DE19945885A1 - Use of gemifloxacin compounds, which can be active against bacterial strains resistant to other antibiotics, in treatment of infections caused by respiratory tract pathogenic bacteria - Google Patents

Abstract

Gemifloxacin compounds are used to modulate the metabolism of respiratory tract pathogenic bacteria, and to treat and prevent infection by such bacteria. Independent claims are included for: (1) modulating metabolism of respiratory tract pathogenic bacteria, comprising contacting the bacteria with a composition comprising a gemifloxacin compound, or derivative of this; and (2) treating or preventing infection by respiratory tract pathogenic bacteria, comprising administering a gemifloxacin compound to a mammal.

Description

Part of the present invention relates to newly identified methods of use quinolone antibiotics, especially a gemifloxacin compound against uropathogenic bacteria such as B. K. pneumoniae, P. mirabilis, E. Gell, P. aeruginosa, E. faecalis and S. aureus, especially S. aureus and E. faecalis.

BACKGROUND OF THE INVENTION

Quinolones have different degrees against a number of bacteria proved to be effective against pathogens. However, because of these pathogens caused diseases increase, there is a need for antimicrobial Compounds that are more effective than the existing group of quinolones.

Gemifloxacin Mesylate (SB-265805) is a new fluoroquinolone that is useful as an effective antibacterial agent. Gemifloxacin compounds are described in detail in patent application PCT / KR98 / 00051 published as WO 98/42705. Patent application EP 688772 discloses new quinoline (naphthyridine) carboxylic acid derivatives including anhydrous (R, S) -7- (3-aminomethyl-4-methoxy iminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of the formula I.

PCT / KR98 / 00051 discloses (R, S) -7- (3-aminomethyl-4-syn-methoxyimino-pyrroli din-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof, including the sesquihydrate.

This document describes the use of a gemifloxacin compound important discovery made against uropathogenic bacteria that the one set gemifloxacin compound was more effective than a number of quinolones, as described in more detail herein. Gemifloxacin compounds are very useful Compounds for the treatment of disease states by a number of uropathogenic pathogens are caused, including those that are resistant to conventional oral therapy, filling a medical gap.

SUMMARY OF THE INVENTION

An object of the invention is a method for changing the metabolism of disease-causing uropathogenic bacteria comprising the step of disease excitatory uropathogenic bacteria with an antibacterially effective amount of Composition comprising a quinolone, in particular a gemifloxacin Compound or an antibacterial derivative thereof.

Another object of the invention is a method in which these are pathogenic uropathogenic bacteria are selected from the group consisting of: K. pneumoniae, P. mirabilis, E. coli, P. aeruginosa, S. aureus and E. faecalis.

The invention also provides a method of preventing bacterial uro infection to treat or prevent pathogenic bacteria, including the step of antibacterially effective amount of a composition comprising a quinolone, in particular a gemifloxacin compound to be administered to a mammal who is suspected of being infected or in danger of being infected with uropathogenic bacteria to get infected.  

A preferred method is provided in which changing the substance alternately inhibiting the growth of bacteria or killing the bacteria rien is.

Another preferred method is provided in which the in-contact Bringing the bacteria includes the further step, said composition in a mammal, especially a human.

Further preferred methods are provided by the invention in which the bacteria are selected from the group consisting of: K. pneumoniae, P. mirabilis, E. coli, P. aeruginosa, S. aureus and E. faecalis.

Numerous changes and modifications that appear to protect the scope of protection th invention belong to those skilled in the art from reading the following writing and the other parts of the present disclosure.

DESCRIPTION OF THE INVENTION

The present invention provides, among other things, methods of using a zu composition ready which is a quinolone, especially a gemifloxacin verbin against uropathogenic bacteria.

In this context, "gemifloxacin compound (s)" means a compound the one as in patent application PCT / KR9S / 00051, published October 1 1998 as WO 98/42705, or anti described in patent application EP 688772 has bacterial activity, and these applications are referenced included in this application.

