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Rifaximin - Fatro worldwide exclusive antibiotic

Rifaximin is a semi-synthetic rifamycin antibiotic produced by Amycolatopsis mediterranei. It is non-absorbable and acts locally in the gut due to its unique chemical properties. Rifaximin has broad-spectrum activity against gram-positive and gram-negative bacteria as well as protozoa through inhibition of bacterial RNA polymerase. Its localized activity and lack of systemic absorption helps preserve other antibiotics and limits development of resistance. Rifaximin also has anti-inflammatory properties through activation of the pregnane X receptor, reducing levels of pro-inflammatory cytokines. Fatroximin dry cow is a rifaximin formulation developed for intramammary administration as dry cow therapy to

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Fatro worldwide exclusive antibiotic Roberto Farina - Fatro
RIFAXIMIN • Class: Rifamycins • Subclass of the larger family Ansamycins • Antibiotics produced by the Gram+ bacterium Amycolatopsis mediterranei • Particularly potent against – Multi-resistant Staph. Aureus – Mycobacteria • Rifaximin: semi-synthetic derivative of rifamycin SV
RIFAXIMIN Physiochemical Properties Zwitterion Pyrido nitrogen positively charged Imidazo nitrogen negatively charged Phenolic hydroxyls Strong tendency to self-associate Ionized at all pH values Additional pyridoimidazole moiety makes it NON-ABSORBABLE ion trapping Acts locally and does not pass into the circulation
RIFAXIMIN Mechanism Of Action • Prevents transcription – the process by which the information in DNA is copied into messenger RNA (mRNA) for protein production. • Inhibits RNA and protein synthesis Binds to the β subunit of prokaryotic DNA-dependent RNA polymerase TRANSCRIPTION ANIMATION
RIFAXIMIN Antimicrobial Activity • Broad spectrum of antibacterial action: – Gram+ and Gram- – Both Aerobes and Anaerobes • Susceptibility of resistant strains of Staph. aureus is particularly interesting • Protozoa – Cryptosporidium, Blastocystis • Reverse transcriptase of certain RNA viruses (retrovirus)
RIFAXIMIN Antimicrobial killing activity • Rapidly kills fast-dividing bacteria as well as “persisters” cells, which remain biologically inactive for long periods evading antibiotic activity – [Pozniak 1999] • Bactericidal • Actually kills bacteria Image
RIFAXIMIN Not Absorbed Systemically • Valuable for therapies applied locally to body surfaces – Skin or mucosae • High local bioavailability • Localized targeting of pathogens • Absence of residues in non-treated organs • Reduced incidence of undesired side effects Scarpignato & Pelosini 2005 100% TOPICAL ANTIMICROBIAL
TOPICAL THERAPY & ANTIBIOTIC RESISTANCE A NOVEL APPROACH TO JUDICIOUS PRESCRIBING PRACTICE • Limited selective pressure for the development of wide-spread bacterial resistance • Preservation of critically important antimicrobials for systemic therapy • Antimicrobial is sequestered in target organs • Very high local concentrations • Circumscribed antimicrobial activity
ANTIMICROBIAL RESISTANCE Resistance of a microorganism to an antimicrobial medicine to which it was previously sensitive (WHO) One of the main problems associated with antibiotics use • Therapeutic failure • Infections persist and may spread Impact on animal health and productivity • Emergence of resistant microorganisms that can infect people (Superbugs) • Great clinical, economic, political and environmental implications Possible impact on human health
PROPER ANTIMICROBIAL SELECTION FIGHTS RESISTANCE Ability to lead to the development of resistant mutants Spread of resistance Stability of the mutants Effect on the susceptibility of other antimicrobial agents Relevant factors that determine the therapeutic value of antibacterials ANTIMICROBIAL RESISTANCE
DEVELOPMENT OF RESISTANCE TO RIFAXIMIN • Studied in detail on several Gram- and Gram+, aerobic and anaerobic strains • Resistance to Rifaximin is rare – [Hoover 1993; Ruiz 2008; Marchese 2000; Ouyang-Latimer 2011; Valentin 2011] • More easily with sub-inhibitory concentrations • Anaerobic atmosphere hinders the selection of rifaximin-resistant bacteria • High concentrations in in an oxygen-deficient milieu: in-vivo occurrence of bacterial resistance with rifaximin is an infrequent phenomenon
Staph. aureus SUSCEPTIBILITY TO ANTIMICROBIALS 6% 31% 31% 8% 36% 77% 36% 84% 86% 89% 94% 92% 82% 93% 99% 0% 25% 50% 75% 100% Sulfa Penicillin Ampicillin Spectinomycin Streptomycin Tetracycline Spiramycin Erythromycin Kanamycin Tylosin Cloxacillin Nafcillin Cefoperazone Flumequine Rifaximin R % I % S % Bertocchi, Varisco, Farina 2000 Kirby-Bauer agar diffusion test Strains isolated from the milk of dairy cows with mastitis (IZS – Brescia, Italy)
SPREAD OF RESISTANCE TO RIFAXIMIN • Resistance due to a chromosomal alteration in the drug target, the DNA-RNA polymerase (rpoB gene) – [Al-Orainey 1990] • Different from the plasmid-mediated resistance common to other antibiotics – [Smith 2002] • The spread of resistance is less frequent than that due to plasmid-mediated transfer (transferred within the same generation, even between different bacterial species) – [Collignon PJ 2002] Not disseminated by plasmids but mediated chromosomally Sulfa Β-lactamTetracycline Fenicol Aminoglicoside multi-R Plasmid
STABILITY OF RIFAXIMIN RESISTANT MUTANTS • Resistance to rifaximin disappear after drug administration is terminated. • Poorer viability of rifaximin-resistant mutants relative to nonresistant (wild-type) bacteria • Resistance to rifaximin doesn’t persist beyond a few weeks after cessation of therapy (specific time- dependent on species of bacteria) De Leo 1986 Disappearance of rifaximin-resistant bacteria after stopping the antibiotic treatment (week 0) RIFAXIMIN
