Gentamicin

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General
Non-proprietary name Gentamicin
other names

Gentamycin

Molecular formula Mixture of substances
External identifiers / databases
CAS number
  • 1403-66-3
  • 1405-41-0 (gentamicin sulfate )
PubChem 3467
DrugBank DB00798
Wikidata Q422482
Drug information
ATC code
Drug class

Aminoglycoside antibiotic

properties
Molar mass Mixture of substances
Melting point

218–237 ° C (gentamicin sulfate)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
08 - Dangerous to health

danger

H and P phrases H: 317-334
P: 261-280-342 + 311
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Gentamicin is an aminoglycoside antibiotic that is used as a medicinal substance in the form of its sulfate salt for bacterial infections. The drug is composed of several individual compounds from the gentamicins group.

history

The first gentamicins were discovered by employees of Schering in New Jersey in 1963 in the products of the bacterial strain Micromonospora purpurea and their antibacterial effect was recognized.

composition

The gentamicin, as it is produced by the bacterium Micromonospora purpurea , is a mixture of structurally very similar aminoglycoside compounds , the gentamicins. The active pharmaceutical ingredient used almost exclusively contains type C gentamicins. It is a mixture consisting of 25–45% gentamicin C 1 , 10–30% gentamicin C 1a and 35–55% gentamicin C 2 , C 2a and C 2b consists. The first drugs containing gentamicin sulfate came onto the market in Germany between 1960 and 1970 under the trade name Refobacin.

Structures of the gentamicins of type C.
Gentamicin R 1 R 2 R 3 CAS number proportion of
Gentamicine 2.svg
C 1 -CH 3 -H -CH 3 25876-10-2 25-45%
C 1a -H -H -H 26098-04-4 10-30%
C 2 -CH 3 -H -H 25876-11-3 35-55%
C 2a -H -CH 3 -H 59751-72-3
C 2b -H -H -CH 3 52093-21-7

pharmacology

Gentamicin is used for the antimicrobial therapy of a wide variety of bacterial infections and is very effective. However, due to its considerable side effects on the kidneys and inner ear, in human medicine it is only used as an emergency medication for severe bacterial infections, especially for nosocomial infections . Gentamicin is used particularly frequently as an emergency antibiotic in pediatrics . The WHO recommends gentamicin as part of the medication against multiple resistant tuberculosis bacteria .

It is also widely used in veterinary medicine because of its effectiveness and relatively low price.

The side effects such as ear and kidney damage ( ototoxicity and nephrotoxicity ) are negligible with topical (local) application, which is why it is mainly used in the form of eye drops and eye and skin ointments.

application areas

Parenteral treatment

Gentamicin is used for the parenteral treatment of acutely life-threatening septic infections, particularly nosocomial infections, in combination with β-lactam antibiotics . Aminoglycosides are still indispensable antibiotics for endocarditis and severe infections caused by Pseudomonas . They are also important in the treatment of mycobacteriosis and in severe infections caused by enterococci , listeria , staphylococci and enterobacteria . The benefit of a longer duration of treatment must be weighed very strictly against the risk of potential toxicity (the risk of toxic effects increases significantly with the duration of treatment). Every aminoglycoside, including gentamicin, can - depending on the dosage, duration of therapy, underlying ailments of the patient and accompanying medications - lead to nephro- and ototoxic side effects. Gentamicin sulfate can be administered parenterally as an intramuscular or slow intravenous injection or as a short infusion in one to three doses per day. Children, adolescents and adults are initially treated with 3 to 5 mg / kg body weight per day. The daily single administration of the entire daily dose in the form of an infusion over 60 minutes is now the standard. Parenteral therapy should not exceed 10-14 days.

Topical application in ophthalmology

Gentamicin is used to treat infections of the anterior segment of the eye.

Surgery / orthopedics

For the treatment of post-operative or post-traumatic soft tissue and bone infections, implantable ball chains containing gentamicin sulfate and bone cement are available. Because of its high heat resistance and low allergenic potency, gentamicin in particular is incorporated into carrier materials, e.g. B. in so-called bone cements (gentamicin-PMMA balls, etc.). These materials have proven themselves in problematic situations in bone surgery. In addition, collagen sponges containing gentamicin are used in various interventions that are absorbable and, in addition to the antibiotic effect, also have a hemostatic effect.

In off-label use , gentamicin sulfate is used to treat Menière's disease . The harmful effect of gentamicin on the sensory cells of the inner ear ( ototoxicity ) is used to destroy the sensory cells and to alleviate the dizzy spells caused by the disease.

Mechanism of action

The aminoglycoside antibiotic gentamicin prevents the reading of the mRNA on the ribosomes by binding to the 30S subunit. This slows down the protein synthesis of the bacteria.

In high concentrations, the substance also influences the protein synthesis of human cells: where a stop signal for the end of protein synthesis encodes in the mRNA, this signal is skipped. Protein synthesis continues until the next stop signal occurs. Skipping does not always occur, but in a few percent of cases.