The present invention was based in part on analyzes to determine the comparative efficacy of gemifloxacin against various uropathogens. One goal of these analyzes was to determine the excretion in the urine and the bactericidal titer (UBT) in volunteers with 320 mg gemifloxacin compared to 400 mg ofloxacin.  

A randomized cross-over study received 16 volunteers (8 men, 8 women) a single dose of 320 mg gemifloxacin compared to 400 mg ofloxacin and urinary excretion and bactericidal titers (UBT) were determined at intervals of up to 144 h. Ofloxacin showed higher Urine concentrations as gemifloxacin. The total excretion (mean, range) of gemifloxacin was 29.7% (8.4-48.7%) and that of ofloxacin was 84.3% (46.5-95.2%) of the drug originally administered. The UBTs, i.e. H. the highest two Dilution (antibiotic-free urine as a diluent) of even more bactericidal Urine was used for a reference strain and nine uropathogens with the following MICs (g / ml) determined for gemifloxacin / ofloxacin: E. coli ATCC 25922 (0.016 / 0.06), K. pneumoniae (0.03 / 0.06), P. mirabilis (0.125 / 0.125), E. coli (0.06 / 0.5), P. aeru ginosa (1/4), S. aureus (0.008 / 0.25), E. faecalis (0.06 / 2), S. aureus (0.25 / 4), E. fae calis (0.5 / 32) and S. aureus (2/32). In general, the UTBs were gram negative Uropathogens higher with ofloxacin than with gemifloxacin and with gram-positive uro pathogenic higher with gemifloxacin than with ofloxacin. Enterobacteriaceae and sensitive gram positive uropathogens were all initial UBTs at least 1: 8 for both drugs and the differences are therefore clinically well Not relevant. However, if a UBT peak of at least 1: 4 for treatment complicated urinary tract infections can be desirable Gemifloxacin dose of 320 mg for P. aeruginosa or a fluoroquinolone resistant strain may be too low. Both 320 mg gemifloxacin and 400 mg Ofloxacin can be used for S. aureus (MIC 2/32) and for E. faecalis (MIC 0.5 / 32) be insufficient. The study suggests that a gemifloxacin dose of 320 mg is generally recommended for clinical testing in urinary tract infections can be.

Gemifloxacin, a new fluoroquinolone, has a broad antibacterial spectrum in vitro against gram-negative bacteria such as. B. Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Klebsiella pneumoniae, but also against gram-positive bacteria such as streptococci and staphylococci. Gemifloxacin has a long plasma half-life (t _1/2 ) and about 20-30% is excreted unchanged in the urine, reaching urine concentrations that are believed to have sufficient antibacterial activity against most bacteria involved in the pathogenesis of urinary tract infections . A single oral dose of gemifloxacin (320 mg) was compared with ofloxacin (400 mg) in healthy volunteers in a combined pharmacokinetic / pharmacodynamic model, determining the respective plasma and urine concentrations and urinary bactericidal effects against isolates of the best known uropathogenic bacteria were.

One study was an open, randomized, cross-over study with 16 healthy ones volunteers (8 men, 8 women), mean age (range): 31.5 Years (1840); mean body weight: 66.5 kg (53,396.7); medium height: 173.5 cm (160179). The subjects received a single dose of 320 mg Gemifloxacin or 400 mg ofloxacin at a 14 day interval between the Gifts.

The urine was collected - 12-0 h before administration and 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120 and 120-144 h after administration. Gemifloxacin was by means of HPLC / MS / MS examined (LLQ in plasma and urine was 0.0100 µg / ml). Ofloxacin was examined by HPLC (LLQ in the plasma was 0.00363 g / ml and in the urine 0.208 µg / ml).

The MICs and MBCs were determined by a micro-dilution method with MuellerHin ton broth. An inoculum of 1.3-9.4 x 10 ⁵ colony forming units (CFU) per ml was used. MIC was defined as the lowest concentration that inhibits visible growth after 18 hours of incubation at 37 ° C and MBC was defined by counting the CFUs on antibiotic-free Columbia agar enriched with 5% blood after an additional 18 hours of incubation at 37 ° C.