ANNUAL VARIATION OF STAPH. AUREUS SENSITIVITY TO RIFAXIMIN From cows with mastitis IZS Tre Venezie Barberio 2000 Year Susceptible 1996 98.9 % 1997 93.4 % 1998 98.1 % 1999 98.7 % Carnevali Nocetti 2001 Year Susceptible 1996 96.95 % 1997 100.0 % 1998 99.49 % 1999 98.88 % 2000 98.28 % From cows with mastitis APA Modena
EFFECT ON THE SUSCEPTIBILITY LEVELS OF OTHER ANTIMICROBIAL AGENTS • There is no evidence of cross-resistance to other non-rifamycin classes of antibiotics – Herbert DuPont 2003 • No-systemic involvement • Preserves other antimicrobial agents, which are able to be used to treat systemic infections, diminishing their pressure on the microorganisms, favoring a lower selection of resistant strains • It does not alter the microbiota population (other than those based in the treated compartment)
NON-ANTIBIOTIC EFFECTS OF RIFAXIMIN • Rifaximin, besides acting against microorganisms, has also beneficial effects on Host Cells • In addition to its antibacterial activity rifaximin exerts antiinflammatory and immunomodulatory effects Scarpignato 2005 BACTERIA ANIMAL CELLS
RIFAXIMIN MODULATES THE INFLAMMATORY RESPONSE • Rifamycins are able to modulate neutrophil functions and display anti-inflammatory actions – [Spisani 1997] • Intra-articular rifamycin has been successfully used in chronic arthritis (juvenile rheumatoid arthritis and ankylosing spondylitis) – [Caruso 1997] • Rifaximin reduces overall inflammatory status modulating pro-inflammatory cytokine release – IL-6, IL-1β, IL-8, IL-12 and interferon-γ, TNFα, chemokines – [Brown 2010; Vitali 2009]
RIFAXIMIN MODULATES INFLAMMATION THROUGH PXR ACTIVATION • Pregnane-X-Receptor mediates the anti-inflammatory activities of Rifaximin – [Cheng 2010; Mencarelli 2011] • PXR is a nuclear receptor (ligand- activated transcription factor) • NR are sensing systems that govern the interactions between genome and internal environment • PXR is activated by different xenobiotics and endobiotics RXR GENE TRANSCRIPTION XRE RFX PXR Expression of proteins involved in detoxification of foreign toxic substances
PREGNANE X RECEPTOR • Master supervisor of detoxification of xenobiotics • Orchestrate energy metabolism and immune responses to stresses caused by xenobiotic • Inhibits nuclear factor NF-κB signaling (nuclear factor kappa-light-chain- enhancer of activated B cells), a first responder to harmful cellular stimuli (DAMPs, PAMPs) • PXR activation results in lower expression of proinflammatory cytokines and chemokines Wahli 2008; Mencarelli 2010 TLR NF-κBPXR XENOBIOTIC RESPONSE PROINFLAMMATORY CYTOKINES CHEMOKINES Mutual negative crosstalk between NF-κB and PXR DAMPs PAMPs HOST CELL ANTIINFLAMMATORYDETOXIFICATION
RIFAXIMIN REDUCES THE EXPRESSION OF INFLAMMATORY GENES IN EPITHELIAL CELLS ACTIVATED BY LIPOPOLISACCARIDES Rifaximin (100 μM) was added to colon biopsies for 3 h, before LPS stimulation (100 μg/ml) for 16 h. At the end of incubation the mRNA was extracted for the quantification *P<0.05 versus untreated biopsies; **P<0.05 versus LPS treated biopsies
Rifaximin antiinflammatory effect in a TNBS- induced colitis model (hPXR mice) TNBS: 2,4,6-Trinitrobenzenesulfonic acid TNBS TNBS + RIFAX H&E-stained colon sections Cheng 2010
INFLAMMATION ROLE IN CLINICAL MASTITIS • The systemic and local inflammatory responses contribute to etiology and pathophysiology of clinical mastitis. • The risk of developing clinical mastitis, from either chronic infections or from new environmental infections, is greatest during the peripartum period – [Shpigel 1998] • The inflammatory response is more aggressive during the peripartum period than late lactation – [Sordillo et al. 1995; , Lehtolainen et al. 2003] • An enhanced inflammatory response with concomitant suppression in other immune responses is involved in the etiology and severity of the clinical mastitis observed in peripartum cows – [Ballou 2012]
INFLAMMATION & METABOLIC DISORDERS • During infections the local release of pro-inflammatory cytokines also trigger an acute phase reaction • Systemic inflammation increases lipolysis and impairs hepatic metabolism, predisposing cows to lipid-related metabolic diseases [Jiang 2008] – reduced feed intake, energy diversion toward febrile response, increased catabolism in adipose tissue and skeletal muscle, acute phase protein synthesis in hepatic tissue and impaired liver function INCREASED RISK OF DEVELOPING KETOSIS AND FATTY LIVER
PXR ACTIVATION BY RIFAXIMIN MAINTAINS EPITHELIAL BARRIER INTEGRITY • Epithelial cells are the first line of defense against harmful agents (bacteria products and toxins) and act as a “barrier” against bacteria • Remarkably similar to hepatocytes in their ability to carry out detoxification • Epithelial cells may become unable to detoxify toxic metabolites in inflammation [Mencarelli 2010] RXR TRANSCRIPTION OF GENES INVOLVED IN EPITHELIAL DETOXIFICATION AND PROTECTION XRE RFX PXR
RIFAXIMIN PRETREATMENT REDUCES BACTERIA BINDING TO EPITHELIAL CELLS p<0.0001 (†) and <0.03 (§) Brown, E., Xue, Q., & Jiang, Z. (2010) Many pathogenic bacteria need to attach to or invade host epithelial cells as a first step in the disease process Escherichia coli (enteroaggregative E. Coli EAEC O42) HEp-2 (laryngeal) HCT-8 (ileocecal) A549 (lung) HeLa (cervical)
RIFAXIMIN PRETREATMENT REDUCES BACTERIAL ADHERENCE AND INTERNALIZATION TO EPITHELIAL CELLS A549 lung epithelial cells Brown, E., Xue, Q., & Jiang, Z. (2010)P < 0.002 Bacillus anthracis
MULTIPLE ACTIONS OF RIFAXIMIN IN FIGHTING INFECTION PATHOGEN KILLING ANTIINFLAMATORY ACTION EPITHELIAL BARRIER PROTECTION EPITHELIAL PROTECTION EPITHELIAL DETOX
RIFAXIMIN IN VETERINARY THERAPY
FATROXIMIN DRY COW FATROXIMIN INTRAMAMMARY OINTMENT INTRAMAMMARY DRY COW THERAPY
