WO2007098868A1

WO2007098868A1 - Use of moxifloxacin in combination with cefixime for treatment of infectious diseases caused by gram-positive and gram-negative pathogens

Info

Publication number: WO2007098868A1
Application number: PCT/EP2007/001397
Authority: WO
Inventors: Igor Knezevic
Original assignee: Bayer Healthcare Ag
Priority date: 2006-03-03
Filing date: 2007-02-19
Publication date: 2007-09-07
Also published as: WO2007098868A8

Abstract

Use of moxifloxacin in combination with cefixime for treatment of infectious diseases caused by Gram-positive and Gram-negative pathogens Abstract The present invention relates to the use of the fluoroquinolone moxifloxacin in combination with the 3rd generation cephalosporine cefixime to treat infectious diseases caused or accompanied by a Gram-positive and/or Gram-negative pathogen like Streptococcus pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus.

Description

Use of moxifloxacin in combination with cefixime for treatment of infectious diseases caused by Gram-positive and Gram-negative pathogens

The present invention relates to the use of the fluoroquinolone moxifloxacin in combination with the 3^rd generation cephalosporin cefixime to treat infectious diseases caused or accompanied by a Gram-positive and/or Gram-negative pathogen like Streptococcus pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus.

Since the introduction of the fluoroquinolones in the 1980s, the use of this class of drugs has rapidly increased to become one of the more common choices of antimicrobials for various types of bacterial infection [I]. This widespread use has had its consequences, as selective pressure has increased resistance for some species over the years [I]. Though resistance to common respiratory pathogens, including Streptococcus pneumoniae, remains <1% in the US, other parts of the world are not so fortunate [2—4]. In addition, resistance in Gram-negative organisms, such as Pseudomonas aeruginosa, has increased significantly [5,6]. Fluoroquinolone resistance can involve two well-documented and separate mechanisms: (1) point mutations in the genes of the quinolone target enzymes, topoisomerase IV and gyrase, or (2) expression of drug efflux pumps that reduce the accumulation of antibiotic in the cell [1, 7].

All fluoroquinolones seem to be affected by P. aeruginosa efflux mechanism [8, 9]. The major drug efflux pumps in P. aeruginosa belong to the RND (resistance nodulation-division) family which is widely spread among other Gram-negative pathogens like E. coli [10]. Due to the prevalence of P. aeruginosa resistance to the fluoroquinolones, an adjunctive agent with antipseudomonal activity is commonly recommended for infections proven or suspected to be caused by this pathogen.

In contrast to Gram-negatives, Gram-positive pathogens like Streptococcus pneumoniae does not possess a selectively permeable outer membrane that can act as a barrier to antibiotics. However, surveillance studies in the US have shown for Streptococcus pneumoniae high-level resistance to penicillin approaching 20% and resistance to the macrolides at over 25% [2,11]. Fortunately, fluoroquinolone resistance (to the respiratory fluoroquinolones such as gatifloxacin, levofloxacin and moxifloxacin) has remained low throughout the United States and Canada (at or below 1%) but signs of increasing resistance are apparent [12,13].

Looking at the overall resistance development, the use of a combination therapy (preferably using antibiotics with different mechanisms of action) seems to be one major option to medicate difficult-to-treat infections in future. The use of combination therapy is common in case of nosocomial infections caused by multi-drug- resistant pathogens like P. aeruginosa (MDRPA). Patients with severe MDRPA infections should be treated with combination therapy, consisting of an antipseudomonal beta-lactam with an aminoglycoside or fluoroquinolone to provide adequate therapy and improve patient outcomes. Synergy has been observed when resistant antipseudomonal drugs were combined in vitro against MDRPA with successful clinical application. [14]. Moreover, several publications describe synergistic effects of fluoroquinolone/cephalosporin combinations when tested against P. aeruginosa or S. pneumoniae. Kϋhn et al. and Flatz et al. could show that the combination of cefotaxime or ceftriaxone with levofloxacin acts synergistically against penicillin-resistant S. pneumoniae when tested by MIC checkerboards and time kill methodology [15, 16].

Several further publications describe the synergistic effects of antipseudomonal fluoroquinolones combined with antipseudomonal β-lactams or aminoglycosides [17, 18, 19, 20, 21]. Moreover, the use of such combinations prevents to some extent resistance development [21, 22].