The bactericidal activity was defined as a reduction in CFUs of <99.9% (<3 logs). Dilution series from 1: 2 to 1: 1024 were carried out using drug-free urine and the UBTs were determined by micro-dilution on a microplate with a final inoculum = 10 ⁵ CFU / ml. The bactericidal activity was determined in accordance with the recommended guidelines of NCCLS ¹ . A UBT of 0 was not considered to be bactericidal and a UBT of 1: 1 was only used when undiluted urine was bactericidal.

The strains included a reference strain sensitive to nalidixic acid (Nal-S) E. coli ATCC 25922 and the following clinical isolates derived from patients with com reproduced urinary tract infections: E. coli (resistant to nalidixin Acid), K. pneumoniae, P. mirabilis, P. aeruginosa, Streptococcus aureus (3rd Strains) and Enterococcus faecalis (2 strains).

UBTs converted to ordinal data; Scale: 1 for UBT = 0 to 12 for UBT 1024. The area under the curve of bactericidal titer in urine (AUBTC) against the Time curve was calculated according to the trapezoid rule. It wasn't a formal one statistical analysis performed.

The laboratory parameters showed no clinically relevant changes and there were no clinically meaningful differences between the phases of the study. Gemifloxacin and ofloxacin have been used by both healthy males well tolerated by female test subjects.

The urine pH and urine volumes were in both phases of the study similar. The mean drug concentrations in the urine were determined. The mean (range) renal excretion up to 144 h was 84.3% (46.5-95.2%) of the Dose for ofloxacin and 29.7% (8.4-48.7%) of the dose for gemifloxacin.

The MICs and MBKs (range 0.008-128 µg / ml) for gemifloxacin and ofloxacin are shown in Table 1 for each test organism. The mean UBTs for the study drugs against the test organisms were determined. In gram-negative uropathogens, the UBTs are generally higher with ofloxacin than with gemifloxacin. In gram-positive uropathogens, the UBTs for gemifloxacin are higher than for ofloxacin. Mean gemifloxacin UBTs exceed 0 for the reference strain for 5 days and decrease from 1: 1024 to 1: 1. The mean ofoxacin UBTs exceed 0 for the reference strain for 4 days and decrease from 1: 1024 to 1: 2. There is a wide range of UBTs, although the variation coefficient of the laboratory process has been found to be low ² . Because the goal of antibiotic treatment is to be effective for all subjects treated, the lower range of UBT results can be considered relevant for clinical dose recommendations. For both drugs in the study, the initial UBTs are at least 1: 8 for Enterobacteriaceae and sensitive gram-positive uropathogens. The differences observed are probably not clinically relevant.

If you have a UBT peak of at least 1: 4 as desirable for the treatment complex urinary tract infections, 320 mg gemifloxacin for P. aeru ginosa or a fluoroquinolone-resistant strain may be too low. Either 320 mg gemifloxacin and 400 mg ofloxacin can be used for the quinolone resistant S. aureus (MIC 2/32) and E. faecalis (MIC 0.5 / 32) may be insufficient.

The AUBTCs of both drugs in the study are shown in Table 2. The AUBTCs of ofloxacin and gemifloxacin are comparable in the reference strain. The AUBTCs in the other test organisms are higher in ofloxacin gram-negative organisms and higher for grif-positive ones for gemifloxacin Organisms (according to the UBT values).

Urine concentrations and renal excretion are higher than with ofloxacin with gemifloxacin. The in vitro activity against the test strains is general higher for gemifloxacin (except for P. mirabilis).

UBTs are higher for gram-positive strains for gemifloxacin, but higher for gram-positive strains for ofloxacin. However, most UBTs are high enough to likely produce clinical efficacy. Oral 320 mg gemifloxacin once daily could generally be recommended for clinical testing in urinary tract infections.

