pharmacological studies of sisomicin in ill children.

Sisomicin, at 4.5 mg/kg per day, was prescribed for the therapy of serious bacterial infections of hospitalized infants, children, and adolescents. Eleven children received full treatment courses, with 10 clinical and 9 bacteriological cures. Three patients with underlying disease (two cystic fibrosis and one aplastic anemia) accounted for the failures. Mean half-life was 98.3 min (range, 26.1 to 159.3), and peak serum concentrations 10 min after intravenous infusion were similar (5 to 6 mug/ml) on days 1, 3, and 5 of therapy. Mean urinary concentrations were 54.3 mug/ml; 31 to 47% of the drug was excreted within the 8-h dosage interval. The drug was tolerated well by all patients; however, one patient, receiving the longest duration of therapy (26 days), developed reversible nephrotoxicity.

Adolescent↗

Comparison of in vitro activity of Sch 21420, a gentamicin B derivative, with those of amikacin, gentamicin, netilmicin, sisomicin, and tobramycin.

Sch 21420 is a new aminoglycoside synthesized from gentamicin B. Susceptibility tests with Sch 21420, amikacin, gentamicin, netilmicin, sisomicin, and tobramycin were performed on a variety of bacterial species including 44 with known mechanisms of resistance to aminoglycosides. Sch 21420 and amikacin had similar effects on all except Haemophilus influenzae and Neisseria species, which were more susceptible to amikacin. Except with some strains of Serratia marcescens, the drugs used were bactericidal. Sch 21420 and amikacin were more stable than the other four aminoglycosides in the presence of the inactivating enzymes produced by some strains. Strains which were very resistant to Sch 21420 and emikacin either were permeability mutants or produced AAC (6')-I inactivating enzyme. The effect of cations on the susceptibilities of these strains to Sch 21420 and amikacin was seen mostly with Pseudomonas aeruginosa and to Sch 21420 with Acinetobacter. Cations did not affect the susceptibilities of other Pseudomonas species, Enterobacteriaceae, Staphylococcus aureus, or Streptococcus faecalis to Sch 21420 or amikacin.

Amikacin↗

Enzymatic inactivation of a new aminoglycoside antibiotic, sisomicin by resistant strains of Pseudomonas aeruginosa.

The antibacterial activity of sisomicin (SS), a new aminoglycoside antibiotic active toward clinical isolates of Pseudomonas aeruginosa, was determined and compared with that of the gentamicin C complex. Both drugs were effective against these strains and showed almost the same antibacterial activity. A few strains were found to be resistant to SS. The antibiotic was inactivated by a cell-free extract from the SS-resistant strains due to acetylation of the drug. Comparative studies of the inactivation of the drugs which lack a 6'-amino group in the amino sugar linked to 2-deoxystreptamine strongly suggested that SS inactivation was due to acetylation of the 6'-amino group of the 4',5'-didehydropurpurosamine moiety.

Acetylation↗

Comparison of sisomicin and gentamicin in bacteriuric patients with underlying diseases of the urinary tract.

Sisomicin and gentamicin (2 mg/kg) were administered in a random fashion to patients with bacteriuria superimposed on abnormalities of the urinary tract. Cure was achieved in a similar number of patients in both groups, but superinfection and reinfection with resistant microorganisms was more frequent in patients receiving gentamicin. Untoward side effects were not frequent in this series, especially if the serious underlying urological disease of most patients is taken into consideration. The susceptibility of the causative pathogens to the antibiotic administered and the severity of the underlying disease were the most important factors in the outcome.

Anti-Bacterial Agents↗

A comparison of the minimum inhibitory concentrations of sisomicin and of fourteen other antibiotics.

The activities of sisomicin and of fourteen other antibiotics have been compared for their inhibitory activity on all the different strains of bacteria isolated from a 3,000 bed hospital. The antibiotic sensitivity tests were performed in liquid medium and expressed as minimum inhibitory concentrations. The tests were performed over a period of four months. The results are discussed.

Anti-Bacterial Agents↗

Determination of sisomicin in eluate from dried blood spot on filter paper disc for monitoring of blood level in rat, by reversed-phase high-performance liquid chromatography after pre-column fluorimetric derivatization.

About 20 microliters of whole blood obtained by venipuncture from rat tail vein was spotted onto a filter paper and the blood spot was punched out (5 mm diameter). Sisomicin (SISO) in the dried blood spot (DBS) was extracted effectively into 0.5 M Na2HPO4 solution by ultrasonication and determined by reversed-phase high-performance liquid chromatography with pre-column derivatization using o-phthalaldehyde and beta-mercaptopropionic acid. This method could be used for the pre-clinical study of SISO blood levels of a number of mice or rats without killing. The results were identical with those for SISO in serum, if corrected for hematocrit values, and were used for the calculation of pharmacokinetic parameters for individual rats. The detection limit of SISO in DBS (10.1 microliters of whole blood) was 1.0 microgram per ml of whole blood.

