Fosfomycin

Structural formula
General
Non-proprietary name	Fosfomycin
other names	(2 R , 3 S ) -3-methyloxiranephosphonic acid ( IUPAC ) ; (1 R , 2 S ) - cis - (1,2-epoxypropyl) phosphonic acid; Phosphomycin;
Molecular formula	C 3 H 7 O 4 P
External identifiers / databases
ECHA InfoCard	100,041,315
PubChem	446987
DrugBank	DB00828
Wikidata	Q183554
Drug information
ATC code	J01 XX01
Drug class	antibiotic
properties
Molar mass	138.06 g · mol -1
Melting point	~ 94 ° C (fosfomycin)
solubility	soluble in water
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Disodium salt;	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
Toxicological data	> 10 g kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Fosfomycin is a medicinal substance ( antibiotic ) that is used in human medicine for severe bacterial infections . Fosfomycin was isolated from streptomycetes in Alicante (Spain) in 1970 and is so far the only epoxide antibiotic available .

application

Fosfomycin is available in the form of the sodium salt for intravenous use. The non-intestinal ( parenteral ) administration form is indicated for the treatment of severe, acute and chronic infections if these are caused by pathogens sensitive to fosfomycin. Fosfomycin is particularly indicated when penicillins and cephalosporins cannot be given or their effectiveness is insufficient due to the localization of the infection and the sensitivity of the pathogen. Fosfomycin is usually administered as part of a combination therapy , especially in the treatment of multi-resistant germs.

In the form of the more easily absorbed salt fosfomycin trometamol, there is also a granulate that is approved for oral use of uncomplicated urinary tract infections in women (single dose treatment; absorption approx. 40%). In the current S3 guideline for the treatment of uncomplicated urinary tract infections , it is recommended as the first choice for the treatment of uncomplicated cystitis due to its favorable resistance situation .

Effectiveness / spectrum of activity

By disrupting the synthesis of murein in the bacterial cell wall, it has a bactericidal effect . It is very effective against the following bacteria:

Gram negatives
- Haemophilus influenzae
- Escherichia coli (including ESBL )
- Citrobacter
- some Proteus species

Gram positive
- Staphylococci (including MRSA )
- Streptococci ( S. pyogenes , S. pneumoniae )

Mechanism of action

Fosfomycin is an epoxide antibiotic. It is an irreversible inhibitor of the enzyme MurA ( UDP- N -acetylglucosamine enolpyruvyl transferase). MurA catalyzes the first step of murein biosynthesis : the transfer of an enolpyruvyl unit from phosphoenolpyruvate (PEP) to UDP- N -acetylglucosamine (UNAG). The products of the reaction are enolpyruvyl UDP- N -acetylglucosamine and phosphate. Fosfomycin alkylates the thiol group of a cysteine side chain (Cys-115, numbering from E. coli MurA), which plays an important role in catalysis.

Fosfomycin can only be absorbed into the bacterial cell in the presence of glucose-6-phosphate , so it presupposes cell death in the target tissue. G6P must be added in vitro .

resistance

Most indole- positive Proteus strains are resistant to fosfomycin. The active ingredient is ineffective against Bacteroides species.

application

Indications

The drug is used for bacterial infections caused by germs sensitive to fosfomycin. These can be osteomyelitis , meningitis , urinary tract inflammation, airway inflammation, inflammation of the skin and soft tissues, infection of the biliary tract, sepsis , endocarditis or oto-rhino-laryngological and ophthalmological infections. As a preventive measure, it is used perioperatively together with metronidazole . In this combination it shows a similar effectiveness as doxycycline , ampicillin or cephalotin .

Synergism

If a combination with other antibiotics is medically indicated, use with another antibiotic with a bactericidal effect is recommended. In vitro studies show that the combination of fosfomycin with β-lactam antibiotics , e.g. B. penicillin , ampicillin , cefazolin , carbapenems , usually additive to synergistic effects can be achieved. Combinations with substances that are effective against staphylococci ( linezolid , quinupristin / dalfopristin, moxifloxacin ) also have a synergistic effect.

Application restriction

Dose reduction in case of impaired kidney function
Dose adjustment in the elderly using creatinine clearance
Control of the serum electrolytes (especially in patients with cardiac insufficiency , edema tendency or secondary hyperaldosteronism ) due to the increased sodium intake (14.5 mmol / g fosfomycin). The increased sodium intake can also cause potassium losses by increasing the potassium excretion (see hypokalaemia ).

