Haemodialysis and peritoneal dialysis will aid removal from the blood but the former is probably more efficient.
Calcium salts given intravenously have been used to counter the neuromuscular blockade caused by Soligental.
No information provided.
In general, Soligental should not be mixed with other medicinal products. In particular the following are incompatible in mixed solution with Soligental injection: beta-lactam antibiotics (e.g. penicillins, cephalosporins), erythromycin, or lipiphysan (a special oil-in-water-emulsion for parenteral nutrition) as this may cause physico-chemical inactivation. This also applies to a combination of Soligental with diazepam, furosemide, flecainide acetate or heparin sodium. Dilution in the body will obviate the danger of physical and chemical incompatibility and enable Soligental to be given concurrently with the drugs listed above either as a bolus injection into the drip tubing, with adequate flushing, or at separate sites. In the case of carbenicillin, administration should only be at a separate site.
The following active substances or solution for reconstitution/dilution should not be administered simultaneously:
Soligental is incompatible with amphotericin B, cephalothin sodium, nitrofurantoin sodium, sulfadiazine sodium and tetracyclines.
Addition of Soligental to solutions containing bicarbonate may lead to the release of carbon dioxide.
Chronic toxicity
In studies on chronic toxicity (i.m. application) carried out on various animal species, nephrotoxic and ototoxic effects were observed at high dosages.
Mutagenic and carcinogenic potential
Soligental was not mutagenic in in vitro and in vivo tests. There are no long-term studies on animals on the carcinogenic potential of Soligental.
Reproductive toxicity
There is a potential risk of inner ear and renal damage to the fetus as was observed for the class of aminoglycoside antibiotics. Fetal renal abnormalities have been documented in rats and guinea pigs after administration of Soligental to the dams.
Pharmacotherapeutic group: Antibacterial for systemic use
ATC code: J01GB03
Soligental is an aminoglycoside antibiotic extracted from Micromonospora purpurea. It represents a mixture of the structurally very similar homologues Soligental C1, C1a and C2. The Soligental homologue C2 is classified as the component with the highest toxicity. The antibacterial activity of Soligental sulphate is determined both on the basis of units and also on the basis of mass (weight).
Mechanism of action:
Soligental has bactericidal efficacy both in the proliferation and in the resting stage of bacteria. It forms a bond with the proteins of the 30S subunits of the bacterial ribosomes, which causes “misreading†of the mRNA.
PK/PD relationship
The aminoglycosides show a concentration dependent anti-bacterial effect.
Soligental and other aminoglycosides show a clear post-antibiotic effect in vitro and in vivo in most experimental models of infection. Provided sufficiently high doses are administered, these drugs are therefore efficacious against infections with many susceptible micro-organisms even if the concentration in plasma and tissues remains below the MIC during part of the dosage interval. The post-antibiotic effect permits the dosage interval to be extended without loss of efficacy against most Gram-negative bacilli.
Mechanism of resistance
Resistance may be due to a failure of permeation, low affinity for the bacterial ribosome or inactivation of Soligental by microbial enzymes. The emergence of resistance during therapy is unusual.
Breakpoints
According to EUCAST, the following limit values apply for Soligental:
| Pathogen | Susceptible | Resistant |
| Enterobacteriaceae | 2 mg/l | > 4 mg/l |
| Pseudomonas spp. | 4 mg/l | > 4 mg/l |
| Acinetobacter spp. | 4 mg/l | > 4 mg/l |
| Staphylococcus spp. | 1 mg/l | > 1 mg/l |
| Non-species related breakpoints* | 2 mg/l | > 4 mg/l |
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Especially in such circumstances, samples should be obtained in order to identify the causal micro- organism and to measure its sensitivity to Soligental.