Gentamicin is bactericidal and in some cases has poor tissue penetration.

effectiveness

Gentamicin is particularly effective in gram-negative pathogens:

With gram-positive pathogens hardly any:

It's ineffective

  • in viral infections and
  • with fungal infections as well
  • in the case of infections by anaerobic bacteria, since the uptake of aminoglycosides in the bacterial cell is dependent on oxygen.
  • not all isolates of the above-mentioned pathogens are automatically sensitive either! If in doubt, testing is recommended.

In an acidic and / or anaerobic environment, the effect of gentamicin is reduced.

unwanted effects

The therapeutic range of gentamicin is narrow . If the plasma concentrations rise above the critical level (due to overdosing or accumulation in the case of impaired renal function), the risk of nephrotoxic reactions and irreversible damage to the inner ear (deafness) of the patient increases dangerously. Decisive for the risk of undesirable side effects are the “trough levels” and above all the duration of the treatment, as there is a continuous accumulation in the kidney cortex. Gentamicin, like all aminoglycosides, cannot enter a cell by passive diffusion, but only by active transport. It is a process of saturation. If the saturation concentration is exceeded, the antibiotic is not absorbed more. This explains why a single high concentration at the target site of toxicity causes fewer effects than long-term contact with low concentrations. Since gentamicin is only eliminated from the tubular cells very slowly, there is an increased risk of toxic effects after previous aminoglycoside therapy (within six weeks). Small amounts of the antibiotic are released from the “deep compartments” (e.g. proximal tubular cells ) for weeks after the end of therapy .

Because of the possible serious side effects, strict indications and dosing according to kidney function (creatinine clearance) are required for gentamicin therapy.

Adverse effects particularly affect the kidneys and ears.

Nephrotoxicity

In 1–10% of the cases, a mostly reversible proximal tubular damage occurs. Gentamicin is introduced into the proximal tubular cells and accumulates in the lysosomes there. The aminoglycoside-induced (mostly reversible) kidney function impairment slows down the further elimination of antibiotics. The combination of gentamicin with other drugs with nephrotoxic components, such as furosemide, certain immunosuppressants, certain antibiotics, etc., intensifies kidney damage. The use of statins to reduce nephrotoxicity is being investigated.

Ototoxicity

Hearing damage occurs in 1–3% of cases. In the inner ear, even a slight transfer of gentamicin into the hair cells leads to the irreversible loss of the sensory hair. This leads to balance disorders and hearing loss beginning in the high frequency range. Balance disorders can occur in up to 14% of the cases. The toxicity, which selectively affects the hair cells of the inner ear, could be explained by the fact that there is a much higher potential difference between the endolymph and the interior of the hair cells (> −150 mV) than at the membranes of other body cells (between −55 and −100 mV). This electrophysiological peculiarity could favor the fact that gentamicin - with long-term high plasma concentrations - is primarily introduced into the hair cell cytoplasm. Hearing disorders start with a reduction in hearing sharpness in the high frequency range and are mostly irreversible. The most important risk factor is a pre-existing renal insufficiency. The risk increases proportionally with the total and daily dose.

There is partly a genetic predisposition for the ototoxic effects of aminoglycosides. So far, two mutations in the mitochondrial genome are known that lead to a high risk of aminoglycoside-related ototoxicity:

  • A1555G mutation in the mitochondrial 12S ribosomal RNA gene
  • Delta T961Cn mutation

It is estimated that approximately 15% of all aminoglycoside-induced deafness cases in the United States are due to the A1555G mutation. In China, the proportion is at least 30%. Nothing is currently known about the frequency of the delta T961Cn mutation. Current data from Germany do not exist. In every case of aminoglycoside-induced deafness, it is advisable to examine the patient for the two mutations mentioned above and, in the event of a “positive” case, to advise all female relatives about an increased risk of aminoglycosides.

In a recently published retrospective study on 33 adult patients it was shown that there is no safe gentamicin dose. In this study, measuring serum gentamicin levels was without predictive of the onset, occurrence, or severity of ototoxicity. Due to the severity and frequency of the side effects and the presence of good alternative drugs, some authors demand that gentamicin be avoided.

A randomized, controlled study shows that the risk of permanent hearing damage can be significantly reduced by the simultaneous administration of acetylsalicylic acid (ASA). The study, which was carried out between 1999 and 2003 at two clinics in China, initially shows how strongly gentamicin is ototoxic: 14 of 106 patients (about 13%) who were given intravenous gentamicin (80 to 160 mg twice daily for the treatment of acute infections) over 5 to 7 days) suffered a hearing threshold decrease of 15 dB or more in one or both ears. In a comparison group of 89 patients who, in addition to gentamicin medication, took 1 gram of ASA 3 times a day for 14 days, only 3 patients (around 3%) experienced hearing impairment. In the opinion of the authors, these results therefore justify the regular use of ASA as an additive to gentamicin, especially since there was no loss of effectiveness of the antibiotic.