THE ROLE OF DRY COW TERAPY 1. Cure of existing IMIs present at drying off – Higher cure rate than that during lactation, particularly for Staph. aureus – A higher dose of antibiotic can be used – Retention time of the antibiotic in the udder is longer – Risk of residues in milk is reduced 2. Prevention of new IMIs during the dry period – Greatest risk of new IMIs during the early and latter portions of the dry period – Fewer new infections during the dry period – Reduced incidence of clinical mastitis at freshening
Route of Administration of Dry Cow Therapy • Advantages – Well researched – Allows delivery of high local concentrations of antibiotic – Allows the use of antibiotics that would not normally partition to the udder when administered systemically. • Disadvantages – Physiological/anatomical damage to the streak canal – Inoculation of organisms at the time of infusion THE INTRAMAMMARY ROUTE IS THE BEST CHOICE FOR DCT INTRAMAMMARY vs. SYSTEMIC FATROXIMIN DC IS SPECIFICALLY DEVELOPED FOR TOPICAL INTRAMAMMARY THEPAPY
IDEALDRYCOWTHERAPY High and Rapid initial antimicrobial concentrations throughout the udder Prolonged period of antibiotic activity The antibiotic should be retained within the udder - no systemic absorption Rapidly milked out following calving to kill existing pathogens to prevent new infections IDEAL DRY COW THERAPY
DRUG ACTION Pharmacodynamic Phase • The effect of the drug against bacteria in the infection site Pharmacokinetic Phase • Absorption (milk:plasma) • Distribution (local and systemic) • Metabolism (systemic) • Excretion (local and systemic) Pharmaceutical Phase • Disintegration of the formulation • Drug dissolution and liberation of the drug in milk The end effect of a drug depends on its ultimate concentration at the site of action
COMMON DRY COW FORMULATIONS vaselin oil, peanut oil petroleum jelly lanolin beeswax aluminium monostearate polysorbate Pyorala S. J Vet Pharmacol Ther. 1987 • All of them, more or less, are irritant • May cause inflammation (chemical mastitis) • Increased SCC when tested in lactation Long acting formulations EXIPIENTS Slow disintegration Slow dissolution
FATROXIMIN DC COMPOSITION Active substance Rifaximin 100 mg Excipients Glyceril monostearate 40 -55 550 mg Macrogol Cetostearyl Ether 75 mg Liquid paraffin light q.s. to 5 ml Pharmaceutical form: Ointment with active substance in suspension Sterile PE 5 ml syringe EP-0222712
FATROXIMIN DC : Pharmaceutical Technology EXCIPIENTS Glycerol Monostearate 40 - 55 •Mixture of mono ,di, triglycerides of palmitic and stearic acid •It confers ideal rheological characteristics and maintains the suspension Macrogol Cetostearyl ether •Ether of Polyethylene glycol (PEG) with fatty alcohols •Hydrophilic emulsifier •It permits high dispersibility of active substance Light Liquid Paraffin • Very highly refined mineral oil • It is a vehicle for active substance with emollient properties Potentially usable for both lactating and dry cow ointments HLB: Hydrophilic-Lipophilic Balance is similar to that of milk RAPID DISPERSION RATE IN MILK FAST DISINTEGRATION FAST DISSOLUTION INSTANT HIGH CONCENTRATIONS AT THE SITE OF ACTION
IN VITRO DISSOLUTION STUDY Dry Udder Secretion Model And Milk Phosphate buffered saline solution (model of secretions during dry period) Milk as a milieu at dry off Volume : 900 ml Temperature : 40°C
0:00:00
0:30:00
4:00:00
8:00:00
24:00:00
FATROXIMIN vs. COMPETITORS DISSOLUTION AND RELEASE TEST 30’ 1 h 2 h 4 h 8 h 24 h Product 2 0.00% 0.00% 3.60% 4.40% 4.70% 5.30% Product 3 0.00% 0.00% 0.60% 0.70% 0.60% 0.80% FATROX 23.60% 52.20% 72.80% 87.30% 99.50% 100.00% 0.00% 25.00% 50.00% 75.00% 100.00% %ofrelease Liquid medium : phosphate buffered saline solution in 900 ml beakers Method of analysis : HPLC: High-performance liquid chromatography
Minimal Inhibitory Concentrations (MIC) MIC50 MIC90 MIC Range Staphylococcus aureus 0.081 0.55 0.012-6.25 Streptococcus uberis 0.18 0.55 0.024-25 Streptococcus agalactiae 0.21 0.46 0.097-1.56 Streptococcus dysgalactiae 0.04 0.45 0.024-6.25 Minor pathogens * 0.023 0.65 0.0007->25 E. Coli 1.56-6.25 * Corynebacterium spp. - CNS - Streptococcus spp. Concentrations of rifaximin are several times higher than the MIC, which makes the in vitro differences of activity between this and other antimicrobials meaningless from a clinical standpoint Concentrations at the site of action largely exceeds MICs observed in vitro Rifaximin is NONABSORBED
PK/PD FATROXIMIN DC 0.01 0.1 1 10 0 7 14 21 28 35 42 Staph.aureus S. uberis S. agalactiae S. disgalactiae E. coli MICs Log10µg/ml Days from DCT
Staphylococcus aureus can invade host cells and persist intracellularly for various periods of time Invasion of a MAC-T cell by S. aureus (TEM analysis ×5,000) Bayles 1998, American Society for Microbiology • Staphylococcus aureus is able to invade alveolar epithelial cells and also survive engulfment by professional phagocytes such as neutrophils and monocytes • It survives in acidic media, including phagolysosomes (pH 5.0 ) S. aureus within alveolar epithelial cells in a mouse model of mastitis (Light microscope, Gram stain) Brouillette 2003 IMAGE IMAGE
RIFAXIMIN ALSO ENTERS CELLS Despite non-absorbed there is evidence that Rifaximin penetrates cells, including epithelial cells and leukocytes Mencarelli 2010 Activity of rifaximin is only slightly affected by pH, conversely from what is observed with other antibiotics Scarpignato 1999 Extraordinary activity against Staph. aureus Low MICs High local concentrations Long action
HIGH THERAPEUTIC EFFICACY Cure of existing IMIs present at drying off 73% 100% 100% 90% 100% 88% 100% Bacteriological cure rate (554 quarters) Sol 1997