Side effects

The drug is well tolerated in animal experiments. The rate of side effects is low. Side effects occur particularly in the area of the gastrointestinal tract .

Occasionally, exanthema , acute hypersensitivity reactions, vomiting, loss of appetite, diarrhea , phlebitis , taste irritation , temporary increase in liver values, shortness of breath, headache, dizziness, fatigue, hypernatraemia , hypokalaemia are mentioned. In individual cases there were visual disturbances.

Trade names

Monopreparations

for parenteral use: Infectofos (D), Fosfomycin Sandoz (A)
for oral use: Monuril (D, A, CH), Fosfuro (D), Generika (D)

Individual evidence

^ ^A ^b The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 730, ISBN 978-0-911910-00-1 .
↑ Data sheet Phosphomycin disodium salt from Sigma-Aldrich , accessed on May 3, 2011 ( PDF ).
↑ Data sheet FOSFOMYCIN TROMETAMOL CRS (PDF) at EDQM , accessed on August 3, 2008.
↑ ^a ^b Information for professionals INFECTOFOS® 5 g, powder for the preparation of an infusion solution. In: Yellow List. October 2015, accessed November 23, 2016 .
↑ Fosfomycin trometamol - reserve preparation or agent of choice for uncomplicated urinary tract infections? Retrieved August 18, 2011 .
^ Wagenlehner, Florian ME; Hoyme, Udo; Kaase, Martin; Five piece, Reinhard; Naber, Kurt G .; Schmiemann, Guido: Clinical Guideline Uncomplicated Urinary Tract Infections (2011). In: Dtsch Arztebl Int 2011; 108 (24): 415-23. Retrieved June 20, 2011 .
↑ Beata Chudzik-Rząd, Sylwia Andrzejczuk, Mariusz Rząd, Krzysztof Tomasiewicz, Anna Malm: Overview on fosfomycin and its current and future clinical significance . In: Current Issues in Pharmacy and Medical Sciences . tape 28 , March 1, 2015, p. 33-36 , doi : 10.1515 / cipms-2015-0039 ( researchgate.net [accessed January 20, 2020]).
↑ Matthew E. Falagas, Konstantina P. Giannopoulou, George N. Kokolakis and Petros I. Rafailidis: fosfomycin: Use Beyond Urinary Tract Infections and gastrointestinal. Oxford Brookes University, 2008

Web links

[MERCK_Index-1] A ^b The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 730, ISBN 978-0-911910-00-1 .

[Sigma-2] Data sheet Phosphomycin disodium salt from Sigma-Aldrich , accessed on May 3, 2011 ( PDF ).

[Ph._Eur.-3] Data sheet FOSFOMYCIN TROMETAMOL CRS (PDF) at EDQM , accessed on August 3, 2008.

[FI_Fosfomycin-4] Information for professionals INFECTOFOS® 5 g, powder for the preparation of an infusion solution. In: Yellow List. October 2015, accessed November 23, 2016 .

[5] Fosfomycin trometamol - reserve preparation or agent of choice for uncomplicated urinary tract infections? Retrieved August 18, 2011 .

[6] Wagenlehner, Florian ME; Hoyme, Udo; Kaase, Martin; Five piece, Reinhard; Naber, Kurt G .; Schmiemann, Guido: Clinical Guideline Uncomplicated Urinary Tract Infections (2011). In: Dtsch Arztebl Int 2011; 108 (24): 415-23. Retrieved June 20, 2011 .

[7] Beata Chudzik-Rząd, Sylwia Andrzejczuk, Mariusz Rząd, Krzysztof Tomasiewicz, Anna Malm: Overview on fosfomycin and its current and future clinical significance . In: Current Issues in Pharmacy and Medical Sciences . tape 28 , March 1, 2015, p. 33-36 , doi : 10.1515 / cipms-2015-0039 ( researchgate.net [accessed January 20, 2020]).

[8] Matthew E. Falagas, Konstantina P. Giannopoulou, George N. Kokolakis and Petros I. Rafailidis: fosfomycin: Use Beyond Urinary Tract Infections and gastrointestinal. Oxford Brookes University, 2008