Neuromuscular blocks

Local application of concentrated aminoglycoside solutions can provoke neuromuscular blockages, e.g. B. on the occasion of heart valve operations.

Precautions

In order to counteract the occurrence of severe side effects from gentamicin, which can occur with systemic administration, critical plasma levels must be avoided, for example by intramuscular injection or slow infusion. Continuous monitoring of renal function (determination of serum creatinine or creatinine clearance before, during and after treatment) is recommended; If necessary, the blood levels should be monitored, especially in the case of kidney function disorders, dialysis patients, long-term therapy, high-dose treatment, e.g. B. in immunodeficiency.

Trade names

Monopreparations

Garamycin (CH), Gentamycin (D), Gencin (D), Gentamytrex (D), Gentax (A), Gent-Ophtal (D), Ophtagram (CH), Refobacin (D, A), Septopal (CH), Sulmycin (D), various generics (D, A)

Combination preparations

Cibaflam (D), Decoderm comp (D, A), Dexa-Gentamicin (D), Dexagent (D), Dexagenta (A), Dexamytrex (D), Diprogenta (D, A, CH), Infectoflam (CH), Inflanegent (D), Ophtasone (CH), Septopal (D, A), Sulmycin (A), Terracortril (D), Triderm (CH), Voltamicin (CH)

Web links

Commons : Gentamicin  - collection of images, videos and audio files

Individual evidence

  1. ↑ a b c d e entry on gentamicin. In: Römpp Online . Georg Thieme Verlag, accessed on March 14, 2011.
  2. ↑ a b Data sheet Gentamicin sulfate from Sigma-Aldrich , accessed on April 3, 2011 ( PDF ).
  3. ^ Entry on gentamicin in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  4. ^ Gentamicin . In: Br Med J . tape 1 , no. 5533 , January 1967, p. 158-159 , PMID 6015651 , PMC 1840594 (free full text).
  5. ↑ S.-H. Sha, J.-H. Qiu, J. Schacht: Aspirin to Prevent Gentamicin-Induced Hearing Loss. In: NEJM. 354, 2006, pp. 1856-1857.
  6. ^ A b W. Forth, D. Henschler, W. Rummel, U. Förstermann, K. Starke: General and special pharmacology and toxicology. 8th edition. Urban & Fischer, 2001, pp. 828-835.
  7. ↑ Klaus Aktories, U. Förstermann, F. Hofmann, Klaus Starke: General and special pharmacology and toxicology. 9th edition. Urban & Fischer, 2004, p. 813.
  8. ^ A b D. Schneider: Checklist Medicines A – Z. 2nd Edition. Thieme, 2004, pp. 354-355.
  9. ↑ A. Jamshidzadeh, R. Heidari, S. Mohammadi-Samani, N. Azarpira, A. Najbi, P. Jahani, N. Abdoli: A comparison between the nephrotoxic profile of gentamicin and gentamicin nanoparticles in mice. In: Journal of Biochemical and Molecular Toxicology . Volume 29, Number 2, February 2015, pp. 57-62, doi: 10.1002 / jbt.21667 . PMID 25293820 .
  10. ↑ S. Dashti-Khavidaki, A. Moghaddas, B. Heydari, H. Khalili, M. Lessan-Pezeshki, M. Lessan-Pezeshki: Statins against drug-induced nephrotoxicity. In: Journal of Pharmacy & Pharmaceutical Sciences . Volume 16, Number 4, 2013, pp. 588-608. PMID 24210066 .
  11. ↑ PJ Govaerts et al .: Aminoglycoside-induced ototoxicity. In: Toxicology Letters . Vol. 52, No. 3, 1990, pp. 227-251.
  12. ↑ Specialist information gentamicin (B. Braun).
  13. ^ Y. Qian, MX Guan: Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation. In: Antimicrobial Agents and Chemotherapy . Volume 53, Number 11, November 2009, pp. 4612-4618, doi: 10.1128 / AAC.00965-08 . PMID 19687236 , PMC 2772318 (free full text).
  14. ↑ N. Fischel-Ghodsian: Mitochondrial deafness renewed. In: Human Mutation. 13, 1999, pp. 261-270.
  15. ↑ F. Owen Black et al.: Permanent Gentamicin Vestibulotoxicity. In: Otology & Neurology. 25, 2004, pp. 559-569.
  16. ↑ P. William: Should Aminoglycoside Antibiotics Be Abandoned? In: The American Journal of Surgery . 180 (6), 2001, pp. 512-516.
  17. ↑ S.-H. Sha, J.-H. Qiu, J. Schacht: Aspirin to Prevent Gentamicin-Induced Hearing Loss. In: NEJM 354, 2006, pp. 1856-1857.
  18. ↑ J. Lautermann, J. Schacht, K. Jahnke: Aminoglykosidototoxixität - Pathomechanisms, Clinic and Prevention Options. In: ENT. 51, 2003, pp. 344-352; doi: 10.1007 / s00106-003-0830-1 .