HIGH PREVENTIVE EFFICACY Prevention of new IMIs during the dry period 5 1 2 6 7 554 Staph. Aureus Pen Resistant… S. uberis CNS E.coli Total quarters New IMIs Sol 1997 Only 3 % of new IMIs The long persistence of Fatroximin in the udder allows effective prevention of new IMIs during the dry period Rifaximin is not absorbed and metabolized very slowly Ultra-Long Action
IMPROVEMENT IN MILK QUALITY LOWER SCC 1,253 1,901 604 290 263 196 H1 - 151 cows H2 - 227 cows H3 - 118 cows SCCx1,000 Before Dry Off Fresh Cows • High antibiotic efficacy • Antiinflammatory action • Non-irritant vehicle Drastic reduction in SCC at lactation Zecconi
• Eliminated totally with colostrum just after calving • Milk free from inhibitory substances • No systemic distribution • NO residues in meat • Rifaximin was the first antibiotic included in Annex II of the MRL regulation (substances non subjected to MRL) IMPROVEMENT IN MILK QUALITY NO RESIDUES IN MILK AND MEAT
TWINSERT An innovative system of administration Allows partial insertion of the cannula reducing the risk of carrying bacteria into the udder
COMPLETE INSERTION PARTIAL INSERTION Boddie 1986
New IMIs after treatment with a short cannula or with a conventional cannula Complete insertion Partial insertion Partial insertion may reduce new IMIs by over 50%. Boddie & Nickerson 1991
CEFAXIMIN L INTRAMMAMMARY THERAPY DURING LACTATION • Antimicrobial combination – Cefacetrile – Rifaximin • Specifically studied for intramammary use during lactation
CEFACETRILE - CEPHACETRILE • First-generation Cephalosporin • Marked activity against Gram+ • Streptococcus agalactiae • Streptococcus spp. • Staph. aureus • CNS • Pretty active against Gram- • E. coli • Klebsiella spp. Inhibition of cell wall synthesis of bacteria Bactericidal activity
SYNERGISTIC EFFECTS OF CEFACETRILE AND RIFAXIMIN IN COMBINATION MIC Cefacetrile MIC Rifaximin MIC Cefaximin-L 2/1 Cefacetrile Rifaximin Staph. aureus 0.474 0.0122 0.0138 0.0069 Str. agalactiae 0.4069 0.1322 0.08345 0.0416 Str. dysgalactiae 0.19532 0.0317 0.0586 0.0292 Str. uberis 1.1718 0.3256 0.506 0.2848 The combination potentiates the activity of the antimicrobials alone by several times, showing high synergistic effects against udder pathogens: • Cefacetrile: 2.5 - 34 times • Rifaximin: 1.5 - 9 times
CEFACETRILE: IMM PHARMACOKINETICS • Rapidly absorbed • Rapidly distributes throughout the mammary tissues, including deep parenchyma • High concentrations are found in mammary tissues up to 24-36 hours after treatment Cefacetrile mammary PK/PD for Staphylococcus aureus
CEFAXIMIN-L Two formulations to meet all therapeutic needs • Vehicle highly soluble in milk • Rapid dissolution and liberation of the drugs in milk • Crosses any occlusions of inflammatory nature • Rapid and widespread diffusion even in case of clogged milk ducts SPRAY OINTMENT
CEFAXIMIN-L: THERAPEUTIC SYSTEM COW-MARKERS Soft rubber markers to be applied to the cow for reliable compliance with withdrawal times SINGLE-USE ANTISEPTIC WIPES Pre-moistened wipes for teat preparation soaked in chlorhexidine for a fast kill of mastitis-causing microorganisms
EFFICACY OF CEFAXIMIN-L IN THE TREATMENT OF MASTITIS DURING LACTATION 78% 76% 88% 92% 62% Str. agalactiae Staph. aureus Strept. spp. (NA) CNS Gram- Zecconi 1992 Bacteriological cure rates after a single treatment with CEFAXIMIN-L ointment BY PATHOGEN
EFFICACY OF CEFAXIMIN-L IN THE TREATMENT OF MASTITIS DURING LACTATION 89% 74% 65% ACUTE SUBACUTE CHRONIC Bacteriological cure rates after a single treatment with CEFAXIMIN-L ointment BY CLINICAL COURSE
IN-VIVO ULTRASONOGRAPHIC STUDY OF MAMMARY DISTRIBUTION & PERSISTENCE Results showed widespread distribution of Cefaximin-L Spray within the udder , including most deep mammary areas, for at least 24 After intramammary application of one can of Cefaximin L Spray, ultrasound was performed immediately after and each 8h, for 2 days
RIFAXIMIN IN PREVENTION AND THERAPY OF DISORDERS OF THE FEMALE REPRODUCTIVE SYSTEM • Rifaximin does not cross organic barriers, thus remains longer and completely active in the uterus • Rifaximin reach concentrations several times higher than MICs for common uterine pathogens • No residues in milk and meat High and long-lasting intrauterine antibiotic activity with no withdrawal times
FATROXIMIN IU FOAM FATROXIMIN I.U. VAGINAL EMULZION • Single-dose spray antimicrobial for intrauterine use • Rapid expansion foaming formulation
INFUSION WITH TRADITIONAL PRODUCTS FATROXIMIN IU FOAM It spreads all over the endometrium, in every uterine area, including the dorsal wall, horns extremities and endometrial folds
TEST ON EXCISED BOVINE UTERUS
ASSESSMENT OF ANTIBIOTIC ACTIVITY • Sterile filter paper disks soaked in uterine secretions • Fragments of endometrial mucosa • From the body of the uterus and from the medial and apical portions of the uterine horns • 6-12-18-24-48-72 h after treatment Clear inhibition zones in all samples Samples from cows culled 72 h after treatment LONG-LASTING ANTIBIOTIC ACTIVITY THROUGHOUT THE UTERINE CAVITY
FATROXIMIN INTRAUTERINE PESSARIES • Small volume & Easy application • Under all operative conditions • In all species for which it is indicated • Controlled Effervescence System • Rapid release • Complete and uniform distribution throughout the endometrium and vaginal epithelium
FATROXIMIN TOPIC SPRAY Prevention & Treatment of skin infections 170-g spray-can
FATROXIMIN TOPIC SPRAY • Broad spectrum bactericidal antimicrobial highly active against microorganisms responsible for skin infections • Not absorbed through the skin • No residues in milk and meat • No withdrawal periods
Rifaximin - Fatro worldwide exclusive antibiotic

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Rifaximin - Fatro worldwide exclusive antibiotic

  • 1.
    Fatro worldwide exclusiveantibiotic Roberto Farina - Fatro
  • 2.