Surprisingly, the inventors discovered that the fluoroquinolone moxifloxacin, when combined with the 3^rd generation cephalosporin cefixime, leads to significant synergistic effects in case of checkerboard MIC testing against Pseudomonas aeruginosa and Streptococcus pneumoniae. Both drugs useful in the invention are not described as antipseudomonas agents. Additionally, a distinct combination possessing synergistic effects against both Gram-negative and Gram-positive pathogens is new. The structures of moxifloxacin and cefixime are published at Dalhoff et al., Stass et al., and Roche [24-26].

Subject of this invention is the use of a combination of moxifloxacin and cefixime in order to treat infectious diseases caused by Gram-negative and Gram-positive pathogens. A possible combination should include a fixed combination for oral administration consisting of a tablet with 400 mg moxifloxacin and 400 mg cefixime. The existing regimen of moxifloxacin is identical to those of cefixime (Moxifloxacin and cefixime are applied as 400 mg tablets once daily) indicating a similar, to some extent complementary pharmacokinetic which supports a combination therapy.

In particular, the invention relates to:

1. A combination, comprising moxifloxacin and cefixime.

2. A pharmaceutical combination, comprising moxifloxacin and cefixime, for the treatment of diseases. The combination is useful for the treatment of diseases, in particular of infectious diseases and bacterial infectious. The combination is especially useful for the treatment of bacterial diseases caused by Pseudomonas aeruginosa, Streptococcus pneumoniae and Staphylococcus aureus. The combination also can comprise pharmaceutical acceptable carriers, solvents and the like.

3. The use of a combination of moxifloxacin and cefixime for the preparation of a medicament for the treatment of infectious diseases.

4. The use according to count 3, wherein the infectious diseases are bacterial infections.

5. The use according to count 4, wherein the bacterial infections are infections caused by at least one pathogen selected from the group consisting of Pseudomonas aeruginosa, Streptococcus pneumoniae and Staphylococcus aureus.

6. The use of moxifloxacin and cefixime for the preparation of a medicament for the treatment of infectious diseases.

7. The use according to count 6, wherein the infectious diseases are bacterial infections.

8. The use according to count 7, wherein the bacterial infections are infections caused by at least one pathogen selected from the group consisting of Pseudomonas aeruginosa, Streptococcus pneumoniae and Staphylococcus aureus.

9. A kit of parts, comprising two or more vials, wherein one vial contains moxifloxacin, potentially mixed with one or more acceptable pharmaceutical carries and one other vial contains cefixime, potentially mixed with one or more acceptable pharmaceutical carrier.

The invention also relates to a method of manufacturing or preparing the kit of parts according to count 9, comprising the steps

- preparing a vial comprising moxifloxacin and - if necessary - a pharmaceutical carrier,

- preparing a carrier containing cefixime and - if necessary - a pharmaceutical carrier,

- combining the vials, potentially with further compounds of the kit to the kit of parts.

The kit of parts can also contain instructions relating to the use of the kit of parts.

A pharmaceutical composition of the moxifloxacin-cefixime combination is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene- diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EM™ (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a pharmaceutically acceptable polyol like glycerol, propylene glycol, liquid polyetheylene glycol, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a polypeptide or antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.

Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. 4,522,811. - o -

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

In general, the therapeutic dose of moxifloxacin and cefixime as a fixed combination or as separate doses administered in appropriate intervals, for instance, twice, three times, four times or more times per day.

The formulations can contain between 0.1 and 99% active ingredients, appropriately 25 - 95% in tablets and capsules und 1 - 50% in case of liquid formulations, i. e. the active ingredients should present in quantities sufficient for administration of therapeutic doses.

The active ingredients can be included in common formulations using inert, non-toxic, pharmaceutically appropriate carriers, excipients, solvents, vehicles, emulsifying and dispersing agents.

Examplary auxiliary substances are: water, non-toxic organis solvents such as paraffϊnes, crop oils (e.g. sesame oil), alcohols (e. g. ethanol, glycerol), glycoles (e. g. polyethylene glycole), solid carriers such as natural or synthetic stone powder (E. g. talcum, silicates), sugars (e. g. lactose), emulsifying and dispersing agents (e. g. polyvinyl pyrrolidone) and other agents such as magnesium sulfate.