All studies were carried out using standard procedures that followed the Are known and familiar to those skilled in the art, unless otherwise described in detail is. Obtain all parts or quantities specified in the following examples on weight unless otherwise stated.

The invention provides a method for changing the metabolism of uropatho gene ready. Specialists can identify uropathogenic bacteria or patients who are infected or suspected of being infected with these organisms be, without difficulty, select the method according to the invention perform. Alternatively, those in the methods according to the invention usable bacteria are those described here.

The step of contacting in all of the methods of the invention can be many Types are carried out that are clearly apparent to those skilled in the art. However, it is preferred that the contacting step involve administering a composition composition comprising a gemifloxacin compound to a human patient ducks that need such a composition, or directly to bacteria in Kul represents medium or buffer solution.

For example, when administered to a human patient or to Bacteria occurring in a human patient or in vitro can cause the compositions comprising a quinolone, especially a gemifloxacin ver binding, preferably drugs, in any effective and appropriate manner be included including, for example, local, oral, anal, vagi naler, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal or intradermal administration.

It is also preferred that these compositions be used in conjunction with a non-sterile or sterile carriers or carriers for use with cells, Tissues or organisms, e.g. B. a pharmaceutical carrier for Administration to a patient is suitable. Such Compositions include, for example, a medium additive or a therapeutically effective amount of a compound according to the invention, a quinolone,  preferably a gemifloxacin compound, and a pharmaceutical compatible carriers or excipients. Such carriers can be saline, buffered saline, dextrose, water, glycerin, ethanol and combinations include, but are not limited to, these. The wording should be in line with the Dosage form to be adjusted.

Quinolone compounds, especially gemifloxacin compounds and together Settlements according to the method of the invention can be used alone or together with other compounds, such as compounds that control bacterial efflux Inhibit pump or antibiotic compounds, especially non-quinolone Connections, e.g. B. beta-lactam antibiotic compounds can be used.

For therapy or as a prophylactic, the active ingredient of an invention Process to a patient, preferably as an injectable composition, for Example administered as a sterile aqueous, preferably isotonic dispersion.

In another embodiment, the gemifloxacin compounds or Zu compositions of the method according to the invention for topical application e.g. B. as ointments, creams, lotions, eye ointments, eye drops, ear drops, Mouthwashes, soaked dressings and sutures and aerosols and can include suitable conventional additives including, for example Preservatives, penetration enhancers and emollients for ointments and creams contain. Such topical formulations can also be conventional acceptable ones Carriers, for example cream or ointment bases and ethanol or oleyl alcohol included in lotions. Such carriers can be from about 1% by weight to about 98% by weight make up the formulation, usually they make up about 80 wt .-% of Wording.

For administration to mammals and especially humans, this is considered that the antibacterially effective amount of a daily dose of the drug from 0.001 mg / kg to 10 mg / kg, typically about 0.1 mg / kg to 1 mg / kg, preferably corresponds to approximately 1 mg / kg. A doctor will definitely be individual for everyone Patients determine the most suitable dosage and this depends on age, ge determine the weight and response of the individual patient. The above dose  are examples of the average case. Of course, it can be special cases exist in which higher or lower dosage ranges are specified are brought and these are within the scope of the invention. Preferably the Dosage chosen so that the metabolism of the bacteria is changed so that the growth of the bacteria is inhibited or stopped or the bacteria abge be killed. The person skilled in the art can also use Ver using other known methods, e.g. B. by using MIC tests, determine.

Another embodiment of the invention provides that the step of the In-Kon clocking according to the method further contacting with a dwell device in a patient. Dwell devices include, but are not limited to, surgical implants, prosthetic devices and Ka theter, d. H. Devices placed in a patient 's body and stay in it for a long time. Such devices include, for example artificial joints, heart valves, pacemakers, vascular grafts, vascular ca thether, cerebrospinal fluid shunts, urinary catheters and continuous Outpatient Peritoneal Dialysis Catheter (CAPD).