    RIFAXIMIN • Class: Rifamycins •Subclass of the larger family Ansamycins • Antibiotics produced by the Gram+ bacterium Amycolatopsis mediterranei • Particularly potent against – Multi-resistant Staph. Aureus – Mycobacteria • Rifaximin: semi-synthetic derivative of rifamycin SV
  • 3.
    RIFAXIMIN Physiochemical Properties Zwitterion Pyrido nitrogenpositively charged Imidazo nitrogen negatively charged Phenolic hydroxyls Strong tendency to self-associate Ionized at all pH values Additional pyridoimidazole moiety makes it NON-ABSORBABLE ion trapping Acts locally and does not pass into the circulation
  • 4.
    RIFAXIMIN Mechanism Of Action •Prevents transcription – the process by which the information in DNA is copied into messenger RNA (mRNA) for protein production. • Inhibits RNA and protein synthesis Binds to the β subunit of prokaryotic DNA-dependent RNA polymerase TRANSCRIPTION ANIMATION
  • 5.
    RIFAXIMIN Antimicrobial Activity • Broadspectrum of antibacterial action: – Gram+ and Gram- – Both Aerobes and Anaerobes • Susceptibility of resistant strains of Staph. aureus is particularly interesting • Protozoa – Cryptosporidium, Blastocystis • Reverse transcriptase of certain RNA viruses (retrovirus)
  • 6.
    RIFAXIMIN Antimicrobial killing activity •Rapidly kills fast-dividing bacteria as well as “persisters” cells, which remain biologically inactive for long periods evading antibiotic activity – [Pozniak 1999] • Bactericidal • Actually kills bacteria Image
  • 7.
    RIFAXIMIN Not Absorbed Systemically •Valuable for therapies applied locally to body surfaces – Skin or mucosae • High local bioavailability • Localized targeting of pathogens • Absence of residues in non-treated organs • Reduced incidence of undesired side effects Scarpignato & Pelosini 2005 100% TOPICAL ANTIMICROBIAL
  • 8.
    TOPICAL THERAPY &ANTIBIOTIC RESISTANCE A NOVEL APPROACH TO JUDICIOUS PRESCRIBING PRACTICE • Limited selective pressure for the development of wide-spread bacterial resistance • Preservation of critically important antimicrobials for systemic therapy • Antimicrobial is sequestered in target organs • Very high local concentrations • Circumscribed antimicrobial activity
  • 9.
    ANTIMICROBIAL RESISTANCE Resistance ofa microorganism to an antimicrobial medicine to which it was previously sensitive (WHO) One of the main problems associated with antibiotics use • Therapeutic failure • Infections persist and may spread Impact on animal health and productivity • Emergence of resistant microorganisms that can infect people (Superbugs) • Great clinical, economic, political and environmental implications Possible impact on human health
  • 10.
    PROPER ANTIMICROBIAL SELECTION FIGHTSRESISTANCE Ability to lead to the development of resistant mutants Spread of resistance Stability of the mutants Effect on the susceptibility of other antimicrobial agents Relevant factors that determine the therapeutic value of antibacterials ANTIMICROBIAL RESISTANCE
  • 11.
    DEVELOPMENT OF RESISTANCETO RIFAXIMIN • Studied in detail on several Gram- and Gram+, aerobic and anaerobic strains • Resistance to Rifaximin is rare – [Hoover 1993; Ruiz 2008; Marchese 2000; Ouyang-Latimer 2011; Valentin 2011] • More easily with sub-inhibitory concentrations • Anaerobic atmosphere hinders the selection of rifaximin-resistant bacteria • High concentrations in in an oxygen-deficient milieu: in-vivo occurrence of bacterial resistance with rifaximin is an infrequent phenomenon
  • 12.
    Staph. aureus SUSCEPTIBILITY TOANTIMICROBIALS 6% 31% 31% 8% 36% 77% 36% 84% 86% 89% 94% 92% 82% 93% 99% 0% 25% 50% 75% 100% Sulfa Penicillin Ampicillin Spectinomycin Streptomycin Tetracycline Spiramycin Erythromycin Kanamycin Tylosin Cloxacillin Nafcillin Cefoperazone Flumequine Rifaximin R % I % S % Bertocchi, Varisco, Farina 2000 Kirby-Bauer agar diffusion test Strains isolated from the milk of dairy cows with mastitis (IZS – Brescia, Italy)
  • 13.
    SPREAD OF RESISTANCETO RIFAXIMIN • Resistance due to a chromosomal alteration in the drug target, the DNA-RNA polymerase (rpoB gene) – [Al-Orainey 1990] • Different from the plasmid-mediated resistance common to other antibiotics – [Smith 2002] • The spread of resistance is less frequent than that due to plasmid-mediated transfer (transferred within the same generation, even between different bacterial species) – [Collignon PJ 2002] Not disseminated by plasmids but mediated chromosomally Sulfa Β-lactamTetracycline Fenicol Aminoglicoside multi-R Plasmid
  • 14.
    STABILITY OF RIFAXIMINRESISTANT MUTANTS • Resistance to rifaximin disappear after drug administration is terminated. • Poorer viability of rifaximin-resistant mutants relative to nonresistant (wild-type) bacteria • Resistance to rifaximin doesn’t persist beyond a few weeks after cessation of therapy (specific time- dependent on species of bacteria) De Leo 1986 Disappearance of rifaximin-resistant bacteria after stopping the antibiotic treatment (week 0) RIFAXIMIN
  • 15.
    ANNUAL VARIATION OFSTAPH. AUREUS SENSITIVITY TO RIFAXIMIN From cows with mastitis IZS Tre Venezie Barberio 2000 Year Susceptible 1996 98.9 % 1997 93.4 % 1998 98.1 % 1999 98.7 % Carnevali Nocetti 2001 Year Susceptible 1996 96.95 % 1997 100.0 % 1998 99.49 % 1999 98.88 % 2000 98.28 % From cows with mastitis APA Modena
  • 16.
    EFFECT ON THESUSCEPTIBILITY LEVELS OF OTHER ANTIMICROBIAL AGENTS • There is no evidence of cross-resistance to other non-rifamycin classes of antibiotics – Herbert DuPont 2003 • No-systemic involvement • Preserves other antimicrobial agents, which are able to be used to treat systemic infections, diminishing their pressure on the microorganisms, favoring a lower selection of resistant strains • It does not alter the microbiota population (other than those based in the treated compartment)
  • 17.