In case of the oral administration tablets can contain additives such as sodium citrate together with aggregates such as starch, gelatine. Aqueous preparations for the oral application can include flavour or colouring additives.

Use of a pharmaceutical combination comprises the sequential or simultaneous administration of the ingredients, especially of the pharmaceutically active ingredients. Examples

Example 1

Method:

The in vitro effect of antimicrobial combination was evaluated by a two-dimensional (8-by-l l) checkerboard microdilution technique. The procedures were similar to the determination of the MIC. The concentrations tested ranged from 2-4 to 1/32 times the MICs. The fractional inhibitory concentration (FIC) index for combinations was calculated as follows [23]:

FIC index = FIQ₄+ ΕIC_B=(A)/(MIC_A) - (B)/(MIC_B)

(A) is the concentration of drug A in a well which is the lowest inhibitory concentration for the appropriate pathogen in its row or column. (MIC _A) is the MIC of drug A for the appropriate pathogen . FIQ₄, the fractional inhibitory concentration of drug A, is derived from dividing (A) by

(MIC_A). (B), (MIC_B), and FICs are defined in the same fashion for drug A. The interaction is defined as synergistic if the FIC index is < 0.5, antagonistic if > 4.0, and additive if between 0.5 and 1.0. Each isolate for every combination was tested in triplicate. For a given isolate with a given combination, if synergism (or additive or antagonism) was observed in two or three runs of the triplicate, synergism (or additive or antagonism) was reported.

The MICs were performed under CLSI conditions (latest update: document M07-A7 - Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard —Seventh Edition).

The strains used in this study are recommended by the CLSI for quality assessment purpose.

Results:

Clear synergism could be demonstrated for the combination moxifloxacin/cefixime against Pseudomonas aeruginosa ATCC 27853. The FICindex of about 0.38 could be reached with a with a combination composed of 0.125μg/ml moxifloxacin and 32 μg/ml cefixime, respectively (Tab. 1).

Synergism could be demonstrated for the combination moxifloxacin/cefixime against Streptococcus pneumoniae ATCC 49619. The FICindex of about 0.5 could be reached with a combination composed of 0.03μg/ml moxifloxacin and 0.5 μg/ml cefixime, respectively (Tab. 2). The effects of the appropriate combination against Staphylococcus aureus ATCC 29213 are additive (FICindex: 0.75). Pseudomonas aeruginosa ATCC 27853 FICin_dex ( ≤ 0,5: synergism / 0,5 - 1 : additive )

Tab. 1 : Checkerboard testing against the pathogen Pseudomonas aeruginosa ATCC 27853

FICin_dex ( ≤ 0,5: synergism / 0,5 - 1 : additive ) Streptococcus pneumoniae ATCC 49619

Tab. 2: Checkerboard testing against the pathogen Streptococcus pneumoniae ATCC 49619 and Stapyhlococcus aureus ATCC 29213.

Example 2

Time kill studies of moxifloxacin in combination with cefixime against Pseudomonas aerusinosa ATCC 27853 and Staphylococcus aureus ATCC 29213

Method:

Time kill studies

All time-kill experiments were performed according the CLSI guideline M26-A: "Methods for Determining Bactericidal Activity of Antimicrobial Agents". Due to the low activity of cefixime against P. aeruginosa (MIC > 64 μg/ml) and S. aureus (MIC 8-16 μg/ml), concentration range was defined based on the published serum concentration of cefixime [27].

Determination of synergy

In view of regrowth after 24h, synergy was defined as a > 2-log₎₀ decrease in the viable counts per ml (cfu/ml) of the combination after 8 and 24h compared to the more active of the two agents alone [28]. Additivity was defined as a > 1-logio decrease in the viable counts per ml at 8 and 24h with the combination relative to the most active single antimicrobial alone [29]. Results:

Synergism could be demonstrated for the combination moxifloxacin/cefixime against Pseudomonas aeruginosa ATCC 27853. At 24h a combination of 3 μg/ml moxifloxacin (MXF) and 2 - 6 μg/ml cefixime (CFX) led to > 3.1 log decrease in viable counts (Tab. 1; for kill curves see Fig.l). In contrast, cefixime had no influence on growth rate of P. aeruginosa ATCC 27853 at concentrations between 2 and 6 μg/ml (data not shown).