A quinolone, especially a gemifloxacin compound or composition according to the invention can be administered by injection to a systemic Effect against relevant bacteria, preferably uropathogenic bacteria, too aim just before a dwell is inserted. Treatment can continued after the operation while the device was in the body become. In addition, the composition can also be used to to prevent perioperative bacterial wound infections during surgical procedures, which are caused by or in with uropathogenic bacteria Related.

In addition to the therapy described above, one can be used in the invention Process used gemifloxacin compound or composition in general can be used as a wound treatment agent to improve the adhesion of bacteria Prevent matrix proteins, especially from uropathogenic bacteria that are in Wound tissue exposed, and for prophylactic use in the  Dental treatment as an alternative to, or in connection with, an anti biotic prophylaxis.

In another embodiment, a quinolone, especially one Gemifloxacin compound or composition used according to the invention to dew a dwell immediately prior to insertion chen. The active ingredient should be for the immersion of wounds or indwelling devices preferably in a concentration of 1 g / ml to 10 mg / ml.

The invention also provides a method of treating or preventing a bacterium infection with uropathogenic bacteria, including the step of ver delivering an antibacterially effective amount of a composition send a quinolone, especially a gemifloxacin compound, to a mammal, preferably a person suspected of having uropathogenic bacteria being infected or at risk of being infected with them.

It is a preferred object of the invention to provide a method in which the uropathogenic bacteria are selected from the group consisting of: K. pneumoniae, P. mirabilis, E. coli, P. aeruginosa, S. aureus and E. faecalis, but it other uropathogenic bacteria can also be included in the procedure. Those skilled in the art can also use the organisms described here other known methods, e.g. B. MIC tests.

Preferred embodiments of the inventions include methods, in which this composition gemifloxacin or a pharmaceutically acceptable ches derivative thereof.

Each reference cited here is included in its entirety with reference closed. Furthermore, every patent application whose priority the application requests spoken, included with reference in their entirety.  

References

1. National Committee of Clinical and Laboratory Standards. Methods for determining antibacterial activity of antimicrobial agents. Tentative guideline. Document M26-T, Volume 12, No. 19.NCCLS: Villanova, PA, September 1992.
2. Well M, Naber KG, Kinzig-Schippers M, Sörgel F. Urinary bactericidal activity and pharmacokinetics of enoxacin versus norfloxacin and ciprofloxacin in healthy volunteers after a single oral dose. Int J Antimicrob Agents 1998; 10: 31-8.

Claims (11)

1. A method of changing the metabolism of uropathogenic bacteria comprising the step of bringing the uropathogenic bacteria into contact an antibacterially effective amount of a composition comprising one Gemifloxacin compound or antibacterial derivatives thereof. 2. The method of claim 1, wherein the uropathogenic bacteria are selected from the group consisting of:
K. pneumoniae, P. mirabilis, E. coli, P. aeruginosa, S. aureus and E. faecalis. 3. A method of treating or preventing a bacterial infection with uropathogenic bacteria comprising the step of administering an anti bacterially effective amount of a composition comprising a mixture floxacin Connection to a mammal suspected of having uropathogenic Bacteria are infected or at risk of being infected with them. 4. The method of claim 3, wherein the uropathogenic bacteria are selected from the group consisting of:
K. pneumoniae, P. mirabilis, E. coli, P. aeruginosa, S. aureus and E. faecalis. 5. The method of claim 3, wherein the mammal is a human. 6. The method of claim 1, wherein changing the metabolism Inhibition of bacterial growth. 7. The method of claim 1, wherein changing the metabolism Is killing the bacteria. 8. The method of claim 1, wherein contacting the bacteria further step of introducing the composition into a mammal.   9. The method of claim 8, wherein the mammal is a human. 10. The method of claim 1, wherein the bacteria are selected from the group consisting of:
E. coli, P. aeruginosa, S. aureus and E. faecalis. 11. The method of claim 1, wherein the bacteria are selected from the Group consisting of: S. aureus and E. faecalis.