    NON-ANTIBIOTIC EFFECTS OFRIFAXIMIN • Rifaximin, besides acting against microorganisms, has also beneficial effects on Host Cells • In addition to its antibacterial activity rifaximin exerts antiinflammatory and immunomodulatory effects Scarpignato 2005 BACTERIA ANIMAL CELLS
  • 18.
    RIFAXIMIN MODULATES THE INFLAMMATORYRESPONSE • Rifamycins are able to modulate neutrophil functions and display anti-inflammatory actions – [Spisani 1997] • Intra-articular rifamycin has been successfully used in chronic arthritis (juvenile rheumatoid arthritis and ankylosing spondylitis) – [Caruso 1997] • Rifaximin reduces overall inflammatory status modulating pro-inflammatory cytokine release – IL-6, IL-1β, IL-8, IL-12 and interferon-γ, TNFα, chemokines – [Brown 2010; Vitali 2009]
  • 19.
    RIFAXIMIN MODULATES INFLAMMATION THROUGHPXR ACTIVATION • Pregnane-X-Receptor mediates the anti-inflammatory activities of Rifaximin – [Cheng 2010; Mencarelli 2011] • PXR is a nuclear receptor (ligand- activated transcription factor) • NR are sensing systems that govern the interactions between genome and internal environment • PXR is activated by different xenobiotics and endobiotics RXR GENE TRANSCRIPTION XRE RFX PXR Expression of proteins involved in detoxification of foreign toxic substances
  • 20.
    PREGNANE X RECEPTOR •Master supervisor of detoxification of xenobiotics • Orchestrate energy metabolism and immune responses to stresses caused by xenobiotic • Inhibits nuclear factor NF-κB signaling (nuclear factor kappa-light-chain- enhancer of activated B cells), a first responder to harmful cellular stimuli (DAMPs, PAMPs) • PXR activation results in lower expression of proinflammatory cytokines and chemokines Wahli 2008; Mencarelli 2010 TLR NF-κBPXR XENOBIOTIC RESPONSE PROINFLAMMATORY CYTOKINES CHEMOKINES Mutual negative crosstalk between NF-κB and PXR DAMPs PAMPs HOST CELL ANTIINFLAMMATORYDETOXIFICATION
  • 21.
    RIFAXIMIN REDUCES THEEXPRESSION OF INFLAMMATORY GENES IN EPITHELIAL CELLS ACTIVATED BY LIPOPOLISACCARIDES Rifaximin (100 μM) was added to colon biopsies for 3 h, before LPS stimulation (100 μg/ml) for 16 h. At the end of incubation the mRNA was extracted for the quantification *P<0.05 versus untreated biopsies; **P<0.05 versus LPS treated biopsies
  • 22.
    Rifaximin antiinflammatory effectin a TNBS- induced colitis model (hPXR mice) TNBS: 2,4,6-Trinitrobenzenesulfonic acid TNBS TNBS + RIFAX H&E-stained colon sections Cheng 2010
  • 23.
    INFLAMMATION ROLE INCLINICAL MASTITIS • The systemic and local inflammatory responses contribute to etiology and pathophysiology of clinical mastitis. • The risk of developing clinical mastitis, from either chronic infections or from new environmental infections, is greatest during the peripartum period – [Shpigel 1998] • The inflammatory response is more aggressive during the peripartum period than late lactation – [Sordillo et al. 1995; , Lehtolainen et al. 2003] • An enhanced inflammatory response with concomitant suppression in other immune responses is involved in the etiology and severity of the clinical mastitis observed in peripartum cows – [Ballou 2012]
  • 24.
    INFLAMMATION & METABOLICDISORDERS • During infections the local release of pro-inflammatory cytokines also trigger an acute phase reaction • Systemic inflammation increases lipolysis and impairs hepatic metabolism, predisposing cows to lipid-related metabolic diseases [Jiang 2008] – reduced feed intake, energy diversion toward febrile response, increased catabolism in adipose tissue and skeletal muscle, acute phase protein synthesis in hepatic tissue and impaired liver function INCREASED RISK OF DEVELOPING KETOSIS AND FATTY LIVER
  • 25.
    PXR ACTIVATION BYRIFAXIMIN MAINTAINS EPITHELIAL BARRIER INTEGRITY • Epithelial cells are the first line of defense against harmful agents (bacteria products and toxins) and act as a “barrier” against bacteria • Remarkably similar to hepatocytes in their ability to carry out detoxification • Epithelial cells may become unable to detoxify toxic metabolites in inflammation [Mencarelli 2010] RXR TRANSCRIPTION OF GENES INVOLVED IN EPITHELIAL DETOXIFICATION AND PROTECTION XRE RFX PXR
  • 26.
    RIFAXIMIN PRETREATMENT REDUCES BACTERIABINDING TO EPITHELIAL CELLS p<0.0001 (†) and <0.03 (§) Brown, E., Xue, Q., & Jiang, Z. (2010) Many pathogenic bacteria need to attach to or invade host epithelial cells as a first step in the disease process Escherichia coli (enteroaggregative E. Coli EAEC O42) HEp-2 (laryngeal) HCT-8 (ileocecal) A549 (lung) HeLa (cervical)
  • 27.
    RIFAXIMIN PRETREATMENT REDUCES BACTERIALADHERENCE AND INTERNALIZATION TO EPITHELIAL CELLS A549 lung epithelial cells Brown, E., Xue, Q., & Jiang, Z. (2010)P < 0.002 Bacillus anthracis
  • 28.
    MULTIPLE ACTIONS OFRIFAXIMIN IN FIGHTING INFECTION PATHOGEN KILLING ANTIINFLAMATORY ACTION EPITHELIAL BARRIER PROTECTION EPITHELIAL PROTECTION EPITHELIAL DETOX
  • 29.
  • 30.
    FATROXIMIN DRY COW FATROXIMININTRAMAMMARY OINTMENT INTRAMAMMARY DRY COW THERAPY
  • 31.
    THE ROLE OFDRY COW TERAPY 1. Cure of existing IMIs present at drying off – Higher cure rate than that during lactation, particularly for Staph. aureus – A higher dose of antibiotic can be used – Retention time of the antibiotic in the udder is longer – Risk of residues in milk is reduced 2. Prevention of new IMIs during the dry period – Greatest risk of new IMIs during the early and latter portions of the dry period – Fewer new infections during the dry period – Reduced incidence of clinical mastitis at freshening
  • 32.