Additive effects could be observed at 8h in case of the combination of 3 μg/ml MXF and 4 or 6 μg/ml CFX.

Tab. 1: Additive (A)/synergistic activity (S) of combinations of moxifloxacin (MXF) plus cefixime (CFX) against the pathogen Pseudomonas aeruginosa ATCC 27853.

Tab. 2: Additive (A)/synergistic activity (S) of combinations of moxifloxacin (MXF) plus cefixime (CFX) against the pathogen Staphylococcus aureus ATCC 29213. In case of Staphylococcus aureus ATCC 29213, synergistic effects were detected for the combination of 0.015 μg/ml MXF and 4 μg/ml CFX at 24h whereas additivity was observed at 8h when the combinations of 0.015 μg/ml MXF and 1 - 4 μg/ml CFX were used (Tab. 2; for kill curves see Fig. 2).

Fig. 1: Time kill curves of combinations of moxifloxacin (MXF: 3 μg/ml) plus cefixime (CFX: 0 - 6 μg/ml) against the pathogen Pseudomonas aeruginosa ATCC 27853.

Fig. 2: Time kill curves of combinations of moxifloxacin (MXF: 0.015 μg/ml) plus cefixime (CFX: 0 - 4 μg/ml) against the pathogen Staphylococcus aureus ATCC 29213.

References:

[1] Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoro-quinolones: focus on respiratory infections. Drugs 2002;62: 13-59.

[2] Karlowsky JA, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, Sahm DF. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998-2002). Clin Infect Dis 2003;36:963-70.

[3] Doern GV, Brown SD. Antimicrobial susceptibility among community-acquired respiratory tract pathogens in the USA: data from PROTEKT US 2000-2001. J Infect 2004;48:56-65.

[4] Jones ME, Blosser-Middleton RS, Thornsberry C, Karlowsky JA, Sahm DF. The activity of levofloxacin and other antimicrobials against clinical isolates of Streptococcus pneumoniae collected worldwide during 1999-2002. Diagn Microbiol Infect Dis 2003;47:579-86.

[5] Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use. JAMA 2003;289:885-8.

[6] NNlS System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 to June 2002. Issued August 2002. Am J Infect Control 2002;30:458-

75.

[7] Broskey J, Coleman K, Gwynn MN, et al. Efflux and target mutations as quinolone resistance mechanisms in clinical isolates of Streptococcus pneumoniae. J Antimicrob Chemother 2000,45:95-9. [8] Masuda N, Sakagawa E, Ohya S, Gotoh N, Tsujimoto H, Nishino T. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXYoprM efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2000;44:3322-7.

[9] Zhang L, Li XZ, Poole K. Fluoroquinolone susceptibilities of efflux-mediated multidrug- resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Burkholderia cepacia. J Antimicrob Chemother 2001;48:549-52.

[10] Nikaido H. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis l998;27:S32-41.

[11] Jones ME, Karlowsky JA, Blosser-Middleton R, et al. Longitudinal assessment of antipneumococcal susceptibility in the United States. Antimicrob Agents Chemother 2002;46:2651-5.

[12] Jones RN, Pfaller MA. Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY antimicrobial surveillance program (North America, 1997-1999). J Clin Microbiol 2000;38:4298-9.

[13] Zhanel GG, Palatnick L, Nichol KA, Bellyou T, Low DE, Hoban DJ. Antimicrobial resistance in respiratory tract Streptococcus pneumoniae isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 2003;47:1867-74.

[14] Obritsch MD, Fish DN, MacLaren R, Jung R. Nosocomial infections due to multidrug- resistant Pseudomonas aeruginosa: epidemiology and treatment options. Pharmacotherapy. 2005;25(10):1353-64.

[15] Flatz L, Cottagnoud M, Kuhn F, Entenza J, Stucki A, Cottagnoud P. Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levo-floxacin-induced resistance in penicillin-resistant pneumococci. J Antimicrob Chemother. 2004;53(2):305-10. Epub 2004 Jan 16.

[16] Kuhn F, Cottagnoud M, Acosta F, Flatz L, Entenza J, Cottagnoud P. Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro. Antimicrob Agents Chemother. 2003;47(8):2487-91.