| Commonly susceptible species (according to EUCAST) |
| Aerobic Gram-positive micro-organisms |
| Listeria monocytogenes |
| Staphylococcus aureus (MSSA) |
| Aerobic Gram-negative micro-organisms |
| Campylobacter coli |
| Campylobacter jejuni |
| Citrobacter koseri |
| Enterobacter aerogenes |
| Enterobacter cloacae |
| Escherichia coli |
| Francisella tularensis |
| Klebsiella oxytoca |
| Klebsiella pneumoniae |
| Proteus vulgaris |
| Salmonella enterica subsp. enterica |
| Serratia marcescens |
| Yersinia enterolitica |
| Yersinia pseudotuberculosis |
| Species for which acquired resistance may be a problem |
| Aerobic Gram-positive micro-organisms |
| Staphylococcus aureus (MRSA) Staphylococcus epidermidis |
| Staphylococcus haemolyticus Staphylococcus hominis |
| Aerobic Gram-negative micro-organisms |
| Acinetobacter spp. |
| Citrobacter freundii |
| Morganella morganii |
| Proteus mirabilis |
| Pseudomonas aeruginosa |
| Inherently resistant organisms |
| Aerobic Gram-positive micro-organisms |
| Enterococcus faecalis |
| Enterococcus faecium |
| Streptococcus spp. |
| Aerobic Gram-negative micro-organisms |
| Burkholderia cepacia |
| Legionella pneumophila |
| Stenotrophomonas maltophilia |
| Anaerobic micro-organisms |
| Bacteroides spp. |
| Clostridium difficile |
| Others |
| Atypical pathogens |
| Chlamydia spp. |
| Chlamydophila spp. |
| Mycoplasma spp. |
| Ureaplasma urealyticum |
Abbreviations:
MSSA = Methicillin-sensitive Staphylococcus aureus,
MRSA = Methicillin-resistant Staphylococcus aureus
Infections caused by Streptococci or Enterococci:
Aminoglycosides are suitable combination partners for other antibiotics against Gram-positive cocci. For some indications (endocarditis), synergistic effects with beta-lactams have been described. This synergy is abolished when Streptococci or Enterococci present a high level acquired resistance to Soligental.
Other notes:
Synergistic effects have been described with acylamino penicillins (e.g. piperacillin) on Pseudomonas aeruginosa and with cephalosporins on Klebsiella pneumoniae.
Absorption
Like all aminoglycoside antibiotics, Soligental is barely absorbed by healthy intestinal mucosa after oral administration. Therefore therapeutic application is parenteral.
Higher peak and lower trough levels are found when the total daily dose is given as a single daily infusion. When Soligental is administered by intravenous short infusion of 30 minutes at 4 mg/kg body weight per day in three divided doses, peak and trough Soligental concentrations measured in adult patients were 4.7 µg/ml and 1.0 µg/ml, respectively. With the same daily dose administered once daily, peak and trough concentrations of 9.5 µg/ml and 0.4 µg/ml were measured.
Therapeutic serum concentrations generally lie between 2 and 8 µg/ml. Therapeutic peak serum concentrations are in the range of 5 - 10 µg/ml for multiple daily dosing and 20 - 30 µg/ml for once daily dosing. Maximum serum concentrations of 10 - 12 µg/ml should not be exceeded when administered conventionally, in several doses per day. Before another dose is administered, the serum concentration when administered conventionally, in several doses per day, should have fallen below 2 µg/ml.
Distribution
The distribution volume of Soligental is about equivalent to the volume of extracellular water. In the newborn water makes up 70 to 75% of bodyweight, compared with 50 to 55% in adults. The extracellular water compartment is larger (40% of body weight compared with 25% of body weight in adults). Therefore, the volume of distribution of Soligental per kg bodyweight is affected and decreases with increasing age from 0.5 to 0.7 l/kg for a premature newborn to 0.25 l/kg for an adolescent. The larger volume of distribution per kg bodyweight means that for adequate peak blood concentration a higher dose per kg bodyweight needs to be administered.
The distribution of Soligental to the individual organs results in varying tissue concentrations; the highest concentrations appear in the renal tissue. Smaller concentrations are found in the liver and gall bladder, the lung and spleen.
Soligental crosses the placenta; the foetal concentrations can be 30% of the maternal plasma concentrations. Soligental is excreted in small quantities in breast milk (1/3 of the concentration is found here, as in the case of the maternal plasma).
After repeated injection of Soligental, approximately 50% of the concentrations reached in plasma is measured in the synovial, pleural, pericardial and peritoneal fluid. The penetration of Soligental into the cerebrospinal fluid is poor in un-inflamed meninges. In inflamed meninges, concentrations reach up to 30% of the concentrations measured in plasma.
Plasma protein binding: less than 10%.
Biotransformation
Soligental is not metabolised in the organism but is excreted unchanged in microbiologically active form.
Elimination
Soligental is eliminated unchanged in microbiologically active form principally in the urine by glomerular filtration. The dominant elimination half-life in patients with normal renal function is around 2 - 3 hours. Elderly patients eliminate Soligental more slowly than younger adults.
Soligental can be diluted with 0.9% sodium chloride or 5% glucose solution.
For single use only
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