    Route of Administrationof Dry Cow Therapy • Advantages – Well researched – Allows delivery of high local concentrations of antibiotic – Allows the use of antibiotics that would not normally partition to the udder when administered systemically. • Disadvantages – Physiological/anatomical damage to the streak canal – Inoculation of organisms at the time of infusion THE INTRAMAMMARY ROUTE IS THE BEST CHOICE FOR DCT INTRAMAMMARY vs. SYSTEMIC FATROXIMIN DC IS SPECIFICALLY DEVELOPED FOR TOPICAL INTRAMAMMARY THEPAPY
  • 33.
    IDEALDRYCOWTHERAPY High andRapid initial antimicrobial concentrations throughout the udder Prolonged period of antibiotic activity The antibiotic should be retained within the udder - no systemic absorption Rapidly milked out following calving to kill existing pathogens to prevent new infections IDEAL DRY COW THERAPY
  • 34.
    DRUG ACTION Pharmacodynamic Phase •The effect of the drug against bacteria in the infection site Pharmacokinetic Phase • Absorption (milk:plasma) • Distribution (local and systemic) • Metabolism (systemic) • Excretion (local and systemic) Pharmaceutical Phase • Disintegration of the formulation • Drug dissolution and liberation of the drug in milk The end effect of a drug depends on its ultimate concentration at the site of action
  • 35.
    COMMON DRY COWFORMULATIONS vaselin oil, peanut oil petroleum jelly lanolin beeswax aluminium monostearate polysorbate Pyorala S. J Vet Pharmacol Ther. 1987 • All of them, more or less, are irritant • May cause inflammation (chemical mastitis) • Increased SCC when tested in lactation Long acting formulations EXIPIENTS Slow disintegration Slow dissolution
  • 36.
    FATROXIMIN DC COMPOSITION Active substance Rifaximin 100 mg Excipients Glycerilmonostearate 40 -55 550 mg Macrogol Cetostearyl Ether 75 mg Liquid paraffin light q.s. to 5 ml Pharmaceutical form: Ointment with active substance in suspension Sterile PE 5 ml syringe EP-0222712
  • 37.
    FATROXIMIN DC :Pharmaceutical Technology EXCIPIENTS Glycerol Monostearate 40 - 55 •Mixture of mono ,di, triglycerides of palmitic and stearic acid •It confers ideal rheological characteristics and maintains the suspension Macrogol Cetostearyl ether •Ether of Polyethylene glycol (PEG) with fatty alcohols •Hydrophilic emulsifier •It permits high dispersibility of active substance Light Liquid Paraffin • Very highly refined mineral oil • It is a vehicle for active substance with emollient properties Potentially usable for both lactating and dry cow ointments HLB: Hydrophilic-Lipophilic Balance is similar to that of milk RAPID DISPERSION RATE IN MILK FAST DISINTEGRATION FAST DISSOLUTION INSTANT HIGH CONCENTRATIONS AT THE SITE OF ACTION
  • 38.
    IN VITRO DISSOLUTIONSTUDY Dry Udder Secretion Model And Milk Phosphate buffered saline solution (model of secretions during dry period) Milk as a milieu at dry off Volume : 900 ml Temperature : 40°C
  • 39.
  • 40.
  • 41.
  • 42.
  • 43.
  • 45.
    FATROXIMIN vs. COMPETITORS DISSOLUTIONAND RELEASE TEST 30’ 1 h 2 h 4 h 8 h 24 h Product 2 0.00% 0.00% 3.60% 4.40% 4.70% 5.30% Product 3 0.00% 0.00% 0.60% 0.70% 0.60% 0.80% FATROX 23.60% 52.20% 72.80% 87.30% 99.50% 100.00% 0.00% 25.00% 50.00% 75.00% 100.00% %ofrelease Liquid medium : phosphate buffered saline solution in 900 ml beakers Method of analysis : HPLC: High-performance liquid chromatography
  • 46.
    Minimal Inhibitory Concentrations(MIC) MIC50 MIC90 MIC Range Staphylococcus aureus 0.081 0.55 0.012-6.25 Streptococcus uberis 0.18 0.55 0.024-25 Streptococcus agalactiae 0.21 0.46 0.097-1.56 Streptococcus dysgalactiae 0.04 0.45 0.024-6.25 Minor pathogens * 0.023 0.65 0.0007->25 E. Coli 1.56-6.25 * Corynebacterium spp. - CNS - Streptococcus spp. Concentrations of rifaximin are several times higher than the MIC, which makes the in vitro differences of activity between this and other antimicrobials meaningless from a clinical standpoint Concentrations at the site of action largely exceeds MICs observed in vitro Rifaximin is NONABSORBED
  • 47.
    PK/PD FATROXIMIN DC 0.01 0.1 1 10 07 14 21 28 35 42 Staph.aureus S. uberis S. agalactiae S. disgalactiae E. coli MICs Log10µg/ml Days from DCT
  • 48.
    Staphylococcus aureus caninvade host cells and persist intracellularly for various periods of time Invasion of a MAC-T cell by S. aureus (TEM analysis ×5,000) Bayles 1998, American Society for Microbiology • Staphylococcus aureus is able to invade alveolar epithelial cells and also survive engulfment by professional phagocytes such as neutrophils and monocytes • It survives in acidic media, including phagolysosomes (pH 5.0 ) S. aureus within alveolar epithelial cells in a mouse model of mastitis (Light microscope, Gram stain) Brouillette 2003 IMAGE IMAGE
  • 49.
    RIFAXIMIN ALSO ENTERSCELLS Despite non-absorbed there is evidence that Rifaximin penetrates cells, including epithelial cells and leukocytes Mencarelli 2010 Activity of rifaximin is only slightly affected by pH, conversely from what is observed with other antibiotics Scarpignato 1999 Extraordinary activity against Staph. aureus Low MICs High local concentrations Long action
  • 50.
    HIGH THERAPEUTIC EFFICACY Cureof existing IMIs present at drying off 73% 100% 100% 90% 100% 88% 100% Bacteriological cure rate (554 quarters) Sol 1997
  • 51.
    HIGH PREVENTIVE EFFICACY Preventionof new IMIs during the dry period 5 1 2 6 7 554 Staph. Aureus Pen Resistant… S. uberis CNS E.coli Total quarters New IMIs Sol 1997 Only 3 % of new IMIs The long persistence of Fatroximin in the udder allows effective prevention of new IMIs during the dry period Rifaximin is not absorbed and metabolized very slowly Ultra-Long Action
  • 52.