[17] Visalli MA, Jacobs MR, Appelbaum PC. Determination of activities of levofloxacin, alone and combined with gentamicin, ceftazidime, cefpirome, and meropenem, against 124 strains of Pseudomonas aeruginosa by checkerboard and time-kill methodology. Antimicrob Agents Chemother. 1998;42(4):953-5.

[18] Piccoli L, Guerrini M, Felici A, Marchetti F. In vitro and in vivo synergy of levofloxacin or amikacin both in combination with ceftazidime against clinical isolates of Pseudomonas aeruginosa. J Chemother. 2005;17(4):355-60.

[19] Gradelski E, Valera L, Bonner D, Fung-Tome J. Synergistic activities of gatifloxacin in combination with other antimicrobial agents against Pseudomonas aeruginosa and related species. Antimicrob Agents Chemother. 2001 Nov; 45 (11): 3220-2.

[20] Montanari MP, Piccoli L, Mingoia M, Marchetti F, Varaldo PE. Synergistic potential of ceftazidime plus amikacin or levofloxacin against Pseudomonas aeruginosa as determined using a checkerboard and a disk diffusion technique. Diagn Microbiol Infect Dis. 2005; 53(2):157-60. Epub 2005 Sep l5.

[21] Burgess DS, Nathisuwan S. Cefepime, piperacillin/tazobactam, gentamicin, ciprofloxacin, and levofloxacin alone and in combination against Pseudomonas aeruginosa. Diagn Microbiol Infect Dis. 2002;44(l):35-41.

[22] Drago L, De Vecchi E, Nicola L, Tocalli L, Gismondo MR. In vitro selection of resistance in Pseudomonas aeruginosa and Acinetobacter spp. by levofloxacin and ciprofloxacin alone and in combination with beta-lactams and amikacin. J Antimicrob Chemother. 2005;56(2):353-9. Epub 2005 Jun 20.

[23] Eliopoulos, G. M., and R. C. Moellering, Jr. Antimicrobial combinations.1996 p. 330-396. In V. Lorian (ed.), Antibiotics in laboratory medicine, 4^th ed. The Williams & Wilkins Co., Baltimore, Md.

[24] Roche, G. Cefϊxime, the first oral third-generation cephalosporin Presse Med. 1989; 18(32):1541-4. French.

[25] Dalhoff A, Petersen U, Endermann R. In vitro activity of BAY 12-8039, a new 8-meth- oxyquinolone. Chemotherapy. 1996; 42(6):410-25.

[26] Stass H, Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J Antimicrob Chemother. 1999; 43 Suppl B:83-90.

[27] Faulkner RD, Fernandez P, Lawrence G, Sia LL, Falkowski AJ, Weiss AI, Yacobi A, Silber BM. Absolute bioviability of cefixime in man. J. Clin. Pharmacol. 1988; 28(8): 700-6. [28] Eliopoulos G M, Moellering, Jr RC. antimicrobial combinations.1996 p. 330-396. In V. Lorian (ed.), Antibiotics in laboratory medicine, 4* ed. The Williams & Wilkins Co., Baltimore, Md.

[29] Jung R, Husain M, Choi MK, Fish DN. Synergistic activities of moxifloxacin combined with piperacillin-tazobactam or cefepime against Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii clinical isolates. Antimicrob Agents Chemother. 2004 Mar; 48(3): 1055-7.

Claims

1. Combination, comprising moxifloxacin and cefixime.

2. Pharmaceutical combination, comprising moxifloxacin and cefixime, for the treatment of diseases.

3. Use of a combination of moxifloxacin and cefixime for the preparation of a medicament for the treatment of infectious diseases.

4. Use according to claim 3, wherein the infectious diseases are bacterial infections.

5. Use according to claim 4, wherein the bacterial infections are infections caused by at least one pathogen selected from the group consisting of Pseudomonas aeruginosa, Streptococcus pneumoniae and Staphylococcus aureus.

6. Use according to claim 4, wherein the bacterial infections are infections caused by at least one pathogen selected from the group consisting of Pseudomonas aeruginosa and Streptococcus pneumoniae.

7. Kit of parts, comprising two or more vials, wherein one vial contains moxifloxacin, potentially mixed with one or more acceptable pharmaceutical carries and one other vial contains cefixime, potentially mixed with one or more acceptable pharmaceutical carrier.