Animals↗

Neuromuscular blocking actions of the aminoglycoside antibiotics sisomicin and micronomicin in the rabbit.

The neuromuscular blocking actions of sisomicin sulfate (SISO), micronomicin sulfate (MCR) and d-tubocurarine (dTc) were studied in 20 rabbits anesthetized with halothane. The i.v. administration of SISO 20-40 mg/kg, MCR 40-80 mg/kg or dTc 0.1-0.3 mg/kg resulted in dose-dependent decreases in twitch tension. The ED50s for SISO, MCR and dTc were 23.5, 58.2 and 0.2 mg/kg, respectively. SISO- and MCR-induced neuromuscular blockade was partially antagonized by neostigmine or by calcium.

Aminoglycosides↗

[In-vitro microbiological evaluation of the action of gentamicin and sisomicin o schizomycetes of the Salmonella genus].

The in vitro activity of Gentamicin and Sisomicin towards 142 clinical isolated Salmonella strains was determined and statisically evaluated. The majority of the Salmonella strains was inhibited by concentrations of both antibiotics ranging between 0.75 mcg/ml and 0.02 mcg/ml in the Minimal Inhibitory Concentration (MIC) test and between 1.5 mcg/ml and 0.02 mcg/ml in the Minimal Bactericidal Concentration (MCB) test.

Anti-Bacterial Agents↗

[Antibacterial activities of sisomicin against fresh clinical isolates].

To investigate antibacterial activities of sisomicin (SISO), MICs of SISO as well as other aminoglycosides (AGs) were determined against many clinical isolates which were obtained in 1991. Results are summarized below: 1. No SISO-resistant strains were observed among isolates of Escherichia coli, Citrobacter diversus, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Proteus mirabilis and Morganella morganii. 2. In comparison with the results of our previous study against isolates obtained in 1986, the rate of methicillin-resistant Staphylococcus aureus (MRSA) was higher, and SISO-resistant strains were observed at a high rate among the MRSA. Also, SISO-resistant strains of Serratia marcescens increased. However, the rate of SISO-resistant strains of Pseudomonas aeruginosa decreased, and among Citrobacter freundii, Enterobacter cloacae and Proteus vulgaris, SISO-resistant strains did not increase over the years. 3. MICs of SISO against Providencia rettgeri and Providencia stuartii were high, suggesting that antibacterial activities of SISO was weak against genus Providencia. 4. For comparison, according to MICs of ofloxacin and imipenem, new quinolone-resistant strains were observed at a high rate among various organisms, and carbapenem-resistant strains were observed at a high rate among S. marcescens and P. aeruginosa. 5. SISO is still one of the useful AGs in the 1990's since it maintains its strong antibacterial activities against most clinical isolates obtained in recent years and its potential as a combination drug with beta-lactams is being reported.

Bacteria↗

[Synergistic action of cefodizime with other antimicrobial agents on clinically isolated microorganisms. II. Synergistic action with sisomicin].

Cefodizime (CDZM) possesses a broad antimicrobial spectrum and a relatively long half life in the blood. In addition, it shows excellent therapeutic efficacies in the treatment of infections in leukopenic animal models, hence it is expected that CDZM may have good efficacies against various infections in immunocompromised hosts. In the meantime, sisomicin (SISO) not only has strong antibacterial activities against Gram-negative rods (GNR), but has relatively low nephrotoxicity and ototoxicity. Thus, we examined antibacterial effectiveness of the combination of CDZM and SISO against clinical isolates in vitro. 1. Antibacterial effects of CDZM+SISO combination were examined using SISO susceptible strains of Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus vulgaris, Morganella morganii and Pseudomonas aeruginosa. Observations that the combination of the 2 drugs showed FIC indices between less than 0.5-less than 1.0 against most of these strains at SISO concentrations of 1 MIC or sub MIC levels strongly suggested the presence of a synergistic action between the 2 drugs against SISO susceptible strains of GNR. 2. Of the strains tested, 10% of C. freundii, 6.7% of E. cloacae, 63.3% of S. marcescens, 23.3% of P. vulgaris and 18.0% of P. aeruginosa were found to be resistant to SISO, and little synergistic effect of the 2 drugs was observed against these strains. 3. As the synergistic effect of the 2 drugs against GNR was observed against SISO susceptible strains including those which were resistant to CDZM, but not against those strains which were resistant to SISO, it seems reasonable to conclude that the appearance of the synergistic effect between the 2 drugs depends on the activity of SISO.

Cefotaxime↗