    IMPROVEMENT IN MILKQUALITY LOWER SCC 1,253 1,901 604 290 263 196 H1 - 151 cows H2 - 227 cows H3 - 118 cows SCCx1,000 Before Dry Off Fresh Cows • High antibiotic efficacy • Antiinflammatory action • Non-irritant vehicle Drastic reduction in SCC at lactation Zecconi
  • 53.
    • Eliminated totallywith colostrum just after calving • Milk free from inhibitory substances • No systemic distribution • NO residues in meat • Rifaximin was the first antibiotic included in Annex II of the MRL regulation (substances non subjected to MRL) IMPROVEMENT IN MILK QUALITY NO RESIDUES IN MILK AND MEAT
  • 54.
    TWINSERT An innovative systemof administration Allows partial insertion of the cannula reducing the risk of carrying bacteria into the udder
  • 55.
  • 56.
    New IMIs aftertreatment with a short cannula or with a conventional cannula Complete insertion Partial insertion Partial insertion may reduce new IMIs by over 50%. Boddie & Nickerson 1991
  • 57.
    CEFAXIMIN L INTRAMMAMMARY THERAPYDURING LACTATION • Antimicrobial combination – Cefacetrile – Rifaximin • Specifically studied for intramammary use during lactation
  • 58.
    CEFACETRILE - CEPHACETRILE •First-generation Cephalosporin • Marked activity against Gram+ • Streptococcus agalactiae • Streptococcus spp. • Staph. aureus • CNS • Pretty active against Gram- • E. coli • Klebsiella spp. Inhibition of cell wall synthesis of bacteria Bactericidal activity
  • 59.
    SYNERGISTIC EFFECTS OFCEFACETRILE AND RIFAXIMIN IN COMBINATION MIC Cefacetrile MIC Rifaximin MIC Cefaximin-L 2/1 Cefacetrile Rifaximin Staph. aureus 0.474 0.0122 0.0138 0.0069 Str. agalactiae 0.4069 0.1322 0.08345 0.0416 Str. dysgalactiae 0.19532 0.0317 0.0586 0.0292 Str. uberis 1.1718 0.3256 0.506 0.2848 The combination potentiates the activity of the antimicrobials alone by several times, showing high synergistic effects against udder pathogens: • Cefacetrile: 2.5 - 34 times • Rifaximin: 1.5 - 9 times
  • 60.
    CEFACETRILE: IMM PHARMACOKINETICS •Rapidly absorbed • Rapidly distributes throughout the mammary tissues, including deep parenchyma • High concentrations are found in mammary tissues up to 24-36 hours after treatment Cefacetrile mammary PK/PD for Staphylococcus aureus
  • 61.
    CEFAXIMIN-L Two formulations tomeet all therapeutic needs • Vehicle highly soluble in milk • Rapid dissolution and liberation of the drugs in milk • Crosses any occlusions of inflammatory nature • Rapid and widespread diffusion even in case of clogged milk ducts SPRAY OINTMENT
  • 62.
    CEFAXIMIN-L: THERAPEUTIC SYSTEM COW-MARKERS Softrubber markers to be applied to the cow for reliable compliance with withdrawal times SINGLE-USE ANTISEPTIC WIPES Pre-moistened wipes for teat preparation soaked in chlorhexidine for a fast kill of mastitis-causing microorganisms
  • 63.
    EFFICACY OF CEFAXIMIN-LIN THE TREATMENT OF MASTITIS DURING LACTATION 78% 76% 88% 92% 62% Str. agalactiae Staph. aureus Strept. spp. (NA) CNS Gram- Zecconi 1992 Bacteriological cure rates after a single treatment with CEFAXIMIN-L ointment BY PATHOGEN
  • 64.
    EFFICACY OF CEFAXIMIN-LIN THE TREATMENT OF MASTITIS DURING LACTATION 89% 74% 65% ACUTE SUBACUTE CHRONIC Bacteriological cure rates after a single treatment with CEFAXIMIN-L ointment BY CLINICAL COURSE
  • 65.
    IN-VIVO ULTRASONOGRAPHIC STUDYOF MAMMARY DISTRIBUTION & PERSISTENCE Results showed widespread distribution of Cefaximin-L Spray within the udder , including most deep mammary areas, for at least 24 After intramammary application of one can of Cefaximin L Spray, ultrasound was performed immediately after and each 8h, for 2 days
  • 72.
    RIFAXIMIN IN PREVENTIONAND THERAPY OF DISORDERS OF THE FEMALE REPRODUCTIVE SYSTEM • Rifaximin does not cross organic barriers, thus remains longer and completely active in the uterus • Rifaximin reach concentrations several times higher than MICs for common uterine pathogens • No residues in milk and meat High and long-lasting intrauterine antibiotic activity with no withdrawal times
  • 73.
    FATROXIMIN IU FOAM FATROXIMINI.U. VAGINAL EMULZION • Single-dose spray antimicrobial for intrauterine use • Rapid expansion foaming formulation
  • 74.
    INFUSION WITH TRADITIONAL PRODUCTS FATROXIMIN IUFOAM It spreads all over the endometrium, in every uterine area, including the dorsal wall, horns extremities and endometrial folds
  • 75.
    TEST ON EXCISEDBOVINE UTERUS
  • 76.
    ASSESSMENT OF ANTIBIOTICACTIVITY • Sterile filter paper disks soaked in uterine secretions • Fragments of endometrial mucosa • From the body of the uterus and from the medial and apical portions of the uterine horns • 6-12-18-24-48-72 h after treatment Clear inhibition zones in all samples Samples from cows culled 72 h after treatment LONG-LASTING ANTIBIOTIC ACTIVITY THROUGHOUT THE UTERINE CAVITY
  • 77.
    FATROXIMIN INTRAUTERINE PESSARIES •Small volume & Easy application • Under all operative conditions • In all species for which it is indicated • Controlled Effervescence System • Rapid release • Complete and uniform distribution throughout the endometrium and vaginal epithelium
  • 78.
    FATROXIMIN TOPIC SPRAY Prevention &Treatment of skin infections 170-g spray-can
  • 79.
    FATROXIMIN TOPIC SPRAY •Broad spectrum bactericidal antimicrobial highly active against microorganisms responsible for skin infections • Not absorbed through the skin • No residues in milk and meat • No withdrawal periods